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Purpose of this study is to evaluate patient characteristics, treatments and outcomes in bone metastasis radiotherapy practice. Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival and incidence of radiation-related adverse events. Pain was evaluated using a numerical rating scale (NRS) from 0 to 10. Irradiated dose was analyzed by the biologically effective dose (BED) assuming α/β = 10. Overall, 232 patients were registered; 224 patients and 302 lesions were fully analyzed. Eastern Cooperative Oncology Group Performance Status was 0/1/2/3/4 in 23%/38%/22%/13%/4%; 59% of patients had spinal metastases and 84% had painful lesions (NRS ≥ 2). BED was <20 Gy (in 27%), 20-30 Gy (24%), 30-40 Gy (36%) and ≥ 40 Gy (13%); 9% of patients were treated by stereotactic body radiotherapy. Grade 3 adverse events occurred in 4% and no grade 4-5 toxicity was reported. Pain relief was achieved in 52% at 2 months. BED is not related to pain relief. The cumulative incidence of SREs was 6.5% (95% confidence interval (CI) 3.1-9.9) at 6 months; no factors were significantly associated with SREs. With spinal lesions, 18% of patients were not ambulatory at baseline and 50% of evaluable patients in this group could walk at 2 months. The 6-month overall survival rate was 70.2% (95% CI 64.2-76.9%). In conclusion, we report real-world details of radiotherapy in bone metastasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Objectives: Raising dementia awareness is essential for building a dementia-friendly community. However, existing studies have underexplored the effects of virtual reality (VR) dementia educational programs for the general public on enhancing positive attitude toward dementia. This study aimed to examine the effectiveness of a VR dementia-friendly educational program called the Drive for Dementia Readiness Inside Virtual Reality (DRIVE) program to improve attitude toward dementia of the general public., Research Design and Methods: A two-arm randomized controlled trial was conducted. Eligibility criteria for participants included being 16 years old and above in Japan and having no professional license in healthcare and social care. We randomized individuals to attend a multi-element VR dementia-friendly educational program (intervention), including simulation, VR films, short films, lectures, and discussions or a lecture-based program (control). Data were collected three times, including at baseline, post-intervention, and 3-month follow-up. The primary outcome was attitude toward dementia. The secondary outcomes were intention of helping behavior for people living with dementia and knowledge of dementia., Results: We recruited 157 community residents, among whom 130 were included in the analysis. Although the mean changes in attitude score were not significantly different between the groups (Hedge's g = .26), the intention of helping behavior score was significantly higher in the intervention group (g = .49)., Discussion and Implication: The DRIVE, a VR-based multi-element dementia-friendly educational intervention, was shown as a promising tool for significantly impacting the intention of helping behavior for people living with dementia to establish dementia-friendly communities., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We found that the culture broth of fungi showed anti-fungal activity against multidrug-sensitive budding yeast. However, we could not identify the anti-fungal compound due to the small quantity. Therefore, we attempted to increase the productivity of the target compound by the introduction of a global secondary metabolism regulator, laeA to the strain, which led to the successful isolation of 10-folds greater amount of MS-347a (1) than Aspergillus sp. FKI-5362. Compound 1 was not effective against Candida albicans and the detailed anti-fungal activity of 1 remains unverified. After our anti-fungal activity screening, 1 was found to inhibit the growth of broad plant pathogenic fungal species belonging to the Ascomycota. It is noteworthy that 1 showed little insecticidal activity against silkworms, suggesting its selective biological activity against plant pathogenic fungi. Our study implies that the combination strategy of multidrug-sensitive yeast and the introduction of laeA is useful for new anti-fungal drug discovery., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Objective: The present study investigated the prognostic factors for follicular thyroid carcinoma (FTC) with the incorporation of the histologic subtype and degree of vascular invasion (VI)., Patients: The records of 474 patients with FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were reviewed in this retrospective cohort study. The Cox proportional hazard model was used to determine factors associated with disease-free survival (DFS) and distant metastasis-free survival., Results: Of the 474 patients, 140 (30%) had minimally invasive FTC, 260 (55%) had encapsulated angio-invasive FTC, and 74 (16%) had widely invasive FTC. Among the 428 patients with M0 FTC, the 10-year DFS rates of patients with minimally invasive FTC (n = 133), encapsulated angio-invasive FTC (n = 247), and widely invasive FTC (n = 48) were 97.3%, 84.2%, and 69.9% (P < .001), respectively. A multivariate analysis identified aged ≥55 years (hazard ratio [HR], 2.204; 95% CI, 1.223-3.969; P = .009), histologic subtype (HR, 2.068; 95% CI, 1.064-4.021; P = .032), VI of ≥2 (HR, 6.814; 95% CI, 3.157-14.710; P < .001), and tumor size >40 mm (HR, 2.014; 95% CI, 1.089-3.727; P = .026) as independent negative prognostic factors for DFS., Conclusion: Our study results may enable us to stratify the prognosis of FTC more accurately by combining the histologic subtype with the degree of VI ≥2, aged ≥55 years, and tumor size >40 mm., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Myosins are important motor proteins that associate with the actin cytoskeleton. Structurally, myosins function as heteromeric complexes where smaller light chains, such as calmodulin (CaM), bind to isoleucine-glutamine (IQ) domains in the neck region to facilitate mechano-enzymatic activity. We recently identified Arabidopsis CaM-like (CML) proteins CML13 and CML14 as interactors of proteins containing multiple IQ domains, including a myosin VIII. Here, we demonstrate that CaM, CML13, and CML14 bind the neck region of all four Arabidopsis myosin VIII isoforms. Among CMLs tested for binding to myosins VIIIs, CaM, CML13, and CML14 gave the strongest signals using in planta split-luciferase protein interaction assays. In vitro, recombinant CaM, CML13, and CML14 showed specific, high-affinity, calcium-independent binding to the IQ domains of myosin VIIIs. CaM, CML13, and CML14 co-localized to plasma membrane-bound puncta when co-expressed with red fluorescent protein-myosin fusion proteins containing IQ and tail domains of myosin VIIIs. In vitro actin motility assays using recombinant myosin VIIIs demonstrated that CaM, CML13, and CML14 function as light chains. Suppression of CML13 or CML14 expression using RNA silencing resulted in a shortened-hypocotyl phenotype, similar to that observed in a quadruple myosin mutant, myosin viii4KO. Collectively, our data indicate that Arabidopsis CML13 and CML14 are novel myosin VIII light chains., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Although elevated serum immunoglobulin A (IgA) levels are thought to exclude a diagnosis of IgG4-related disease (IgG4-RD), IgG4-RD has been definitively diagnosed in some patients despite elevated serum IgA levels. This study aimed to clarify the prevalence of elevated IgA levels in patients with IgG4-RD and to compare the clinical features of IgG4-RD patients with and without elevated IgA levels., Methods: The clinical features of 169 IgG4-RD patients were retrospectively compared among those with and without elevated serum IgA levels., Results: Of the 169 patients with IgG4-RD, 17 (10.1%) had elevated serum IgA levels. Those with elevated serum IgA levels showed higher serum C-reactive protein levels and lower prevalence of relapse than those without. Other clinical features did not differ significantly, including inclusion scores of the American College of Rheumatology/European League Against Rheumatism classification criteria. Cox regression analysis showed that elevated serum IgA levels were associated with a lower incidence of relapse. Moreover, patients with elevated serum IgA levels showed prompt improvement in response to glucocorticoids in the IgG4-RD responder index., Conclusions: Some patients diagnosed with IgG4-RD have high serum IgA levels. These patients may form a subgroup, characterized by good response to glucocorticoids, less frequent relapse, mildly elevated serum C-reactive protein levels, and possible complications of autoimmune diseases., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Aneurysmal dermatofibroma (ADF) and hemosiderotic dermatofibroma (HDF) are rare variants of dermatofibroma (DF) characterized by distinct histologic features. While HDF is traditionally considered a precursor to ADF, supporting evidence is limited, and the etiology remains unclear. A retrospective analysis of 2128 DF cases (2016-2019) was conducted to investigate the clinicopathologic characteristics of ADF, HDF, and other DFs., Methods: Histopathologically diagnosed DF cases were examined for ADF and HDF. Univariate analyses were performed to compare clinicopathologic features., Results: Among the cases, 168 (7.9%) were ADF and 29 (1.4%) were HDF. Aneurysmal dermatofibroma and HDF shared several common characteristics, including lower occurrence in females, larger size, and increased cellularity (all P < .0001). Notably, 29% of ADFs lacked hemosiderin deposition. Aneurysmal dermatofibroma primarily manifested on exposed areas (face and forearm, both P < .001). In contrast, 41% of HDFs occurred on the lower leg (P = .018), and all lower leg HDFs exhibited signs of venous stasis, distinguishing them from other HDFs (P < .0001)., Conclusions: Our findings indicate a potential close relationship between ADF and HDF. Contrary to conventional beliefs, we also presented the possibility of ADF progressing into HDFs. Physical trauma may induce ADF, and HDFs may emerge from ADFs in conjunction with venous stasis in the lower extremities., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Microbiome of the Built Environment (MoBE) is profoundly implicated in various sectors, including food science. The balance between beneficial and pathogenic microbes in these facilities directly influences product quality and public health. Maintaining a careful check on MoBE and external microbes is vital to the food industry to ensure quality control. There is also a risk of contamination in the meat processing facility as well. However, over-sanitization can increase drug-resistant microbes, highlighting the importance of balanced microbial management. Additionally, facility design, influenced by understanding MoBE, can optimize the growth of beneficial microbes and inhibit pathogenic microbes. Microbial mapping, an emerging practice, offers insights into microbial hotspots within facilities, resulting in targeted interventions. As the food industry evolves, the intricate understanding and management of MoBE will be pivotal to ensuring optimal food quality, safety, and innovation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Mycobacteria are the major human pathogens with the capacity to become dormant persisters. Mycobacterial DNA-binding protein 1 (MDP1), an abundant histone-like protein in dormant mycobacteria, induces dormancy phenotypes, e.g. chromosome compaction and growth suppression. For these functions, the polycationic intrinsically disordered region (IDR) is essential. However, the disordered property of IDR stands in the way of clarifying the molecular mechanism. Here we clarified the molecular and structural mechanism of DNA compaction by MDP1. Using high-speed atomic force microscopy, we observed that monomeric MDP1 bundles two adjacent DNA duplexes side-by-side via IDR. Combined with coarse-grained molecular dynamics simulation, we revealed the novel dynamic DNA cross-linking model of MDP1 in which a stretched IDR cross-links two DNA duplexes like double-sided tape. IDR is able to hijack HU function, resulting in the induction of strong mycobacterial growth arrest. This IDR-mediated reversible DNA cross-linking is a reasonable model for MDP1 suppression of the genomic function in the resuscitable non-replicating dormant mycobacteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The purpose of this study was to show the safety of volumetric modulated arc therapy (VMAT) with deep inspiration breath-hold (DIBH) in hypofractionated radiotherapy for left-sided breast cancer after breast-conserving surgery in a clinical setting. Twenty-five Japanese women, aged 20-59 years, who were enrolled in this prospective non-inferiority study received VMAT under the condition of DIBH with 42.4 Gy/16 fractions for whole-breast irradiation (WBI) ± boost irradiation for the tumor bed to show the non-inferiority of VMAT with DIBH to conventional fractionated WBI with free breathing. The primary endpoint was the rate of occurrence of radiation dermatitis of Grade 3 or higher or pneumonitis of Grade 2 or higher within 6 months after the start of radiotherapy. This study was registered with UMIN00004321. All of the enrolled patients completed the planned radiotherapy without interruption. The evaluation of adverse events showed that three patients (12.0%) had Grade 2 radiation dermatitis. There was no other Grade 2 adverse event and there was no patient with an adverse event of Grade 3 or higher. Those results confirmed our hypothesis that the experimental treatment method is non-inferior compared with our historical results. There was no patient with locoregional recurrence or metastases. In conclusion, VMAT under the condition of DIBH in hypofractionated radiotherapy for left-sided breast cancer after breast-conserving surgery can be performed safely in a clinical setting., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Pain and post-operative nausea and vomiting are the main factors that impair the quality of recovery after surgery. Very few reports have analyzed patient-reported outcomes to investigate the efficacy of an enhanced recovery after surgery protocol to alleviate these symptoms after head and neck surgeries with free tissue transfer reconstruction., Methods: We investigated post-operative pain and post-operative nausea and vomiting in 47 patients who underwent head and neck surgeries with free tissue transfer reconstruction with enhanced recovery after surgery support between February 2021 and August 2022. Patient-reported outcomes were assessed using the visual analog scale and Japanese version of the Quality of Recovery-40., Results: Significant increases in the mean visual analog scale scores for pain and post-operative nausea and vomiting were observed only on post-operative Day 1 compared with preoperative values (pain: 3.19 ± 2.78 vs. 1.96 ± 2.42, P = 0.0408; post-operative nausea and vomiting: 1.52 ± 2.09 vs. 0.54 ± 1.37, P = 0.0194). From post-operative Day 2, there were no significant differences between the pre- and post-operative visual analog scale scores, and no significant increases in the incidences of moderate or severe pain and post-operative nausea and vomiting compared with preoperatively. The Japanese version of the Quality of Recovery-40 score for post-operative pain showed no significant deterioration compared with preoperatively, while the Japanese version of the Quality of Recovery-40 score for post-operative nausea and vomiting showed significant deterioration compared with the preoperative value on post-operative Days 2, 4 and 7., Conclusions: The visual analog scale and Japanese version of the Quality of Recovery-40 scores for post-operative pain and visual analog scale score for post-operative nausea and vomiting suggested that the enhanced recovery after surgery strategy favorably controlled pain and post-operative nausea and vomiting after head and neck surgeries with free tissue transfer reconstruction. However, as the post-operative Japanese version of the Quality of Recovery-40 score for post-operative nausea and vomiting was lower than the preoperative value, there is still a need for further improvement of the enhanced recovery after surgery pathway., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome ( n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [ P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [ P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [ P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: This study aimed to clarify mortality trends and their related factors in immunoglobulin G4-related disease (IgG4-RD) with various organ involvement., Methods: We retrospectively reviewed the medical records of patients with IgG4-RD at a single rheumatology centre in Japan. We calculated the standardized mortality ratio using Japanese national mortality statistics. Cox regression analyses were also performed to assess mortality-related factors., Results: A total of 179 patients with IgG4-RD were included with a median follow-up period of 47 months. The standardized mortality ratio in our cohort was 0.86 (95% confidence interval 0.41-1.59). Univariate Cox regression analyses indicated that the number of affected organs at diagnosis (hazard ratio 1.45, 95% confidence interval 1.02-2.05), estimated glomerular infiltration rate <45 ml/min/1.73 m2 at diagnosis (vs. ≥45, hazard ratio 8.48, 95% confidence interval 2.42-29.79), and the presence of malignancy during the clinical course (hazard ratio 5.85, 95% confidence interval 1.62-21.15) had a significant impact on the time to death., Conclusions: Our findings suggest that in the rheumatology department, IgG4-RD does not significantly affect long-term patient survival. However, multi-organ involvement, renal dysfunction, and malignancy may be associated with higher mortality trends in IgG4-RD. Early detection and appropriate management of risk factors may improve the long-term prognosis of patients with IgG4-RD., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis., Methods: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated., Results: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06)., Conclusion: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study aimed to develop and validate a collapsed cone convolution for magnetic resonance-guided radiotherapy (CCCMR). The 3D energy deposition kernels (EDKs) were generated in water in a 1.5-T transverse magnetic field. The CCCMR corrects the inhomogeneity in simulation geometry by referring to the EDKs according to the mass density between the interaction and energy deposition points in addition to density scaling. Dose distributions in a water phantom and in slab phantoms with inserted inhomogeneities were calculated using the Monte Carlo (MC) and CCCMR. The percentage depth dose (PDD) and off-axis ratio (OAR) were compared, and the gamma passing rate (3%/2 mm) was evaluated. The CCCMR simulated asymmetric dose distributions in the simulation phantoms, especially the water phantom, and all PDD and OAR profiles were in good agreement with the findings of the MC. The gamma passing rates were >99% for each field size and for the entire region. In the inhomogeneity phantoms, although the CCCMR underestimated dose in the low mass density regions, it could reconstruct dose changes at mass density boundaries. The gamma passing rate for the entire region was >95% for the field size of 2 × 2 cm2, but it was 68.9-86.7% for the field sizes of ≥5 × 5 cm2. Conclusively, in water, the CCCMR can obtain dose distributions comparable to those with the MC. Although the dose differences between them were mainly in inhomogeneity regions, the possibility of the effective use of the CCCMR in small field sizes was demonstrated., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objectives: We evaluated the potential of preoperative fluorine-18-fluorodeoxyglucose positron emission tomography to predict invasive thymic epithelial tumours in patients with computed tomography-defined clinical stage I thymic epithelial tumours ≤5 cm in size who are generally considered to be candidates for minimally invasive approaches., Methods: From January 2012 to July 2022, we retrospectively analysed patients who exhibited tumour-node-metastasis (TNM) clinical stage I thymic epithelial tumours with lesion sizes ≤5 cm as determined by computed tomography. All patients underwent fluorine-18-fluorodeoxyglucose positron emission tomography preoperatively. We analysed the association of maximum standardized uptake values with both the World Health Organization histological classification and the TNM staging classification., Results: A total of 107 patients with thymic epithelial tumours (thymomas, 91; thymic carcinomas, 14; carcinoids, 2) were evaluated. Nine patients (8.4%) were pathologically upstaged: TNM pathological stage II in 3 (2.8%), III in 4 (3.7%) and IV in 2 (1.9%). Among these 9 upstaged patients, 5 had thymic carcinoma with stage III/IV, 3 had type B2/B3 thymoma with stage II/III and 1 had type B1 thymoma with stage II. Maximum standardized uptake values were a predictive factor that distinguished pathological stage >I thymic epithelial tumours from pathological stage I [best cut-off value, 4.2; area under the curve = 0.820] and thymic carcinomas from other thymic tumours (best cut-off value, 4.5; area under the curve = 0.882)., Conclusions: Thoracic surgeons should carefully determine the surgical approach for high fluorodeoxyglucose-uptake thymic epithelial tumours and keep in mind the issues associated with thymic carcinoma and potential combined resections of neighbouring structures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Capacitation is an important event in the completion of fertilization by mammalian sperm. Cholesterol efflux is a trigger of capacitation. In general, cholesterol acceptors of albumin and β-cyclodextrins are used to induce capacitation during in vitro fertilization. Previously, we reported that methyl-β-cyclodextrin (MBCD), which is composed of seven glucoses, had a higher ability to induce capacitation than bovine serum albumin (BSA) in frozen-thawed mouse sperm. Comparison of albumin and cyclodextrins is helpful for understanding the mechanism of capacitation. In this study, we examined the effects of albumin, MBCD, and a different type of cyclodextrin, dimethyl-α-cyclodextrin (DMACD), which is composed of six glucoses, on several events of sperm capacitation. We showed that DMACD induced sperm capacitation and promoted fertilization ability. The time required to increase the fertilization rate differed among BSA, MBCD, and DMACD. BSA and MBCD enhanced cholesterol and phospholipid efflux, whereas DMACD enhanced only phospholipid efflux. BSA, MBCD, and DMACD increased sperm membrane fluidity, rearrangement of the lipid raft, and the acrosome reaction. These findings suggest that phospholipid efflux is a novel trigger of capacitation. Increasing the choice of sperm capacitation inducers may be useful for improving in vitro fertilization (IVF) techniques not only in mice, but also in various species in which it has been difficult to produce embryos by IVF., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort., Methods and Results: Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes., Conclusion: LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Accelerated hypofractionated radiotherapy with 3 Gy per fraction is routinely performed for central lung tumors in Japan. However, the tolerable doses to mediastinal organs at risk during this procedure are unclear. This study aimed to clarify the rate of toxicities and tolerable doses to mediastinal organs., Methods: Patients treated with accelerated hypofractionated radiotherapy using a total dose of 60-75 Gy, with 3 Gy per fraction, for central lung tumors (July 2009-April 2021) were retrospectively reviewed. We extracted patients who received ≥30 Gy irradiation to each mediastinal organ and analyzed dosimetric factors, including doses to 0.03, 0.5, 1, 4 and 10 mL of each organ, in relation to grade 3-5 toxicities, except for radiation pneumonitis., Results: In total, 251 organs in 91 (ultra-central, 24) lesions were analyzed, with a median follow-up duration of 26 months (range, 4-94). The prescribed doses were 75/72/69/66/63/60 Gy for 52/14/16/3/2/4 lesions, respectively. Grade 3 bronchopulmonary hemorrhage was confirmed in two (2.2%) patients, whose tumors were located ultra-centrally. The two patients with toxicity received up to 74.5 and 71.6 Gy to the bronchus. Among patients who received 70 Gy or more to the bronchus, the incidence rate was 7% (2/28 patients)., Conclusion: The rate of severe toxicities was low (2.2%). Although we did not identify the dose tolerance of the organs, because of the low incidence rate, we did note that doses of >70 Gy to the bronchus were likely to cause bronchopulmonary hemorrhage., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Thioflavin T, a cationic benzothiazole dye, is typically used to detect amyloid fibrils. In this study, we analyzed the staining properties of Bacillus subtilis cells using several fluorescent dyes, including thioflavin T analogs, 2-(4'-methylaminophenyl) benzothiazole (BTA-1), and 2-(4-aminophenyl) benzothiazole (APBT). Thioflavin T stained vegetative cells in the early log phase and outer layer structures of forespores and mature spores. The inner parts of forespores and heat-killed mature spores were also stained with thioflavin T. Congo red, auramine O, and rhodamine B stained forespores and mature spores similar to thioflavin T. In contrast, APBT and BTA-1 fluorescence was detected in the outer layers of vegetative cells, mother cells, forespores, and mature spores, indicating that they bind to the cell membrane and/or cell wall. The combination of the fluorescent dyes used in this study will help analyze morphogenetic processes during the sporulation and the damage mechanisms of vegetative cells and spores., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001., Methods: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method., Results: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples., Conclusions: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

The skin microbiome, which varies widely between individuals, plays a crucial role in human health. It also interacts with the environment in various ways, including during the preparation of fermented food. Nukadoko is a pickle and traditional fermented food in Japan that utilizes lactic acid bacteria to ferment vegetables. When preparing or maintaining Nukadoko, it is mixed with bare hands. Despite the known interaction between Nukadoko and human skin, no studies have explored its impact on Nukadoko quality or skin microbiome changes. This study examines these effects during Nukadoko maintenance. Three participants were asked to stir commercially available late-stage Nukadoko for 14 days and not stir it for the remaining 14 days to examine microbial settlement and shedding. Microbiome analysis was performed on human skin and Nukadoko. We found that microorganisms from rice bran beds can temporarily settle on human skin but are shed quickly. Stirring rice bran beds by hand may have short-term effects on the skin microbiome. This study provides insights into the communication between human and food microbiomes in traditional Japanese fermented foods., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Drug-induced liver injury (DILI) is a major factor influencing new drug withdrawal; therefore, an appropriate toxicity assessment at the preclinical stage is required. Previous in silico models have been established using compound information listed in large data sources, thereby limiting the DILI risk prediction for new drugs. Herein, we first constructed a model to predict DILI risk based on a molecular initiating event (MIE) predicted by quantitative structure-activity relationships, admetSAR parameters (e.g. cytochrome P450 reactivity, plasma protein binding, and water-solubility), and clinical information (maximum daily dose [MDD] and reactive metabolite [RM]) for 186 compounds. The accuracy of the models using MIE, MDD, RM, and admetSAR alone were 43.2%, 47.3%, 77.0%, and 68.9%, while the "predicted MIE + admetSAR + MDD + RM" model's accuracy was 75.7%. The contribution of MIE to the overall prediction accuracy was little effect or rather worsening it. However, it was considered that MIE was a valuable parameter and that it contributed to detect high DILI risk compounds in the early development stage. We next examined the effect of stepwise changes in MDD on altering the DILI risk and estimating the maximum safety dose (MSD) for clinical use based on structural information, admetSAR, and MIE parameters because it is important to estimate the dose that could prevent the DILI onset in clinical conditions. Low-MSD compounds might increase the DILI risk, as these compounds were classified as "most-DILI concern" at low doses. In conclusion, MIE parameters were especially useful to check the DILI concern compounds and to prevent the underestimation of DILI risk in the early stage of drug development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This report describes a patient diagnosed with immunoglobulin G4 (IgG4)-related pancreatitis and kidney disease 7 years after the onset of undiagnosed lymphadenopathy. A 48-year-old Japanese woman presented with fatigue and leg oedema. Computed tomography showed perigastric lymphadenopathy, for which she underwent a laparoscopic biopsy of the perigastric lymph nodes. Although histopathological examination of the lymph nodes did not lead to a definitive diagnosis, serological tests revealed elevated serum IgG4 levels (558 mg/dl) and IgG4 immunostaining of the lymph nodes showed IgG4-positive plasma cell infiltration, leading to the suspicion of IgG4-related disease. Further workup revealed no organ lesion other than lymphadenopathy. At age 55 years, despite having no subjective symptoms, contrast-enhanced computed tomography showed low-density lesions in the tail of the pancreas and the left kidney. Histopathological examination showed lymphocyte infiltration, consisting of a mixture of plasma cells and eosinophils, in both organs and obliterative phlebitis in the pancreas. IgG4 immunostaining of the kidney specimens showed 160 IgG4-positive cells per high-powered field, with the IgG4+/IgG+ cell ratio being almost 100%, leading to a diagnosis of IgG4-related pancreatitis and kidney disease. Treatment with prednisolone for 2 months resulted in lesion improvement. Although the diagnosis of IgG4-related lymphadenopathy is often challenging in patients with lymphadenopathy alone, findings in the present patient emphasise the importance of long-term follow-up, as it may allow early detection of involvement of other organs by IgG4-related disease., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

X-ray microscopes adopting computed tomography enable nondestructive 3D visualization of biological specimens at micron-level resolution without conventional 2D serial sectioning that is a destructive/laborious method and is routinely used for analyzing renal biopsy in clinical diagnosis of kidney diseases. Here we applied a compact commercial system of laboratory-based X-ray microscope to observe a resin-embedded osmium-stained 1-mm strip of a mouse kidney piece as a model of renal biopsy, toward a more efficient diagnosis of kidney diseases. A reconstructed computed tomography image from several hours of data collection using CCD detector allowed us to unambiguously segment a single nephron connected to a renal corpuscle, which was consistent with previous reports using serial sectioning. Histogram analysis on the segmented nephron confirmed that the proximal and distal tubules were distinguishable on the basis of their X-ray opacities. A 3D rendering model of the segmented nephron visualized a convoluted structure of renal tubules neighboring the renal corpuscle and a branched structure of efferent arterioles. Furthermore, another data collection using scientific complementary metal-oxide semiconductor detector with a much shorter data acquisition time of 15 min provided similar results from the same samples. These results suggest a potential application of the compact laboratory-based X-ray microscope to analyze mouse renal biopsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

Introduction: This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma., Methods: Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component., Results: Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component., Conclusions: Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: This study aimed to investigate the intraventricular blood flow pattern of patients with left bundle branch block (LBBB) using four-dimensional flow magnetic resonance imaging (4D-flow MRI)., Methods and Results: We performed 4D-flow MRI for 16 LBBB patients (LBBB group) and 16 propensity score-matched patients with a normal QRS duration (non-LBBB group). The energy loss (EL) in the left ventricle was evaluated. In both groups, blood flow from the mitral valve to the apex of the heart and left ventricular (LV) outflow tract during LV diastole were observed. Vortices were also observed in both groups. There were two patterns of vortices: unidirectional clockwise rotation and counterclockwise rotation taking place from the mid-diastole to the systole (reverse pattern). The reverse pattern was observed significantly more frequently in the LBBB group (LBBB 94% vs. non-LBBB 19%, P < 0.001). The interobserver agreement for the streamline analysis was good (kappa = 0.68). The maximum EL was significantly higher in the LBBB group [LBBB 12 (11-15) mW vs. non-LBBB 8.0 (6.2-9.7) mW, P < 0.001]., Conclusion: Left bundle branch block patients may suffer from inefficient LV haemodynamics reflected by non-physiological counterclockwise vortices and increased EL. Thus, the shape of the vortices and EL in the left ventricle can serve as markers of LV mechanical dyssynchrony in LBBB patients and could be investigated as predictors of response to cardiac resynchronization therapy., Competing Interests: Conflict of interest: The co-author Yasuo Takehara is an endowed chair of the department funded by a private company HiMedic Nagoya; however, the status is irrelevant to the contents of the paper. Other authors declare no conflicts of interest or relationships with industry., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objective: Stereotactic body radiotherapy is used to treat spinal metastases; however, 10% of patients experience local failure. We aimed to clarify the outcomes of the second course of stereotactic body radiotherapy for spinal metastases with a uniform fractionation schedule at our institution., Methods: Data of patients treated with a second salvage stereotactic body radiotherapy course at the same spinal level or adjacent level from July 2018 to December 2020 were retrospectively reviewed. The initial prescribed dose was 24 Gy in two fractions, and the second dose 30 or 35 Gy in five fractions. The spinal cord dose constraint at the second course was 15.5 Gy at the maximum point dose. The endpoints were local failure and adverse effects. Local failure was defined as tumor progression using imaging., Results: We assessed 19 lesions in 17 patients, with radioresistant lesions in 14 (74%) cases, the second stereotactic body radiotherapy to the same/adjacent spinal level in 13/6 cases, the median interval between stereotactic body radiotherapy of 23 (range, 6-52) months, and lesions compressing the cord in 5 (26%) cases. The median follow-up period was 19 months. The 12- and 18-month local failure rates were 0% and 8%, respectively. Radiation-induced myelopathy, radiculopathy and vertebral compression fractures were observed in 0 (0%), 4 (21%) and 2 (11%) lesions, respectively. Three patients with radiculopathy experienced almost complete upper or lower limb paralysis., Conclusions: The second course of salvage stereotactic body radiotherapy for spinal metastases achieved good local control with a reduced risk of myelopathy. However, a high occurrence rate of radiation-induced radiculopathy has been confirmed., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Guanosine tetraphosphate (ppGpp) is known as an alarmone that mediates bacterial stress responses. In plants, ppGpp is synthesized in chloroplasts from GTP and ATP and functions as a regulator of chloroplast gene expression to affect photosynthesis and plant growth. This observation indicates that ppGpp metabolism is closely related to chloroplast function, but the regulation of ppGpp and its role in chloroplast differentiation are not well understood. In rice, ppGpp directly inhibits plastidial guanylate kinase (GKpm), a key enzyme in GTP biosynthesis. GKpm is highly expressed during early leaf development in rice, and the GKpm-deficient mutant, virescent-2 (v2), develops chloroplast-deficient chlorotic leaves under low-temperature conditions. To examine the relationship between GTP synthesis and ppGpp homeostasis, we generated transgenic rice plants over-expressing RSH3, a protein known to act as a ppGpp synthase. When RSH3 was overexpressed in v2, the leaf chlorosis was more severe. Although the RSH3 overexpression in the wild type caused no visible effects, pulse amplitude modulation fluorometer measurements indicated that photosynthetic rates were reduced in this line. This finding implies that the regulation of ppGpp synthesis in rice is involved in the maintenance of the GTP pool required to regulate plastid gene expression during early chloroplast biogenesis. We further investigated changes in the expressions of RelA/SpoT Homolog (RSH) genes encoding ppGpp synthases and hydrolases during the same period. Comparing the expression of these genes with the cellular ppGpp content suggests that the basal ppGpp level is determined by the antagonistic action of multiple RSH enzymatic activities during early leaf development in rice., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Whole-liver radiotherapy for diffuse liver metastases can improve symptoms and abnormal liver-related blood data. However, whole-liver radiotherapy is uncommonly used in clinical practice in Japan. Therefore, we aimed to clarify palliative radiotherapy outcomes in Japanese patients with liver metastases., Methods: We retrospectively reviewed databases in our institution to identify patients treated with radiotherapy (8 Gy in a single fraction) for multiple liver metastases between December 2014 and April 2021. The endpoints included pain response, liver-related blood data and adverse effects. We investigated aspartate transaminase, alanine transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl transpeptidase and albumin. The mean values at whole-liver radiotherapy and after 2-4 weeks were compared using the Wilcoxon rank-sum test., Results: A total of 73 cases in 71 patients were included. The median clinical target volume was 2118 ml (range, 133-7867 ml). Fifty-seven patients (78%) had finished aggressive treatment at the time of radiotherapy. The median follow-up period was 6 weeks. The pain response rate was 64% (18/28). The mean values of five parameters significantly improved 2-4 weeks after radiotherapy compared to those at baseline: aspartate transaminase (118 vs. 83 U/l P < 0.01); alanine transaminase (84 vs. 61 U/l P < 0.01); lactate dehydrogenase (1351 vs. 1007 U/l P = 0.027); alkaline phosphatase (1624 vs. 1216 U/l P < 0.01) and γ-glutamyl transpeptidase (663 vs. 450 U/l P = 0.037). No patients experienced radiation-induced liver disease., Conclusions: Palliative radiotherapy is efficient and safe in Japanese patients with liver metastases. These findings will help encourage whole-liver radiotherapy use in Japan., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: We aimed to investigate the epidemiological characteristics of osteonecrosis of the femoral head (ONFH) using the designated intractable diseases (DID) database in Japan., Methods: Data on patients who had received public subsidies for medical costs due to ONFH from 2012 to 2013 were extracted from the DID database. The incidence and prevalence of ONFH, distribution of gender, age, and the prevalence of associated risk factors were assessed. These epidemiological characteristics were compared with those of another nationwide ONFH survey conducted during a similar period., Results: Data on 3264 newly diagnosed patients (incident cases) and 20,042 patients registered until 2013 (prevalent cases) were evaluated. The corrected annual incidence and prevalence of ONFH per 100,000 were 3.0 and 18.2-19.2, respectively. The ratio of males to females was 1.4 in 2012 and 1.2 in 2013, respectively. Peak distribution was observed at ages 40s and 60s in males and females, respectively. The prevalence of the risk factors were steroid-associated: 39%, alcohol-associated: 30%, both: 4%, and none: 27%., Conclusions: The DID database data showed a similar distribution of gender and age to that in other nationwide surveys but lower incidence and prevalence of ONFH. Sampling bias may affect the epidemiological characteristics of ONFH., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Magnesium is an important nutrient for plants, but much is still unknown about plant Mg2+ transporters. Combining with the structural prediction of AlphaFold2, we used mutagenesis and 28Mg uptake assay to study the highly conserved "GMN" motif of Arabidopsis thaliana MRS2-1 (AtMRS2-1) transporter. We demonstrated that the glycine and methionine in GMN motif are essential for AtMRS2-1 to transport Mg2+., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: PC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways., Methods: Fifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics, and safety were assessed until discharge. RSV infection was confirmed by reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples., Results: In the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated., Conclusions: Nebulized PC786 demonstrated a significant antiviral effect against RSV, warranting further clinical study., Clinical Trials Registration: ClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Dynamic tumor tracking (DTT) is a method of respiratory motion management in radiotherapy. It reduces the radiation field but risks delivering an insufficient radiation dose to the tumor. We investigated the local control of DTT-stereotactic body radiotherapy (SBRT) for lung tumors., Methods: Patients treated with SBRT for early-stage, non-small-cell lung cancer and lung metastases (2013-18) were retrospectively reviewed. Patients with tumor motion >1 cm were treated with DTT-SBRT (DTT group); those with tumor motion ≤1 cm were treated with static-SBRT (static group). A static planning target volume for the static-SBRT plan was also created for patients in the DTT group, and planning target volume reduction relative to the planning target volume for the DTT-SBRT plan was assessed. Patients were matched in a 1:1 ratio using a propensity score predictive of the SBRT technique., Results: Of the 245 lesions in 218 patients (median follow-up, 25.4 months), 69 were treated with DTT-SBRT and 176 with static-SBRT. The median planning target volume reduction in the DTT group was 30.3%. After propensity score matching, 124 lesions were included (62 per group). Two-year local control rates for the DTT and static groups were 94.2 and 95.9%, respectively, for all lesions (P = 0.19) and 96.3 and 94.5%, respectively, for matched lesions (P = 0.79). In univariate analysis, DTT-SBRT was not associated with local control for all lesions (hazard ratio, 2.06; P = 0.20) or matched lesions (hazard ratio, 1.22; P = 0.79). No grade 4/5 toxicities were observed., Conclusions: DTT-SBRT for lung tumors reduced the planning target volume, but not local control rates. DTT was useful for respiratory motion management., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Eukaryotic uL11 contains a conserved MPPKFDP motif at the N-terminus that is not found in archaeal and bacterial homologs. Here, we determined the solution structure of human uL11 by NMR spectroscopy and characterized its backbone dynamics by 15N-1H relaxation experiments. We showed that these N-terminal residues are unstructured and flexible. Structural comparison with ribosome-bound uL11 suggests that the linker region between the N-terminal domain and C-terminal domain of human uL11 is intrinsically disordered and only becomes structured when bound to the ribosomes. Mutagenesis studies show that the N-terminal conserved MPPKFDP motif is involved in interacting with the P-complex and its extended protuberant domain of uL10 in vitro. Truncation of the MPPKFDP motif also reduced the poly-phenylalanine synthesis in both hybrid ribosome and yeast mutagenesis studies. In addition, G→A/P substitutions to the conserved GPLG motif of helix-1 reduced poly-phenylalanine synthesis to 9-32% in yeast ribosomes. We propose that the flexible N-terminal residues of uL11, which could extend up to ∼25 Å from the N-terminal domain of uL11, can form transient interactions with the uL10 that help to fetch and fix it into a position ready for recruiting the incoming translation factors and facilitate protein synthesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background and Objectives: Dementia awareness initiatives aim to promote helping behaviors toward people living with dementia. We applied the bystander intervention process model in the context of the general public's helping behaviors toward people living with dementia, and we sought to identify the mechanisms underlying the association between dementia knowledge and helping behaviors., Research Design and Methods: In a survey featuring vignettes for the general public in Japan ( N = 904), we presented four situations in which people could exhibit helping behaviors toward a person with dementia. Guttman scale analysis was used to test this sequential ordering of the bystander intervention process model: (a) interpreting the need to help, (b) perceiving personal responsibility, and (c) intention to provide help. Mediation analysis was used to examine whether the effects of knowledge on helping behaviors were mediated by attitude toward people living with dementia and the bystander intervention process., Results: The results support the two-step model in which interpreting the situation as one where assistance is required is a prerequisite of helping behavior. Dementia knowledge had a significant total effect on intention to provide help (β = 0.136, p < .001). Interpretation (indirect effect: β = 0.092, p < .001), as well as attitude (indirect effect: β = 0.044, p < .001), was found to completely mediate the effect of dementia knowledge on intention to provide help., Discussion and Implications: Dementia awareness initiatives designed to promote helping behaviors should focus on knowledge transfer, improving the general public's attitudes toward people living with dementia, and their ability to interpret when such people need assistance., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

In order to characterize the probable protease gene yabG found in the genomes of spore-forming bacteria, Bacillus subtilis yabG was expressed as a 35 kDa His-tagged protein (BsYabG) inEscherichia coli cells. During purification using Ni-affinity chromatography, the 35 kDa protein was degraded via several intermediates to form a 24 kDa protein. Furthermore, it was degraded after an extended incubation period. The effect of protease inhibitors, including certain chemical modification reagents, on the conversion of the 35 kDa protein to the 24 kDa protein was investigated. Reagents reacting with sulphhydryl groups exerted significant effects strongly suggesting that the yabG gene product is a cysteine protease with autolytic activity. Site-directed mutagenesis of the conserved Cys and His residues indicated that Cys218 and His172 are active site residues. No degradation was observed in the C218A/S and H172A mutants. In addition to the chemical modification reagents, benzamidine inhibitedGraphical Abstract the degradation of the 24 kDa protein. Determination of the N-terminal amino acid sequences of the intermediates revealed trypsin-like specificity for YabG protease. Based on the relative positions of His172 and Cys218 and their surrounding sequences, we propose the classification of YabG as a new family of clan CD in the MEROPS peptidase database., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population., Methods: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese., Results: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl., Conclusion: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In this article, we highlight the fundamental importance of the simultaneous use of dose-volume histogram (DVH) and dose-function histogram (DFH) features based on functional images calculated from 4-dimensional computed tomography (4D-CT) and deformable image registration (DIR) in developing a multivariate radiation pneumonitis (RP) prediction model. The patient characteristics, DVH features and DFH features were calculated from functional images by Hounsfield unit (HU) and Jacobian metrics, for an RP grade ≥ 2 multivariate prediction models were computed from 85 non-small cell lung cancer patients. The prediction model is developed using machine learning via a kernel-based support vector machine (SVM) machine. In the patient cohort, 21 of the 85 patients (24.7%) presented with RP grade ≥ 2. The median area under curve (AUC) was 0.58 for the generated 50 prediction models with patient clinical features and DVH features. When HU metric and Jacobian metric DFH features were added, the AUC improved to 0.73 and 0.68, respectively. We conclude that predictive RP models that incorporate DFH features were successfully developed via kernel-based SVM. These results demonstrate that effectiveness of the simultaneous use of DVH features and DFH features calculated from 4D-CT and DIR on functional image-guided radiotherapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: To clarify the clinical significance of development of urinary abnormality in mixed connective tissue disease (MCTD)., Methods: Forty-one patients with an initial diagnosis of MCTD, followed at five hospitals between April 1, 2000 and December 31, 2013, were included. The relationship between urinary abnormality and various clinical parameters were retrospectively analyzed. Urinary abnormality was defined as proteinuria and/or hematuria detected by urinalysis. Development of other connective tissue diseases (CTDs) was defined as satisfaction of the criteria of each respective disease., Results: Of 41 patients (34 females, 7 males, mean age at diagnosis 42.2 ± 15.2 years), 16 developed urinary abnormality (UrA(+) patients). The total incidences of development of other CTDs were higher in the UrA(+) patients than UrA(-) (62.5% versus 16.0%, p = .01). In the comparison between UrA(+) and UrA(-) patients, there were no significant differences in follow-up duration or last determined estimated glomerular filtration rate (eGFR), although eGFR decreased more significantly in the UrA(+) patients than UrA(-). (-20.2 ± 17.2 vs -6.1 ± 13.8 ml/min/1.73m2, p = .01; -21.0 ± 18.9 vs -6.7 ± 14.1%, p = .03)., Conclusion: Urinary abnormality during the clinical course in MCTD is predictive of a higher incidence of developing other CTDs. Furthermore, it might also predict long-term renal prognosis in patients with an initial diagnosis of MCTD., (© 2021 Japan College of Rheumatology.)

Objectives: Alcohol intake and smoking are modifiable lifestyle-related risk factors for osteonecrosis of the femoral head (ONFH). We investigated geographic differences in ONFH incidence in Japan and the correlation with alcohol intake and smoking to develop prevention strategies for ONFH in Japan., Methods: This ecological study was conducted in Japan primarily using the following data sources: nationwide epidemiological survey and national survey. We estimated the annual ONFH incidence and the prevalence of alcohol drinking and smoking in each prefecture. Prefectural incidence and prevalence were calculated by sex and age-standardization., Results: The mean annual ONFH incidence per 100,000 population was 3.08 in men and 1.63 in women, respectively. There was no significant correlation between ONFH incidence and the prevalence of any levels of alcohol intake, while smoking ≥20 cigarettes/day showed a significant and moderate correlation in men (r = 0.47, p = .01). This correlation remained significant after adjustment for the prevalence of any levels of alcohol intake (standardized partial regression coefficient = 0.47-0.49, p = .009-.01)., Conclusion: ONFH incidence is geographically variable in Japan, and this may be partly explained by the distribution of smoking prevalence. Smoking cessation may contribute to an effective decline in the overall ONFH incidence in Japan., (© 2021 Japan College of Rheumatology.)

Background: Stereotactic body radiotherapy is a new treatment modality for long bone metastasis and has not been discussed in literature. We aimed to clarify stereotactic body radiotherapy outcomes for long bone metastases., Methods: Data of patients receiving stereotactic body radiotherapy for long bone metastases (July 2016-November 2020) were retrospectively reviewed. The prescribed dose was 30 or 35 Gy in five fractions. The endpoints were local failure and adverse effects. Local failure was defined as radiological tumor growth within the irradiation field. Adverse effects were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5., Results: Nineteen osseous lesions in 17 patients were assessed. The target lesions included 13 femoral, 4 humeral and 2 radial lesions. The median follow-up duration was 14 (range, 3-62) months. The 12- and 18-month local failure rates were 0 and 11%, respectively. Following 2 and 46 months of stereotactic body radiotherapy, two lesions (11%) resulted in painful femoral fractures (grade 3). Both patients underwent bipolar hip arthroplasty and could walk normally after surgery. In the late phase, one patient developed radiculopathy (almost complete paralysis of grasp) and another developed grade 2 limb edema. Other grade 2 or more severe acute and late toxicities were not observed during the follow-up period., Conclusions: Stereotactic body radiotherapy for long bone metastases achieved excellent local control and caused two femoral fractures. We argue that stereotactic body radiotherapy for curative intent should not be contraindicated in long bone oligometastasis because fractures do not directly contribute to life expectancy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In atopic dermatitis (AD), phosphodiesterase 4 (PDE4) inhibition reduces proinflammatory mediators and cytokines. Difamilast is a new selective PDE4 inhibitor., Objectives: To demonstrate the superiority of topical difamilast to vehicle in Japanese paediatric patients with AD., Methods: This was a phase III randomized, double-blind, vehicle-controlled trial. Patients aged 2-14 years with an Investigator Global Assessment (IGA) score of 2 or 3 received difamilast 0·3% (n = 83), difamilast 1% (n = 85) or vehicle (n = 83) ointment twice daily for 4 weeks., Results: The primary endpoint was the percentage of patients with an IGA score of 0 or 1 with improvement by at least two grades at week 4. The success rates in IGA score at week 4 were 44·6%, 47·1% and 18·1% in the difamilast 0·3%, difamilast 1% and vehicle groups, respectively. Both difamilast groups demonstrated significantly higher success rates in IGA score compared with vehicle at week 4 [difamilast 0·3% (P < 0·001); difamilast 1% (P < 0·001)]. Regarding secondary endpoints, improvements in Eczema Area and Severity Index (EASI; improvement of ≥ 50%, ≥ 75% and ≥ 90% in overall score) at week 4 were significantly higher in patients in the difamilast 0·3% and 1% groups than those in the vehicle group. EASI score in the difamilast 0·3% and 1% groups was significantly reduced compared with that of patients in the vehicle group at week 1. The significant difference between both the difamilast groups and the vehicle groups was maintained from week 1 through to week 4. Most treatment-emergent adverse events were mild or moderate, and no serious events or deaths were reported., Conclusions: Difamilast 0·3% and 1% ointments are superior to vehicle and well tolerated in Japanese paediatric patients with AD., (© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objectives: In IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), involvement of two or more sets of lacrimal glands (LGs) and/or major salivary glands (MSGs) is regarded as a specific finding with diagnostic significance. This study aimed to clarify the influence of this factor on the overall clinical picture of IgG4-DS., Methods: We retrospectively reviewed the medical records of 130 patients with IgG4-related disease, 97 of whom were diagnosed with IgG4-DS. We determined their clinical features according to the presence/absence of involvement of ≥2 sets of LGs and/or MSGs and compared the results with those obtained in 33 DS-limited patients., Results: The IgG4-DS patients comprised 60 men and 37 women (median age 65 years). The median serum IgG4 level at diagnosis was 548 mg/dL. The patients with involvement of ≥2 sets ( n  = 44) had significantly more affected organs, lower serum C3 and C4 levels, and a tendency to have higher serum IgG levels and IgG4-RD responder index than did those without it ( n  = 53). In the 33 DS-limited patients, these two groups had no significant differences in clinical features., Conclusions: Involvement of ≥2 sets of LGs and/or MSGs suggests greater systemic disease activity mainly reflected by involvement of more organs.

1'-Acetoxychavicol acetate (ACA) is found in Thai ginger (Alpinia galanga) and is a powerful agonist of transient receptor potential ankyrin 1 (TRPA1). In a diet-induced obesity mouse model, ACA reduced fat deposition. Sympathetic nerve activation was also indicated in the ACA-fed group. This study is expected to promote the utilization of food containing TRPA1 agonists to treat obesity., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: It is still controversial whether intensity-modulated radiotherapy has an obvious advantage over conventional radiotherapy. The purposes of this study were to evaluate prognostic factors in pre-treatment characteristics for nasopharyngeal carcinoma and to compare treatment outcomes in patients who received intensity-modulated radiotherapy and patients who received two-dimensional radiotherapy or three-dimensional radiotherapy., Methods: We reviewed patients with nasopharyngeal carcinoma who received chemoradiotherapy in our hospital during the period from 2000 to 2017, and we excluded patients who had a history of surgery for nasopharyngeal carcinoma and those who had distant metastases before treatment. A total of 72 patients who were treated by radiotherapy with concurrent chemotherapy were enrolled. All of the patients were irradiated with a total dose of 58-70 Gy. Overall survival, locoregional control and progression-free survival rates were compared in the groups treated by intensity-modulated radiotherapy and two-dimensional/three-dimensional radiotherapy. Propensity score matching was performed to homogenize the two groups., Results: The median follow-up period was 62.5 months. After propensity score matching, in patients treated with intensity-modulated radiotherapy, the 5-year rate of overall survival, locoregional control and progression-free survival were 73.5, 95.2 and 72.7%, respectively. In patients treated with two-dimensional/three-dimensional radiotherapy, the 5-year rate of overall survival, locoregional control and progression-free survival were 69.1, 67.7 and 51.8%, respectively. There was a significant difference between the groups only in locoregional control. Late toxicities of grade 2 or higher were occurred in 38.5 and 24.2% of the patients treated by two-dimensional/three-dimensional radiotherapy and intensity-modulated radiotherapy, respectively., Conclusions: Our results suggested that intensity-modulated radiotherapy is more effective than two-dimensional/three-dimensional radiotherapy in patients with nasopharyngeal carcinoma, especially in locoregional control., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)