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ABSTRACT Objective Methods Results Conclusion To investigate the association between dental attendance with periodontal care and the risk of dialysis initiation in patients with type 2 diabetes mellitus (T2D).This retrospective cohort study used data from the Japan Medical Data Center (JMDC) claims database (January 2015 to August 2022). Patients with T2D, aged 40–74, were included. Dental attendance with periodontal care and initiation of dialysis were used as the exposure and outcome variables, respectively. We fitted the Cox proportional hazards model, including potential confounders, to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs).Among 99,273 participants (mean age = 54.4 years [SD = 7.8], male = 71.9%), the incidence rate of dialysis initiation was 0.92 per 1000 person‐years. After adjusting for all covariates, those with periodontal care (HR = 0.68 [95%CI = 0.51–0.91] for ≥ 1 time/year and HR = 0.56 [95%CI = 0.41–0.77] for ≥ 1 time/6 months) had a significantly lower risk of dialysis initiation compared to those without dental attendance.Periodontal disease care in patients with T2D is associated with a reduced risk of dialysis initiation by 32%–44%. This suggests that integrating periodontal care into diabetes management may help prevent the progression of diabetic nephropathy and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Aim: Tooth loss has various causes; however, its cause‐specific effects on health outcomes remain unclear. This study evaluated whether the association between past/current smoking and risk of dementia was mediated by tooth loss. Materials and Methods: This 9‐year‐follow‐up prospective cohort study targeted adults aged ≥65 years. Dementia incidence during 2013–2019, smoking status (never, past/current) in 2010 and the number of remaining teeth (≤19, ≥20) in 2013 were the outcome, exposure and mediator, respectively. We used causal mediation analysis to fit the Cox proportional hazards model and estimated the hazard ratio (HR) and 95% confidence interval (CI) of the natural indirect effect (NIE) of smoking on dementia incidence through tooth loss and their mediated proportions. Results: Among 32,986 participants (mean age 72.6 years [1 SD = 5.4]; men 48.4%), the dementia incidence during follow‐up was 2.11/100 person‐years. Tooth loss significantly mediated the association between past/current smoking and dementia incidence; the NIE of fewer remaining teeth for past/current smokers compared to never smokers was HR = 1.03 (95% CI: 1.02–1.05), and the mediated proportion was 18.0%. Conclusions: Tooth loss significantly mediates the association between past/current smoking and an increased risk of dementia among older adults. [ABSTRACT FROM AUTHOR]

Purpose: Quantitative T1 mapping has the potential to replace biopsy for noninvasive diagnosis and quantitative staging of chronic liver disease. Conventional T1 mapping methods are confounded by fat and B1+$$ {B}_1^{+} $$ inhomogeneities, resulting in unreliable T1 estimations. Furthermore, these methods trade off spatial resolution and volumetric coverage for shorter acquisitions with only a few images obtained within a breath‐hold. This work proposes a novel, volumetric (3D), free‐breathing T1 mapping method to account for multiple confounding factors in a single acquisition. Theory and Methods: Free‐breathing, confounder‐corrected T1 mapping was achieved through the combination of non‐Cartesian imaging, magnetization preparation, chemical shift encoding, and a variable flip angle acquisition. A subspace‐constrained, locally low‐rank image reconstruction algorithm was employed for image reconstruction. The accuracy of the proposed method was evaluated through numerical simulations and phantom experiments with a T1/proton density fat fraction phantom at 3.0 T. Further, the feasibility of the proposed method was investigated through contrast‐enhanced imaging in healthy volunteers, also at 3.0 T. Results: The method showed excellent agreement with reference measurements in phantoms across a wide range of T1 values (200 to 1000 ms, slope = 0.998 (95% confidence interval (CI) [0.963 to 1.035]), intercept = 27.1 ms (95% CI [0.4 54.6]), r2 = 0.996), and a high level of repeatability. In vivo imaging studies demonstrated moderate agreement (slope = 1.099 (95% CI [1.067 to 1.132]), intercept = −96.3 ms (95% CI [−82.1 to −110.5]), r2 = 0.981) compared to saturation recovery‐based T1 maps. Conclusion: The proposed method produces whole‐liver, confounder‐corrected T1 maps through simultaneous estimation of T1, proton density fat fraction, and B1+$$ {B}_1^{+} $$ in a single, free‐breathing acquisition and has excellent agreement with reference measurements in phantoms. [ABSTRACT FROM AUTHOR]

This fourth edition of the Japanese Clinical Practice Guidelines for Prostate Cancer 2023 is compiled. It was revised under the leadership of the Japanese Urological Association, with members selected from multiple academic societies and related organizations (Japan Radiological Society, Japanese Society for Radiation Oncology, the Department of EBM and guidelines, Japan Council for Quality Health Care (Minds), Japanese Society of Pathology, and the patient group (NPO Prostate Cancer Patients Association)), in accordance with the Minds Manual for Guideline Development (2020 ver. 3.0). The most important feature of this revision is the adoption of systematic reviews (SRs) in determining recommendations for 14 clinical questions (CQs). Qualitative SRs for these questions were conducted, and the final recommendations were made based on the results through the votes of 24 members of the guideline development group. Five algorithms based on these results were also created. Contents not covered by the SRs, which are considered textbook material, have been described in the general statement. In the general statement, a literature search for 14 areas was conducted; then, based on the general statement and CQs of the Japanese Clinical Practice Guidelines for Prostate Cancer 2016, the findings revealed after the 2016 guidelines were mainly described. This article provides an overview of these guidelines. [ABSTRACT FROM AUTHOR]

Purpose: The objective was to develop a fully automated algorithm that generates confidence maps to identify regions valid for analysis of quantitative proton density fat fraction (PDFF) and R2*$$ {R}_2^{\ast } $$ maps of the liver, generated with chemical shift–encoded MRI (CSE‐MRI). Confidence maps are urgently needed for automated quality assurance, particularly with the emergence of automated segmentation and analysis algorithms. Methods: Confidence maps for both PDFF and R2*$$ {R}_2^{\ast } $$ maps are generated based on goodness of fit, measured by normalized RMS error between measured complex signals and the CSE‐MRI signal model. Based on Cramér‐Rao lower bound and Monte‐Carlo simulations, normalized RMS error threshold criteria were developed to identify unreliable regions in quantitative maps. Simulation, phantom, and in vivo clinical studies were included. To analyze the clinical data, a board‐certified radiologist delineated regions of interest (ROIs) in each of the nine liver segments for PDFF and R2*$$ {R}_2^{\ast } $$ analysis in consecutive clinical CSE‐MRI data sets. The percent area of ROIs in areas deemed unreliable by confidence maps was calculated to assess the impact of confidence maps on real‐world clinical PDFF and R2*$$ {R}_2^{\ast } $$ measurements. Results: Simulations and phantom studies demonstrated that the proposed algorithm successfully excluded regions with unreliable PDFF and R2*$$ {R}_2^{\ast } $$ measurements. ROI analysis by the radiologist revealed that 2.6% and 15% of the ROIs were placed in unreliable areas of PDFF and R2*$$ {R}_2^{\ast } $$ maps, as identified by confidence maps. Conclusion: A proposed confidence map algorithm that identifies reliable areas of PDFF and R2*$$ {R}_2^{\ast } $$ measurements from CSE‐MRI acquisitions was successfully developed. It demonstrated technical and clinical feasibility. [ABSTRACT FROM AUTHOR]

We consider a model of internal competition, where projects developed by agents with different preferences compete for resources in an organization. Allowing a manager—who has moderate preferences—to control the allocation of resources has benefits when preferences are not too diverse. In particular, the manager acts as a mediator, forcing agents to compromise when competing projects succeed, thus providing better insurance to agents and increasing their effort. Our framework provides a theoretical foundation for two influential views of a manager—as the "visible hand" that allocates resources, and as a "power broker" who resolves conflict in an organization. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Subungual abscesses are rare, and information about them through imaging findings is lacking. Carbon dioxide laser drainage and antibiotics are effective treatment strategies for subungual abscesses. We report a case of a 47‐year‐old male healthcare worker with a subungual abscess that improved after manual drainage alone. Ultrasound and magnetic resonance images showed a tumor (with blood flow) between the nail plate and distal phalanx. Culture tests revealed Staphylococcus aureus. The patient's symptoms resolved quickly and the nail returned to normal after 4 months. This is possibly the first report of a subungual abscess with ultrasound and magnetic resonance imaging findings. [ABSTRACT FROM AUTHOR]

Background: Hyaline fibromatosis syndrome (HFS) is a congenital disorder characterized by subcutaneous skin nodules, congenital multiple arthrogryposis, gingival hyperplasia, and chronic pain. The intellectual ability of patients with HFS is generally normal. This syndrome arises from variants of ANTXR2. Thus far, about 100 cases have been reported but few of these were reported from Japan. Methods: This study reports five additional Japanese patients with genetically confirmed HFS, from unrelatd families, and discusses the clinical course and quality of life of these patients. Results: At our last visit the ages of the patients were 3–19 years (the median age was 5 years). All the patients had arthrogryposis, skin nodules, and gingival hyperplasia, and four patients had chronic pain, all of which are distinctive, clinical characteristics of HFS. Four of the patients (80%) had pruritic skin nodules, and three experienced sleep disruptions due to pruritis. The visceral complications are an index of HFS severity. One patient in the present cohort had a mucosal abnormality without any gastrointestinal symptoms. Conclusion: Preventive and routine management of pruritis caused by skin nodules should be shared with the patient's family. Even asymptomatic patients might have endoscopic finding, which would be a soft marker that could predict the development of protein losing enteropathy. [ABSTRACT FROM AUTHOR]

Background: Accurate 3D semantic segmentation models are essential for many clinical applications. To train a model for 3D segmentation, voxel‐level annotation is necessary, which is expensive to obtain due to laborious work and privacy protection. To accurately annotate 3D medical data, such as MRI, a common practice is to annotate the volumetric data in a slice‐by‐slice contouring way along principal axes. Purpose: In order to reduce the annotation effort in slices, weakly supervised learning with a bounding box (Bbox) was proposed to leverage the discriminating information via a tightness prior assumption. Nevertheless, this method requests accurate and tight Bboxes, which will significantly drop the performance when tightness is not held, that is when a relaxed Bbox is applied. Therefore, there is a need to train a stable model based on relaxed Bbox annotation. Methods: This paper presents a mixed‐supervised training strategy to reduce the annotation effort for 3D segmentation tasks. In the proposed approach, a fully annotated contour is only required for a single slice of the volume. In contrast, the rest of the slices with targets are annotated with relaxed Bboxes. This mixed‐supervised method adopts fully supervised learning, relaxed Bbox prior, and contrastive learning during the training, which ensures the network exploits the discriminative information of the training volumes properly. The proposed method was evaluated on two public 3D medical imaging datasets (MRI prostate dataset and Vestibular Schwannoma [VS] dataset). Results: The proposed method obtained a high segmentation Dice score of 85.3% on an MRI prostate dataset and 83.3% on a VS dataset with relaxed Bbox annotation, which are close to a fully supervised model. Moreover, with the same relaxed Bbox annotations, the proposed method outperforms the state‐of‐the‐art methods. More importantly, the model performance is stable when the accuracy of Bbox annotation varies. Conclusions: The presented study proposes a method based on a mixed‐supervised learning method in 3D medical imaging. The benefit will be stable segmentation of the target in 3D images with low accurate annotation requirement, which leads to easier model training on large‐scale datasets. [ABSTRACT FROM AUTHOR]

Sinus macrophages in draining lymph nodes (DLNs) are involved in anti‐tumor immune reactions. CD169 (Sialoadhesin, Siglec‐1) is expressed on sinus macrophages and is considered a surrogate marker for the immunostimulatory phenotype of macrophages. In this study, the significance of sinus macrophages in immunotherapy was evaluated using mouse models. Treatment with anti‐programmed death‐ligand 1 (PD‐L1) antibody suppressed the subcutaneous tumor growth of MC38 and E0771 cells but was not effective against MB49 and LLC tumors. Decreased cytotoxic T‐lymphocyte (CTL) infiltration in tumor tissues and CD169 expression in sinus macrophages were observed in MB49 and LLC cells compared to corresponding parameters in MC38 and E0771 cells. The anti‐tumor effects of the anti‐PD‐L1 antibody on MC38 and E0771 cells were abolished when sinus macrophages in DLNs were depleted, suggesting that sinus macrophages are involved in the therapeutic effect of the anti‐PD‐L1 antibody. Naringin activated sinus macrophages. Naringin inhibited tumor growth in MB49‐ and LLC‐bearing mice but did not affect that in MC38‐ and E0771‐bearing mice. The infiltration of CTLs in tumor tissues and their activation were increased by naringin, and this effect was impaired when sinus macrophages were depleted. Combination therapy with naringin and anti‐PD‐L1 antibody suppressed MB49 tumor growth. In conclusion, CD169‐positive sinus macrophages in DLNs are critical for anti‐tumor immune responses, and naringin suppresses tumor growth by activating CD169‐positive sinus macrophages and anti‐tumor CTL responses. The activation status of sinus macrophages has been suggested to differ among tumor models, and this should be investigated in future studies. [ABSTRACT FROM AUTHOR]

The development of useful biomaterials has resulted in significant advances in various fields of science and technology. The demand for new biomaterial designs and manufacturing techniques continues to grow, with the goal of building a sustainable society. In this study, two types of DNA‐cationic surfactant complexes were synthesized using commercially available deoxyribonucleic acid from herring sperm DNA (hsDNA, <50 bp) and deoxyribonucleic acid from salmon testes DNA (stDNA, ~2000 bp). The DNA‐surfactant complexes were blended with a polylactic acid (PLA) biopolymer and electrospun to obtain nanofibers, and then copper nanoparticles were synthesized on nanofibrous webs. Scanning electron microscopic images showed that all nanofibers possessed uniform morphology. Interestingly, different diameters were observed depending on the base pairs in the DNA complex. Transmission electron microscopy showed uniform growth of copper nanoparticles on the nanofibers. Fourier‐transform infrared spectroscopy spectra confirmed the uniform blending of both types of DNA complexes in PLA. Both stDNA‐ and hsDNA‐derived nanofibers showed greater biocompatibility than native PLA nanofibers. Furthermore, they exerted significant antibacterial activity in the presence of copper nanoparticles. This study demonstrates that DNA is a potentially useful material to generate electrospun nanofibrous webs for use in biomedical sciences and technologies. [ABSTRACT FROM AUTHOR]

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context‐dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP‐rich environment based on curation of two publicly available RNA‐sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine‐rich repeats and immunoglobulin‐like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth‐suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA‐approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient‐derived organoids could offer functional biomarkers for predicting potential responders to this regimen. [ABSTRACT FROM AUTHOR]

Aim: Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi‐human leukocyte antigen‐binding heat shock protein 70/glypican‐3 peptides with a novel adjuvant combination of hLAG‐3Ig and poly‐ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial. Methods: In this phase I study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end‐points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin–eosin staining and immunohistochemistry for heat shock protein 70, glypican 3, CD8 and programmed death‐1. Results: A total of 20 human leukocyte antigen‐matched patients received this vaccination therapy with an acceptable side‐effect profile. All patients underwent planned surgery without vaccination‐related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ T cells into tumors with target antigen expression was observed in 12 of 20 (60%) patients. Conclusions: This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ T cells infiltration into tumors. [ABSTRACT FROM AUTHOR]

Background: While chimeric antigen receptor (CAR)‐T cell therapy has demonstrated excellent efficacy in hematopoietic malignancies, its clinical application in solid cancers has yet to be achieved. One of the reasons for such hurdle is a lack of suitable CAR targets in solid cancers. Methods: GM2 is one of the gangliosides, a group of glycosphingolipids with sialic acid in the glycan, and overexpressed in various types of solid cancers. In this study, by using interleukin (IL)‐7 and chemokine (C‐C motif) ligand 19 (CCL19)‐producing human CAR‐T system which we previously developed, a possibility of GM2 as a solid tumor target for CAR‐T cell therapy was explored in a mouse model with human small‐cell lung cancer. Results: Treatment with anti‐GM2 IL‐7/CCL19‐producing CAR‐T cells induced complete tumor regression along with an abundant T cell infiltration into the solid tumor tissue and long‐term memory responses, without any detectable adverse events. In addition, as measures to control cytokine‐release syndrome and neurotoxicity which could occur in association with clinical use of CAR‐T cells, we incorporated Herpes simplex virus‐thymidine kinase (HSV‐TK), a suicide system to trigger apoptosis by administration of ganciclovir (GCV). HSV‐TK‐expressing anti‐GM2 IL‐7/CCL19‐producing human CAR‐T cells were efficiently eliminated by GCV administration in vivo. Conclusions: Our study revealed the promising therapeutic efficacy of anti‐GM2 IL‐7/CCL19‐producing human CAR‐T cells with an enhanced safety for clinical application in the treatment of patients with GM2‐positive solid cancers. [ABSTRACT FROM AUTHOR]

Purpose: Quantitative volumetric T1 mapping in the liver has the potential to aid in the detection, diagnosis, and quantification of liver fibrosis, inflammation, and spatially resolved liver function. However, accurate measurement of hepatic T1 is confounded by the presence of fat and inhomogeneous B1+$$ {B}_1^{+} $$ excitation. Furthermore, scan time constraints related to respiratory motion require tradeoffs of reduced volumetric coverage and/or increased acquisition time. This work presents a novel 3D acquisition and estimation method for confounder‐corrected T1 measurement over the entire liver within a single breath‐hold through simultaneous estimation of T1, fat and B1+$$ {B}_1^{+} $$. Theory and Methods: The proposed method combines chemical shift encoded MRI and variable flip angle MRI with a B1+$$ {B}_1^{+} $$ mapping technique to enable confounder‐corrected T1 mapping. The method was evaluated theoretically and demonstrated in both phantom and in vivo acquisitions at 1.5 and 3.0T. At 1.5T, the method was evaluated both pre‐ and post‐ contrast enhancement in healthy volunteers. Results: The proposed method demonstrated excellent linear agreement with reference inversion‐recovery spin‐echo based T1 in phantom acquisitions at both 1.5 and 3.0T, with minimal bias (5.2 and 45 ms, respectively) over T1 ranging from 200–1200 ms. In vivo results were in general agreement with reference saturation‐recovery based 2D T1 maps (SMART1Map, GE Healthcare). Conclusion: The proposed 3D T1 mapping method accounts for fat and B1+$$ {B}_1^{+} $$ confounders through simultaneous estimation of T1, B1+$$ {B}_1^{+} $$, PDFF and R2*$$ {R}_2^{\ast } $$. It demonstrates strong linear agreement with reference T1 measurements, with low bias and high precision, and can achieve full liver coverage in a single breath‐hold. [ABSTRACT FROM AUTHOR]

Here, we report a case of mediastinal mesenchymal tumor with a pericytic neoplasm feature that responded to radiation therapy. A 43‐year‐old man visited our hospital with a complaint of esophageal obstruction and chest pain. Chest computed tomography revealed a middle mediastinal tumor and a mesenchymal tumor was diagnosed with a pericytic neoplasm feature by video‐assisted thoracoscopic biopsy. The definitive treatment for soft tissue tumor is surgical resection; however, the mediastinal tumor was unresectable because of esophageal and tracheal invasion. Radiation therapy was administered and there was a partial tumor response and 2 years disease‐free status. With a review of the literature, we discuss the clinical and pathological characteristics of this rare tumor and its treatment. [ABSTRACT FROM AUTHOR]

Background: Although various new drugs have been developed for neurological diseases, many diseases have no effective treatment or only inadequate efficacy. Here we introduce some examples of effective Kampo treatment. Key Findings: (1) Parasomnia in the elderly is preceded by the onset of diffuse Lewy body disease, with symptoms such as nightmares and loud screaming in the middle of the night. Keishikaryukotsuboreito (KSTRB), indicated in the classics for treating parasomnia, was effective in alleviating the symptoms. KSTRB is also used for enuresis that persists into adulthood. (2) Chronic subdural hematomas (CSDHs), treated by hematoma removal with burr‐hole surgery, recur at a rate of up to 20%. Goreisan (GRS) reduces hematoma volume and prevents postoperative CSDH recurrence. Homogeneous CSDH was most responsive to GRS in preventing recurrence. (3) Migraine frequently interferes with daily life. Keishibukuryogan (KBG), which alleviates blood stasis, was effective for patients with both menstruation‐associated migraine and scintillating scotomas. (4) Many traditional herbal medicines are listed in the Korean Medicine Clinical Practice Guideline for Stroke in Korea. Chunghyuldan, a related formula of Orengedokuto (OGT), is mainly used to prevent stroke. Conclusion: Kampo medicine is being applied in new and effective ways to treat various neurological diseases. Hopefully, more clinicians will recognize the usefulness of such Kampo medicines and utilize them in their daily practice. [ABSTRACT FROM AUTHOR]

Background: The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression‐free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study. Methods: Progression‐free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Progression‐free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20–0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39–3.66). Overall survival adjusted for the imbalance of Memorial Sloan‐Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18–2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03–7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment‐emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms. Conclusions: These findings support lenvatinib plus pembrolizumab as a potential first‐line treatment for Japanese patients with advanced renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Constructing polaritonic devices in monolithic, ultra‐compact photonic architectures with monolayer‐featured exciton‐emitters is decisive to exploit the coherent superposition between entangled photonic and excitonic eigenstates for potential realizations of optical nonlinearities, macroscopic condensations, and superfluidity. Here, a feasible strategy for exciton‐polariton formations is demonstrated by implementing a Tamm‐plasmon (TP) polaritonic device with the active material composed of single‐monolayered perovskite (CsPbBr3) quantum dots (QDs). The metallic character of the TP configuration is able to concentrate its resonance mode into a confined region beyond the diffraction limit, which highly overlaps, both spatially and spectrally, with the single‐monolayered CsPbBr3 QDs embedded inside. The mode volume of the device is hence reduced dramatically, leading to an enhanced light–matter coupling strength for the polaritonic emission at room temperature. In particular, it is found that the dispersion relation of the TP polaritonic device is tunable by detuning the excitonic and photonic eigenmodes and that the polariton–polariton interaction energy is strongly dependent on the polariton's spin state. The presented strategy is a determinant step toward the realization of strong light–matter coupling and polariton spintronics in the CsPbBr3 QDs with a single‐monolayered feature. [ABSTRACT FROM AUTHOR]

Background: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC). It contains multiple tumor‐associated peptides (TUMAPs) that are naturally present in human cancers. Methods: In a phase I/II study, we treated a total of 10 Japanese patients with advanced RCC who were human leukocyte antigen A (HLA‐A)*02 +. Vaccination involved i.d. injection of GM‐CSF (75 μg), followed within 15–30 min by i.d. injection of IMA901 (containing 413 μg of each peptide). No treatment with either anticancer agents or immunosuppressants was allowed within 4 weeks before entering the trial. Patients were scheduled to receive 7 vaccinations during the first 5 weeks of treatment (induction period), followed by 10 further vaccinations at 3‐week intervals for up to 30 weeks (maintenance period). The primary endpoints were safety and tolerability, while the secondary endpoints were PFS, OS, and immunogenicity. Results: There were no treatment‐related serious adverse events or deaths during the study period. When the response was assessed after 4 months, 10% of patients showed a partial response, 80% had stable disease, and 10% had progressive disease. Among patients in whom the T‐cell response was analyzed, five patients showed a vaccine‐induced T‐cell response against at least one HLA class I‐restricted TUMAP and two patients had T‐cell responses to multiple TUMAPs. PFS was 5.5 months and OS was 18 months. Conclusions: This study demonstrated the safety and tolerability of IMA901 vaccine in Japanese RCC patients, and also showed that vaccination elicited an immune response. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between cleft width and otitis media (OM) and to determine whether a wide cleft palate (CP) is a risk factor of the incidence, type, amount of middle ear effusion, and prolonged morbidity in OM. Study Design: Retrospective cohort study. Methods: Children with CP who underwent palatoplasty between 2014 and 2018 were analyzed. Cleft width was measured at palatoplasty. The incidence of otitis media with effusion (OME) and acute otitis media (AOM), the type and amount of middle ear effusion, and OME duration and age at resolution were assessed in relation to cleft width. Results: One hundred eighteen children were included. The CP types were Veau I in 16, II in 35, III in 48, and IV in 19 patients. The incidence of OME and AOM before palatoplasty was 83.1% and 49.2%, respectively. Cleft width did not differ significantly between patients with or without OME but was significantly greater in those with, than in those without, AOM (p <.001), in those with mucoid, than in those with serous, effusion (p =.012), and in those with complete, than in those with partial, effusion (p =.01). Regardless of cleft width or type, OME persisted for a median duration of 50 months. Conclusions: Cleft width was significantly associated with the incidence of AOM and the type and amount of middle ear effusion before palatoplasty. However, it was not significantly related to the incidence, age at resolution, or duration of OME. Regardless of cleft width or type, OM in children with CP requires long‐term follow‐up. Level of Evidence: 2b. [ABSTRACT FROM AUTHOR]

The three major standard therapies, that is, surgery, chemotherapy, and radiation therapy have conventionally been applied to the treatments for cancers and have saved many patients. In addition, for intractable, refractory, or advanced malignancies that cannot be cured by the three standard therapies, immunotherapy is an important subject of basic and clinical researches. Immune checkpoint inhibitor therapy (ICI) has shown significant therapeutic efficacies on some types of tumors in large‐scale randomized clinical trials, making a major impact on clinical oncology by scientifically proving and establishing the effectiveness of an immunotherapy. In 2018, ICI was awarded the Nobel Prize in Physiology or Medicine, and immunotherapy is now becoming the "fourth" standard therapy for cancers. Recently, adoptive cell therapies, in which genetically modified T cells with enhanced reactivity against tumors are infused into the patients, have been attracting considerable attention as a hopeful immunotherapy following ICI. Particularly, chimeric antigen receptor (CAR)‐T‐cell therapies demonstrate marked therapeutic efficacies against some hematologic malignancies, and have been approved in many countries. However, current CAR‐T‐cell therapy is considered to be little effective against solid tumors, which is one of the challenging issues to be overcome in CAR‐T‐cell therapy. In this review, we at first introduce CAR and CAR‐T cell, and then focus on the recent progress of CAR‐T‐cell therapy against solid tumors as well as the novel concept on a role of CAR‐T cells, aiming to further understandings of the novel cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Spider silk has garnered attention as a structural material and a medical resource for next generation because it is tough, lightweight, and biodegradable. Nonwoven silk fabrics are emerging in research and industries owing to advanced electrospinning techniques. Several studies have reported nonwoven fabrics made of spider silk‐like proteins, which are originated from recombinant expression systems, with lower molecular weights than the natural counterpart. The lower molecular weight causes a lack of mechanical strength and durability, preventing the evaluation of industrial potential of the spider silk‐based nonwoven fabric to use as a structural and medical material. In this study, an electrospun nonwoven fabric is produced using native spider silk fibers forcibly reeled from live spiders. The spider silk‐based nonwoven fabrics demonstrate cell compatibility, and the mechanical properties are superior to the silkworm silk‐based nonwoven fabrics. The availability of spider silk‐based nonwoven fabrics introduces an unexplored set of potential uses, along with the context of sustainable development goals. [ABSTRACT FROM AUTHOR]

SUMMARY: Bud dormancy helps woody perennials survive winter and activate robust plant development in the spring. For apple (Malus × domestica), short‐term chilling induces bud dormancy in autumn, then prolonged chilling leads to dormancy release and a shift to a quiescent state in winter, with subsequent warm periods promoting bud break in spring. Epigenetic regulation contributes to seasonal responses such as vernalization. However, how histone modifications integrate seasonal cues and internal signals during bud dormancy in woody perennials remains largely unknown. Here, we show that H3K4me3 plays a key role in establishing permissive chromatin states during bud dormancy and bud break in apple. The global changes in gene expression strongly correlated with changes in H3K4me3, but not H3K27me3. High expression of DORMANCY‐ASSOCIATED MADS‐box (DAM) genes, key regulators of dormancy, in autumn was associated with high H3K4me3 levels. In addition, known DAM/SHORT VEGETATIVE PHASE (SVP) target genes significantly overlapped with H3K4me3‐modified genes as bud dormancy progressed. These data suggest that H3K4me3 contributes to the central dormancy circuit, consisting of DAM/SVP and abscisic acid (ABA), in autumn. In winter, the lower expression and H3K4me3 levels at DAMs and gibberellin metabolism genes control chilling‐induced release of dormancy. Warming conditions in spring facilitate the expression of genes related to phytohormones, the cell cycle, and cell wall modification by increasing H3K4me3 toward bud break. Our study also revealed that activation of auxin and repression of ABA sensitivity in spring are conditioned at least partly through temperature‐mediated epigenetic regulation in winter. Significance Statement: The active histone methylation mark H3K4me3 underpins the changes in expression of genes involved in metabolic pathways involving phytohormones, the cell cycle, and cell wall modification during bud dormancy and break in apple. This research uncovers an epigenetic mechanism that establishes a permissive chromatin state at critical regulators underlying floral bud dormancy progression and bud break in perennials. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate preliminary outcomes of a prospective trial of magnetic resonance imaging‐ultrasound fusion‐guided ultrafocal high‐dose‐rate brachytherapy in localized prostate cancer. Methods: In our prospective study, data from patients who underwent this treatment between April 1, 2020 and March 31, 2021 were analyzed. In the procedure, the applicator needle was inserted through the perineum to target the lesion on the multiparametric magnetic resonance imaging, which was fused onto the transrectal ultrasound image. The prescription dose was set at a single fraction of 19 Gy. Data from patients who received whole‐gland high‐dose‐rate brachytherapy were extracted and compared with data from patients who received ultrafocal high‐dose‐rate brachytherapy, to evaluate the frequency of acute adverse events. Results: Eight patients underwent ultrafocal high‐dose‐rate brachytherapy with a median observation period of 7.75 months (range 5.96–15.36 months). No acute genitourinary or gastrointestinal adverse events were observed in this cohort. The planned procedure was completed in all patients, and no unexpected adverse events were observed; however, prostate‐specific antigen failure was detected in one patient. In the 25 patients who underwent whole‐gland high‐dose‐rate brachytherapy, acute genitourinary and gastrointestinal adverse events were observed in 88% and 20% of the patients, respectively. Ultrafocal high‐dose‐rate brachytherapy was a significant factor in avoiding acute adverse genitourinary events in univariate and multivariate analyses (P < 0.001 and P = 0.032, respectively). Conclusions: Magnetic resonance imaging‐ultrasound fusion‐guided ultrafocal high‐dose‐rate brachytherapy in localized prostate cancer is a safe and feasible treatment without acute genitourinary and gastrointestinal adverse events. Long‐term observation and further investigation are warranted. [ABSTRACT FROM AUTHOR]

Head and forehead hyperhidrosis (HFH) is a disease that causes a large amount of sweating from the head region, and it significantly reduces patients' quality of life. Only a few reports have shown the effectiveness of botulinum toxin type A (BTX‐A) local injection therapy (BTX‐A therapy) for HFH. To clarify the benefits of BTX‐A for HFH, BTX‐A therapy was performed in 15 patients, and its efficacy was evaluated. The amount of sweating was measured by the ventilation capsule method and Minor's iodine‐starch test. Evaluation was also performed using the Hyperhidrosis Disease Severity Scale (HDSS) and the Dermatology Life Quality Index (DLQI). In most cases, a remarkable antiperspirant effect was observed from 2 weeks after the injection, and the effect lasted for approximately 30 weeks. HDSS and DLQI improved along with the decrease in sweating. Two patients (13.3%) complained of transient mild ptosis. There were no serious side‐effects. This study showed that BTX‐A therapy is a safe and effective treatment for HFH. [ABSTRACT FROM AUTHOR]

Aim: Currently, there is little evidence on the relationship between laughter and the risk of dementia, and since laughter is mainly a social behavior, we aimed to examine the association between various occasions for laughter and the risk of dementia in Japanese older adults. Methods: We draw upon 6‐year follow‐up data from the Japan Gerontological Evaluation Study, including 12 165 independent older adults aged 65 years or over. Occasions for laughter were assessed using a questionnaire, while dementia was diagnosed using the standardized dementia scale of the long‐term care insurance system in Japan. Cox proportional hazards models were estimated, yielding hazard ratios and 95% confidence intervals (CIs). Results: The multivariable hazard ratio of dementia incidence for all participants in the groups for high versus low variety of occasions for laughter was 0.84 (95% CI: 0.72–0.98, P for trend <0.001). A greater variety of occasions for laughter was associated with a lower risk of dementia 0.78 (95% CI: 0.63–0.96, P for trend <0.001) among women, but was less pronounced for men, with significant associations only for the medium group. Laughing during conversations with friends, communicating with children or grandchildren, and listening to the radio were primarily associated with decreased risk. Conclusion: A greater variety of laughter occasions in individual and social settings was associated with a reduced risk of dementia. Geriatr Gerontol Int 2022; 22: 392–398. [ABSTRACT FROM AUTHOR]

Purpose: T1‐weighted and T2‐weighted (T1w and T2w) imaging are essential sequences in routine clinical practice to detect and characterize a wide variety of pathologies. Many approaches have been proposed to obtain T1w and T2w contrast, although many challenges still remain, including long acquisition time and limitations that favor 2D imaging. In this study, we propose a novel method for simultaneous T1w and T2w imaging using RF phase‐modulated 3D gradient‐echo imaging. Theory: Configuration theory is used to derive closed‐form equations for the steady state of RF phase‐modulated gradient‐echo signal. These equations suggest the use of small RF phase increments to provide orthogonal signal contrast with T2w and T1w in the real and imaginary components, respectively. Background phase can be removed using a two‐pass acquisition with opposite RF phase increments. Methods: Simulation and phantom experiments were performed to validate our proposed method. Volunteer images of the brain and knee were acquired to demonstrate the clinical feasibility. The proposed method was compared with T1w and T2w fast spin‐echo imaging. Results: The relative signal intensity of images acquired using the proposed method agreed closely with simulations and fast spin‐echo imaging in phantoms. Images from volunteer imaging showed very similar contrast compared to conventional fast spin‐echo imaging. Conclusion: Radiofrequency phase‐modulated gradient‐echo with small RF phase increments is an alternative method that provides simultaneous T1w and T2w contrast in short scan times with 3D volumetric coverage. [ABSTRACT FROM AUTHOR]

Summary: DNA topoisomerase 1 (TOP1) plays general roles in DNA replication and transcription by regulating DNA topology in land plants and metazoans. TOP1 is also involved in specific developmental events; however, whether TOP1 plays a conserved developmental role among multicellular organisms is unknown.Here, we investigated the developmental roles of TOP1 in the moss Physcomitrium (Physcomitrella) patens with gene targeting, microscopy, 3D image segmentation and crossing experiments.We discovered that the disruption of TOP1α, but not its paralogue TOP1β, leads to a defect in fertilisation and subsequent sporophyte formation in P. patens. In the top1α mutant, the egg cell was functional for fertilisation, while sperm cells were fewer and infertile with disordered structures. We observed that the nuclei volume of wild‐type sperm cells synchronously decreases during antheridium development, indicating chromatin condensation towards the compact sperm head. By contrast, the top1α mutant exhibited attenuated cell divisions and asynchronous and defective contraction of the nuclei of sperm cells throughout spermatogenesis.These results indicate that TOP1α is involved in cell division and chromatin condensation during spermatogenesis in P. patens. Our results suggest that the regulation of DNA topology by TOP1 plays a key role in spermatogenesis in both land plants and metazoans. [ABSTRACT FROM AUTHOR]

Beet necrotic yellow vein virus (BNYVV) is the causal agent of rhizomania, the most serious sugar beet disease worldwide. Since the first finding in Japan in 1969, BNYVV became widespread throughout Hokkaido in a few decades and led to the introduction of Rz1‐resistant sugar beet cultivars in the 1990s. Here, we report the historical progress of the BNYVV epidemic in Hokkaido from 1969 to 2019. Previous analysis on samples from 1991 showed that BNYVV isolates were classified into three strains (named O, D, and T) based on the RNA3‐encoded p25 gene. The O‐type viruses were widely detected in Hokkaido, while the D‐ and T‐type viruses were detected in limited areas. The RNA5, encoding the p26 gene, was initially contained in some D‐ and O‐type isolates but not in any T‐type isolates. Interestingly, recent sample analysis revealed that RNA5‐containing T‐type viruses, seemingly more virulent than the other two strains, were widely detected in Hokkaido. Additionally, a small group of virus isolates harbouring a new p25 gene (named C) was found in limited areas. These results suggest that the T‐type viruses, which accompanied RNA5, have been preferentially spread from a limited area to other districts over the last few decades and that this spread might be strongly associated with the recent introduction of Rz1‐resistant sugar beet cultivars. BNYVV‐positive samples also contained mainly beet soil‐borne virus and traces of beet virus Q, both of which are the first to be recorded in Japan. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP), which is characterized by pancreatic enlargement and irregular narrowing of the main pancreatic duct, is difficult to differentiate from malignancy. The irregular narrowing of the pancreatic duct, which can be detected via endoscopic retrograde cholangiopancreatography, is a characteristic feature of AIP; however, distinguishing between localized AIP and pancreatic cancer based on pancreatic duct imaging is difficult. This study overviews the efficacy of endoscopic ultrasound (EUS)‐guided pancreatic sampling for the histopathological diagnosis of AIP. Recent enhancements in needle biopsy methodologies and technologies have contributed to improvement in the diagnostic efficacy of this technique. The guidance provided in this study for the histological diagnosis of AIP is anticipated to further advance in the histopathological diagnosis of AIP using EUS‐guided pancreatic sampling. [ABSTRACT FROM AUTHOR]

Aim: We have previously reported the therapeutic benefits of kamikihito for managing cancer‐related fatigue (CRF) in patients with hormone‐sensitive prostate cancer. Now, due to the routine use of enzalutamide and similar agents for treating castration‐resistant prostate cancer (CRPC), managing enzalutamide‐related fatigue is imperative. Here, we objectively evaluated the effectiveness of kamikihito on fatigue in CRPC patients receiving enzalutamide. Methods: Kamikihito was administered for 12 weeks to 11 patients receiving enzalutamide. We measured the changes in the levels of fatigue (using the Chalder Fatigue Scale (CFS)), depression (using the Center for Epidemiologic Studies Depression Scale (CES‐D)), oxidative stress (by measuring derivatives of reactive oxygen metabolites (d‐ROMs) and biological antioxidant potential (BAP) levels), various cytokines, insomnia (using actigraphy), and in‐vivo metabolites (by metabolomics analysis). Results: Kamikihito improved CFS and CES‐D scores, thus improving fatigue and depression in enzalutamide‐treated patients; however, it did not improve oxidative stress levels. Further, actigraphy showed prolongation of sleeping time, while the levels of various cytokines showed no change. Metabolomics analysis confirmed decrease in lipids and increase in amino acids that correlated with improvement in fatigue. Conclusion: Kamikihito corrected the abnormalities in lipid metabolism, which may have improved the production of amino acids, leading to reduced CRF in CRPC patients receiving enzalutamide. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is structurally and functionally distinct from other regions of the axon, yet alterations in the milieu of the AIS after brain injury have not been well characterized. In this study, we have examined extracellular and intracellular changes in the AIS after hypoglossal nerve injury. Microglial adhesions to the AIS were rarely observed in healthy controls, whereas microglial adhesions to the AIS became apparent in the axonal injury model. Regarding intra‐AIS morphology, we focused on mitochondria because mitochondrial flow into the injured axon appears critical for axonal regeneration. To visualize mitochondria specifically in injured axons, we used Atf3:BAC transgenic mice whose mitochondria were labeled with GFP in response to nerve injury. These mice clearly showed mitochondrial localization in the AIS after nerve injury. To precisely confirm the light microscopic observations, we performed three‐dimensional ultrastructural analysis using focused ion beam/scanning electron microscopy (FIB/SEM). Although the healthy AIS was not surrounded by microglia, tight microglial adhesions with thick processes adhering to the AIS were observed after injury. FIB/SEM simultaneously allowed the observation of mitochondrial localization in the AIS. In the AIS of non‐injured neurons, few mitochondria were observed, whereas mitochondria were abundantly localized in the cell body, axon hillock, and axon. Intriguingly, in the injured AIS, numerous mitochondria were observed throughout the AIS. Taken together, axonal injury changes the extracellular glial environment surrounding the AIS and intracellular mitochondrial localization in the AIS. These changes would be crucial responses, perhaps for injured neurons to regenerate after axonal injury. [ABSTRACT FROM AUTHOR]

The prevalence of primary axillary hyperhidrosis in Japan is 5.75% (males, 6.60%; females, 4.72%) in the population aged 5–64 years. No study on comprehensively evaluated direct medical costs, hygiene product costs, and productivity loss in axillary hyperhidrosis patients has been published in Japan. The aim of this study was to estimate the cost of illness for axillary hyperhidrosis in Japan by conducting a nationwide insurance claims database analysis and a cross‐sectional Web‐based survey. Among patients diagnosed with primary axillary hyperhidrosis at least once between November 2012 and October 2019, health insurance receipt data of 1447 patients were analyzed. A cross‐sectional Web‐based survey was conducted on 321 patients aged 16–59 years with axillary hyperhidrosis to calculate hygiene product costs and productivity loss using a Work Productivity and Activity Impairment questionnaire. Furthermore, nationwide estimation was performed for the hygiene product costs and productivity loss based on the number of patients estimated from the prevalence. The annual direct medical costs per axillary hyperhidrosis patient were ¥91 491 in 2016, ¥93 155 in 2017, and ¥75 036 in 2018. In all of these years, botulinum toxin type A injection accounted for approximately 90% of the total costs. The annual total cost of hygiene products per axillary hyperhidrosis patient was ¥9325. The overall work impairment (%) of working patients with axillary hyperhidrosis was 30.52%, and its monthly productivity loss was ¥120 593/patient. The activity impairment (%) of full‐time housewives with axillary hyperhidrosis was 49.05% and its monthly productivity loss was ¥176 368/patient. The annual hygiene product cost based on the nationwide estimation was ¥24.5 billion and the monthly productivity loss was ¥312 billion. The significant cost associated with axillary hyperhidrosis was clarified. If out‐of‐pocket expenses for treatments not covered by health insurance are included in the estimation, the cost will further increase. [ABSTRACT FROM AUTHOR]

It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize male mice expressing green fluorescence protein under the serotonin transporter (SERT) promoter to map the topography of serotonergic fibers across the rostro‐caudal extent of each brain area. We demonstrate previously unreported regional density and fine‐grained anatomy of serotonergic fibers. Our findings include: (a) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, (b) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, (c) unique, filamentous type of straight terminal fibers within the nucleus accumbens, (d) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, (e) cortical labeling density gradually decreases rostro‐caudally, (f) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and (g) most of the highly labeled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)‐T cell therapy has shown salient efficacy in cancer immunotherapy, particularly in the treatment of B cell malignancies. However, the efficacy of CAR‐T for solid tumors remains inadequate. In this study, we displayed that c‐met is an appropriate therapeutic target for papillary renal cell carcinoma (PRCC) using clinical samples, developed an anti‐human c‐met CAR‐T cells, and investigated the anti‐tumor efficacy of the CAR‐T cells using an orthotopic mouse model as pre‐clinical research. Administration of the anti‐c‐met CAR‐T cells induced marked infiltration of the CAR‐T cells into the tumor tissue and unambiguous suppression of tumor growth. Furthermore, in combination with axitinib, the anti‐tumor efficacy of the CAR‐T cells was synergistically augmented. Taken together, our current study demonstrated the potential for clinical application of anti‐c‐met CAR‐T cells in the treatment of patients with PRCC. [ABSTRACT FROM AUTHOR]

Tetrathionate hydrolase (4THase) plays an important role in dissimilatory sulfur oxidation in the acidophilic iron‐ and sulfur‐oxidizing bacterium Acidithiobacillus ferrooxidans. The structure of recombinant 4THase from A. ferrooxidans (Af‐Tth) was determined by X‐ray crystallography to a resolution of 1.95 Å. Af‐Tth is a homodimer, and its monomer structure exhibits an eight‐bladed β‐propeller motif. Two insertion loops participate in dimerization, and one loop forms a cavity with the β‐propeller region. We observed unexplained electron densities in this cavity of the substrate‐soaked structure. The anomalous difference map generated using diffraction data collected at a wavelength of 1.9 Å indicated the presence of polymerized sulfur atoms. Asp325, a highly conserved residue among 4THases, was located near the polymerized sulfur atoms. 4THase activity was completely abolished in the site‐specific Af‐Tth D325N variant, suggesting that Asp325 plays a crucial role in the first step of tetrathionate hydrolysis. Considering that the Af‐Tth reaction occurs only under acidic pH, Asp325 acts as an acid for the tetrathionate hydrolysis reaction. The polymerized sulfur atoms in the active site cavity may represent the intermediate product in the subsequent step. PDB Code(s): 6L8A and 7CQY; [ABSTRACT FROM AUTHOR]

Aims/Introduction: Continuous glucose monitoring (CGM) metrics, such as times in range (TIR) and time below range, have been shown to be useful as clinical targets that complement glycated hemoglobin (HbA1c) for patients with type 2 diabetes mellitus. We investigated the relationships between TIR, glycemic variability and patient characteristics in patients with type 2 diabetes mellitus. Materials and Methods: We carried out continuous glucose monitoring in 281 outpatients with type 2 diabetes mellitus who participated in a multicenter cohort (Hyogo Diabetes Hypoglycemia Cognition Complications) study. Results: The results are shown as the median (interquartile range). The age, disease duration and HbA1c were 68 years (62–71 years), 13 years (7–23 years) and 6.9% (6.5–7.5%), respectively. TIR and standard deviation obtained by continuous glucose monitoring worsened significantly with increasing disease duration. Multiple regression analyses showed that disease duration (standard partial regression coefficient, β = −0.160, P = 0.003), diabetic peripheral neuropathy (β = −0.106, P = 0.033) and urinary albumin excretion (β = −0.100, P = 0.043) were useful explanatory factors for TIR. In contrast, HbA1c (β = −0.398, P < 0.001) and the use of antidiabetic drugs potentially associated with severe hypoglycemia (β = 0.180, P = 0.028), such as sulfonylureas, glinides and insulin, were useful explanatory factors for time below range in the elderly patients with type 2 diabetes mellitus. Conclusions: The results of this study suggest that disease duration and diabetic complications are associated with TIR deterioration. In addition, low HbA1c levels and the use of antidiabetic drugs potentially associated with severe hypoglycemia might worsen the time below range in the elderly. [ABSTRACT FROM AUTHOR]

Beet necrotic yellow vein virus (BNYVV) generally has a four‐segmented positive‐sense RNA genome (RNAs 1–4), but some European and most Asian strains have an additional segment, RNA5. This study examined the effect of RNA5 and RNA3 on different sugar beet cultivars using a Polymyxa‐mediated inoculation system under field and laboratory conditions. In field tests, the degree of sugar yield served as an index for assessing the virulence of BNYVV strains. Japanese A‐II type isolates without RNA5 caused mostly 15%–90% sugar yield reductions, depending on the susceptibility of sugar beet cultivars, whereas the isolates with RNA5 induced more than 90% yield losses in the seven susceptible cultivars, but small yield losses in one Rz1‐resistant and Rizor cultivars. However, a laboratory‐produced isolate containing RNA5 but lacking RNA3 caused higher yield losses in Rizor than in susceptible plants, and induced scab‐like symptoms on the root surface of both susceptible and resistant plants. In laboratory tests, A‐II type isolates without RNA5 had low viral RNA accumulation levels in roots of Rizor and Rz1‐resistant plants at early stages of infection, but in the presence of RNA5, viral RNA3 accumulation levels increased remarkably. This increased RNA3 accumulation was not observed in roots of the WB42 accession with the Rz2 gene. In contrast, the presence of RNA3 did not affect RNA5 accumulation levels. Collectively, this study demonstrated that RNA5 is involved in the development of scab‐like symptoms and the enhancement of RNA3 accumulation, and suggests these characteristics of RNA5 are associated with Rz1‐resistance breaking. [ABSTRACT FROM AUTHOR]