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ABSTRACT Background The Asian Working Group for Cachexia (AWGC) proposed a new definition of cachexia; however, its impact on cachexia prevalence and overlaps with other conditions, such as sarcopenia and malnutrition, are unclear. We investigated these aspects and the prognostic value of cachexia based on the AWGC on mortality in older patients with heart failure (HF). Methods This study was a secondary analysis of a prospective multicentre cohort, namely, the FRAGILE‐HF cohort study. Older (≥ 65 years) patients who had been hospitalized due to decompensated HF were enrolled. We assessed the presence/absence of cachexia based on the AWGC and Evans' criteria. Sarcopenia and malnutrition based on the Asian Working Group for Sarcopenia 2014 and the Global Leadership Initiative on Malnutrition criteria were also assessed to compare their prevalence and the overlaps between them. Patients were stratified in relation to the presence/absence of cachexia based on the AWGC criteria, and their mortality rates were compared. Results Of the 861 enrolled patients (median [interquartile range] age, 80 years [73–85 years]; male, 58.9%), cachexia, as evaluated based on the AWGC and Evans' criteria, sarcopenia and malnutrition, was present in 74.1%, 36.2%, 20.6% and 55.2% of patients, respectively. AWGC‐defined cachexia was most common in the four conditions. All‐cause death events occurred in 153 (18.1%) patients in 2 years. AWGC‐defined cachexia (adjusted hazard ratio [aHRs], 1.442; 95% confidence interval [95% CI], 0.931–2.233; p = 0.101) was not associated with all‐cause mortality in older patients with HF after adjusting for other HF prognosis factors, such as the B‐type natriuretic peptide and the Meta‐Analysis Global Group in Chronic risk score, whereas cachexia evaluated based on Evans's criteria (aHRs, 1.547; 95% CI, 1.118–2.141; p = 0.009), sarcopenia (aHRs, 1.737; 95% CI, 1.214–2.485; p = 0.003), and malnutrition (aHRs, 1.581; 95% CI, 1.094–2.284; p = 0.015) was associated with all‐cause mortality. Conclusions Three‐quarters of older patients with HF had cachexia as evaluated by the AWGC criteria, and this was not associated with a worse prognosis. As the new AWGC cachexia criteria will result in a significantly larger proportion of patients being diagnosed with cachexia, the implementation of the criteria in clinical practice requires further consideration. Trial Registration: UMIN‐CTR unique identifier: UMIN000023929

Abstract Aims In heart failure (HF), inflammation is linked to malnutrition and impaired physical function. In this study, we aimed to assess how novel nutritional–inflammatory markers and lymphocyte‐to‐C‐reactive protein ratio (LCR) and score (LCS) are associated with the nutritional status, physical function, and prognosis of patients with HF. Methods and results This study was a secondary analysis of the FRAGILE‐HF study, a prospective observational study conducted across 15 hospitals in Japan. We included 1212 patients (mean age, 80.2 ± 7.8 years; 513 women) hospitalized with HF, who were classified into three groups according to their LCS score: 0 (n = 498), 1 (n = 533), and 2 (n = 181). Baseline data on physical examination, echocardiography, blood test results (including lymphocyte counts and CRP levels), and oral medication usage were collected in a clinically compensated state before discharge. Nutritional status and physical function were evaluated using several indices and tests. The primary outcome of this study was all‐cause death within 2 years. Univariate and multivariate linear regression analyses were performed to evaluate the associations among the nutritional status, physical function, and LCR/LCS. Patients with an LCS score of 2 were older and had a lower body mass index than those in the other two groups. Multivariate linear regression analysis revealed that lower LCR and higher LCS were independently associated with worse nutritional status, lower handgrip strength, shorter physical performance battery score, and shorter 6‐min walk distance. At 2 years, all‐cause death occurred in 254 patients: 86 (17.6%), 113 (21.5%), and 55 (30.9%) with LCS scores of 0, 1, and 2, respectively (P = 0.001). Cox proportional hazards analysis revealed that LCR and LCS were significantly associated with 2‐year mortality even after adjusting for the conventional risk model (LCS score, 0 vs. 2: hazard ratio, 1.64; 95% confidence interval [CI]; 1.14–2.35; P = 0.007; log‐transformed LCR: hazard ratio, 0.88; 95% CI, 0.81–0.95; P = 0.002). LCR yielded additional prognostic predictability compared with the conventional risk model (continuous net reclassification improvement, 0.153; 95% CI, 0.007–0.299; P = 0.041). Conclusions LCR and LCS emerge as potential predictors of nutritional status, physical function, and prognosis in older patients with HF.

Abstract We use three-dimensional culture systems of human pluripotent stem cells for differentiation into pituitary organoids. Three-dimensional culture is inherently characterized by its ability to induce heterogeneous cell populations, making it difficult to maintain constant differentiation efficiency. That is why the culture process involves empirical aspects. In this study, we use deep-learning technology to create a model that can predict from images of organoids whether differentiation is progressing appropriately. Our models using EfficientNetV2-S or Vision Transformer, employing VENUS-coupled RAX expression, predictively class bright-field images of organoids into three categories with 70% accuracy, superior to expert-observer predictions. Furthermore, the model obtained by ensemble learning with the two algorithms can predict RAX expression in cells without RAX::VENUS, suggesting that our model can be deployed in clinical applications such as transplantation.

Basilar artery (BA) fenestration and its occlusion are relatively rare conditions. Mechanical thrombectomy for fenestrated BA occlusion has a high risk of complications. One limb occlusion or partial occlusion of fenestration mimics arterial stenosis or dissection. We present the case of a 75-year-old woman who presented with slight dysarthria, which subsequently worsened. Magnetic resonance imaging, magnetic resonance angiography, and basi-parallel anatomical scanning (BPAS) revealed BA fenestration and occlusion of the larger limb of the fenestrated BA, for which we performed thrombectomy with aspiration and achieved Thrombolysis in Cerebral Infarction Grade 3 flow restoration without procedure-related complications. If BA occlusion occurs at a site where a thrombus does not normally occur, confirming the anatomy of the BA before thrombectomy is desirable. As we obtained information on BA fenestration and occluded limb diameter using preoperative BPAS, we were able to safely achieve effective recanalization by guiding a relatively large-diameter aspiration catheter to the thrombus coaxially with a micro-guidewire and microcatheter.

Introduction: Disc degeneration is a risk factor of pyogenic spondylitis. However, its degree in patients with pyogenic spondylitis is unknown. This study aimed to determine differences in disc degeneration between patients with pyogenic spondylitis and those with noninfectious lumbar spondylosis. Methods: A total of 85 patients with lumbar pyogenic spondylitis (the infected group) and 156 with lumbar spondylosis who underwent posterior lumbar interbody fusion (the noninfected group) were retrospectively evaluated. Patients with a previous history of spinal fusion, tuberculous spondylitis, and multilevel infection and those receiving dialysis were excluded. Magnetic resonance imaging of the lumbar spine was conducted. Each disc at the L1/2-L5/S levels was graded. The total score of the four discs, excluding the affected disc, was used as the modified disc degenerative disease (DDD) score. Propensity score matching was performed using independent variables such as age, sex, diabetes mellitus, cancer, and steroid use. The modified DDD scores at all and each disc level were compared between the two matched groups. Results: After matching, 48 patients in the infected group and 88 in the noninfected group were finally included in the study. The mean modified DDD scores of the infected and noninfected groups were 7.63 and 5.40, respectively. The modified DDD scores at all and each disc level were higher in the infected group than in the noninfected group. Conclusions: The incidence of disc degeneration at all and each disc level was higher in patients with pyogenic spondylitis than in those with noninfectious lumbar spondylosis.

Introduction: Patients with adult spinal deformity (ASD) lean forward with their trunks when walking, even if they can remain upright during static standing. However, it remains unclear which part of the spinal column is involved in forward trunk tilt and the details of the relationships between sagittal alignment during static standing and changes in dynamic parameters during walking. Therefore, this study aimed to clarify the above by analyzing the walking motion of ASD patients using inertial measurement units (IMUs). Methods: Preoperative ASD patients were included in this study. Dynamic parameters during gait were measured by IMUs attached on the skin at the T1, T12, and S1 spinous processes, thigh, and lower leg. Walking data were divided into three phases of 10 s each (initial, middle, and final), and the average dynamic parameters at each phase were statistically compared. The relationships between the standing radiographic and dynamic parameters in the final phase were evaluated by linear regression analyses. Results: A total of 34 patients were included in this study. Their mean age was 72 years. The inclination of IMUs on the T1, T12, and S1 and the flexion angle of T12-S1 IMUs significantly increased over time. Pelvic tilt (PT) of standing radiography was positively correlated with the inclination angles of T12 (r2=0.22, p=0.0048) and S1 (r2=0.16, p=0.0178) and the flexion angle of T12-S1 IMUs (r2=0.29, p=0.0011). Conclusions: This study showed that anteversion of the trunk in patients with ASD is due to an increase in lumbar forward bending and anterior tilt of the pelvis. Lumbar forward bending was significantly correlated with PT on standing radiography. It is important to consider the presence of poorer posture during gait than during standing when we evaluate patients with high PT.

Abstract Background The potential of carbon ion radiation therapy (CIRT) as a curative treatment for localized prostate cancer (PCa) has garnered attention due to its characteristic dose distribution. We prospectively collected and analyzed over five years to investigate the outcomes of localized PCa treated with CIRT at our institution. Patients and methods The study included patients with histologically confirmed prostate adenocarcinoma. CIRT treatment was administered at a total dose of 57.6 Gy (RBE) in 16 fractions over four weeks. Uroflowmetry (UFM) and residual urine measurements were performed at various time points: before CIRT treatment, one month after starting CIRT, three months after treatment, and annually for five years starting from 1 year after the completion of CIRT. Prostate volume was measured using transrectal ultrasonography (TRUS). Results A total of 304 prostate cancer patients were analyzed. UFM parameters were significantly worsened immediately after the treatment. However, they recovered to pretreatment levels after three months and remained stable until five years post-treatment. Notably, Average flow rate showed significant improvement after three years of treatment compared to before the treatment. Prostate volume decreased to 80% of baseline in patients treated with CIRT alone and to 60–70% of baseline in those receiving combined CIRT and either short- or long-term ADT. The logistic-binomial analysis identified post-voiding residual urine volume (PVR) as a significant factor for predicting adverse events in the acute phase. Conclusions Following CIRT treatment, the voiding parameters in PCa patients significantly deteriorated immediately. However, after three months, they returned to their pre-treatment levels and remained stable for five years.

Purpose The study aimed to compare the diagnostic performance of washout-parametric imaging (WOPI) with that of conventional contrast-enhanced ultrasound (cCEUS) in differentiating focal liver lesions (FLLs). Methods A total of 181 FLLs were imaged with contrast-enhanced ultrasound using Sonazoid, and the recordings were captured for 10 minutes in a prospective setting. WOPI was constructed from three images, depicting the arterial phase (peak enhancement), the early portal venous phase (1-minute post-injection), and the vasculo-Kupffer phase (5 or 10 minutes post-injection). The intensity variations in these images were color-coded and superimposed to produce a single image representing the washout timing across the lesions. From the 181 FLLs, 30 hepatocellular carcinomas (HCCs), 30 non-HCC malignancies, and 30 benign lesions were randomly selected for an observer study. Both techniques (cCEUS and WOPI) were evaluated by four off-site readers. They classified each lesion as benign or malignant using a continuous rating scale, with the endpoints representing "definitely benign" and "definitely malignant." The diagnostic performance of cCEUS and WOPI was compared using the area under the receiver operating characteristic curve (AUC) with the DeLong test. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). Results The difference in average AUC values between WOPI and cCEUS was 0.0062 (95% confidence interval, -0.0161 to 0.0285), indicating no significant difference between techniques. The interobserver agreement was higher for WOPI (ICC, 0.77) than cCEUS (ICC, 0.67). Conclusion The diagnostic performance of WOPI is comparable to that of cCEUS in differentiating FLLs, with superior interobserver agreement.

Abstract Background We conducted a prospective observational study to elucidate the long-term prognosis and management of chronic obstructive pulmonary disease (COPD) in clinical practice in Japan in the mid-2010s. Methods This prospective cohort study included 29 facilities. Data from 427 patients clinically diagnosed with COPD, enrolled between September 2013 and April 2016, were analyzed. Interstitial pneumonia was excluded through a central multidisciplinary discussion. Follow-up data were collected for up to 5 years after patient registration. Results At the time of registration, 53 patients clinically diagnosed with COPD did not have airflow limitation (AFL). In the cohort with AFL (n = 374), 232 patients completed a 5-year follow-up, while 49 patients died during the 1576.6 person-years of observation. The mean age was 71.7 years with an overall 5-year survival rate of 85.4%. Stratified by % forced expiratory volume in one second (FEV1), survival rates were 93.6% in the mild and moderate AFL group, 82.5% in the severe AFL group, and 66.1% in the very severe AFL group. The prognosis of the subpopulation without AFL was poor with a 5-year survival of 81.6%. This subpopulation exhibited respiratory symptoms, low vital capacity and total lung capacity, and emphysematous changes. Conclusions Our study presents the 5-year survival and real-world clinical practice scenario of a prospective cohort of patients clinically diagnosed with COPD in Japan in the mid-2010s. The survival rates of our cohort were numerically better than the Japanese cohort in the 1990s, regardless of the high median age of this cohort. Overall, 12.4% of the patients in this cohort with no AFL at registration exhibited respiratory symptoms and distinct spirometric patterns, and had a poor prognosis.

Abstract Background Lateral lumbar interbody fusion (LLIF) via a retroperitoneum approach has gained popularity due to minimal invasiveness, which avoids resection of the spinous process and laminae. However, as challenges in grafting autogenous bone persist, artificial bone has been tested in Japan to fill the spinal cage. Platelet-rich plasma (PRP) contains growth factors and anti-inflammatory cytokines to promote cellular proliferation and repair damaged tissues. While the effects of PRP on tendon and ligament repair are widely known, any effects on bone healing are scarcely reported. However, PRP-loaded artificial bone carries potential to improve intervertebral bone fusion. Objective This study assessed whether PRP enhances intervertebral bone fusion in LLIF surgery using β-tricalcium phosphate artificial bone. Methods The current study was a prospective, randomized, controlled trial. We evaluated 13 consecutive patients undergoing LLIF surgery in our hospital. Patients received artificial bone impregnated with PRP or without PRP within the same fusion cage. The primary outcome was the intervertebral bone fusion rate at 6 and 12 months postoperatively, evaluated using CT imaging. The intervertebral bone fusion rates with and without PRP loading and with and without contact part between the endplate and the artificial bone were compared. Secondary outcomes included clinical evaluations using visual analog scale scores for low back pain, buttock-leg pain, and leg numbness from the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOA-BPEQ) and the Oswestry Disability Index (ODI), plus adverse events information. Results Of the 13 patients (29 vertebral segments) included, bone fusion was observed in 43.4% of the PRP group and 26.1% of the non-PRP group at 6 months (p = 0.216). At 12 months, fusion rates were 60.9% with PRP and 34.8% without PRP (p = 0.074). The fusion rate was significantly higher in cases with good contact between the vertebral endplate and the artificial bone (p = 0.0004). Clinical scores improved postoperatively. Adverse events were in accordance with expectations from LLIF surgery and no PRP-specific events occurred. Conclusion PRP did not significantly improve intervertebral bone fusion rates in LLIF surgeries, particularly in cases with poor contact between the vertebral endplate and artificial bone. While PRP may have a limited role in enhancing bone fusion, maintaining good contact between the vertebral endplate and artificial bone is crucial for successful outcomes. Further research is needed to explore optimal uses of PRP in spinal fusion surgeries.

Abstract Background Although subdural hematoma is a rare complication after spinal anesthesia, there have been no reports of an intracranial epidural hematoma after cesarean section with spinal anesthesia. Case presentation A 32-year-old nulliparous woman at the 35th week of a twin pregnancy underwent an emergency cesarean section due to her first contraction. She had no preoperative complications and the spinal anesthesia was uneventful, with 0.5% bupivacaine 12 mg and fentanyl 15 µg from the L3/4 intervertebral space. She complained of headache and nausea 15 min after spinal anesthesia, demonstrating a consciousness disturbance after surgery. Computed tomography 2 h after the cesarean section revealed an intracranial epidural hematoma. She underwent decompressive craniotomy 1 h later. Conclusion This case highlights the possible development of an intracranial epidural hematoma in low-risk obstetric patients.

Abstract Aims Knowing the upper time limit for successful weaning from temporary mechanical circulatory support in cardiogenic shock will help with decision‐making regarding advanced heart failure (HF) therapy or considering withdrawal of care. The aim of this study was to investigate the association between the support duration and successful weaning from veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) in patients with cardiogenic shock. Methods and results A retrospective single‐centre cohort study was conducted between January 2013 and June 2023. It included 100 consecutive patients with cardiogenic shock who were treated with VA‐ECMO. Patients with out‐of‐hospital cardiac arrest were excluded. The primary outcome was successful weaning from VA‐ECMO (i.e., VA‐ECMO decannulation and survival to discharge). The association between the length of support duration and the weaning success rate was analysed. Patients were divided into three groups according to ECMO support duration: Group A (≤7 days), Group B (8–14 days), and Group C (≥15 days). Multivariable logistic regression analysis was used to evaluate the impact of the length of support duration on successful weaning of VA‐ECMO. The median age was 67 years, and 73% of study participants were male. The underlying aetiologies of cardiogenic shock were as follows: acute myocardial infarction, 50; fulminant myocarditis, 19; cardiomyopathy, 15; valvular heart disease, 8; and other, 8. Seventy‐five patients (75%) were attempted to wean VA‐ECMO, and 67 moved on to decannulation. In total, 43 (43%) patients were successfully weaned from VA‐ECMO. The median length of ECMO support duration was 8 [3–15] days. Compared with those who underwent successful ECMO decannulation, those who did not had a significantly longer support duration of VA‐ECMO (5 [3–9] days vs. 12 [3–22] days, P = 0.004). The weaning success rate was significantly higher in patients with short support duration; 58% (29/50), 40% (10/25), 16% (4/25) in Groups A, B, and C, respectively (P = 0.002). Overall, none of the patients supported for over 24 days (0/11) were successfully weaned from VA‐ECMO. On multivariable logistic regression analysis, the length of support duration was independently associated with successful weaning after adjusting for age, sex, underlying aetiology, and left ventricular ejection fraction (odds ratio, 0.813 [per 3 days]; 95% confidence interval, 0.679–0.914; P = 0.025). Conclusions Long support duration of VA‐ECMO was significantly associated with a low rate of successful weaning in patients with cardiogenic shock. Patients who require VA‐ECMO for over 1 week should start considering advanced HF therapy or withdrawal of care.

Abstract Aims Mitral stenosis (MS) occasionally coexists with aortic stenosis (AS). Limited data are available regarding the functional class and clinical outcomes of patients who undergo transcatheter aortic valve implantation (TAVI) for combined AS and MS. This study compared the clinical outcomes in patients with and without MS who underwent TAVI for severe AS and assessed the impact of mitral annulus calcification (MAC) severity, transmitral gradient (TMG) and mitral valve area (MVA) on outcomes in patients with combined AS and MS. Methods We investigated patients in the OCEAN‐TAVI registry who underwent TAVI. MS was defined as an MVA ≤ 1.5 cm2 or TMG ≥ 5 mmHg. The composite of all‐cause death and admission for heart failure was compared between patients with and without MS. The impact of MAC, TMG and MVA on outcomes was assessed in patients with combined AS and MS. Results We identified 106 patients with MS (MAC 84%; TMG 6.4 ± 2.6 mmHg; MVA 1.10 ± 0.31 cm2) and 6570 without MS as controls. The MS group was older (85 ± 5 vs. 84 ± 5 years, P = 0.033), more of women (85 vs. 67%, P

Abstract Aims Left atrial (LA) volume index (LAVI) in chronic heart failure (HF) predicts cardiovascular outcomes. However, the association between LAVI reduction during acute decompensated HF (ADHF) and its prognostic potential is limited. We hypothesized that LA reverse remodelling (LARR) after ADHF therapy would be associated with better clinical outcomes. Methods This retrospective study analysed clinical outcomes and the LAVI reduction rate of 363 out of 861 patients hospitalized for ADHF who underwent two‐point echocardiography at admission and discharge between January 2015 and December 2019. The mean age was 74.3 ± 13.6 years, and the mean ejection fraction (EF) was 38.9 ± 15.2%. The follow‐up echocardiogram was performed 13.0 [9.5, 20] days after admission. As the median LAVI reduction rate was 7.02%, the LARR was defined as an LAVI reduction rate >7%. Results During the 34.0 ± 20.2 months of follow‐up, 117 patients (32.2%) reached the primary endpoint defined as cardiovascular death and rehospitalization for ADHF. Kaplan–Meier survival analysis showed that patients with LARR had a better prognosis. Multivariate analysis indicated that LARR was an independent predictor of cardiovascular events. Similar findings were observed in the subgroup analyses of patients with persistent/permanent atrial fibrillation and those with non‐HF with reduced EF. Among patients who were brain natriuretic peptide (BNP) responders, defined as a relative reduction of >70% in BNP from admission to discharge, non‐LARR was observed in 41.6%. BNP responders without LARR experienced worse prognoses. Conclusions LARR in the early vulnerable phase after hospitalization for ADHF was associated with better long‐term clinical outcomes.

Abstract Neutrino detectors are among the largest photon detection instruments, built to capture scarce photons upon energy deposition. Many discoveries in neutrino physics, including the neutrino itself, are inseparable from the advances in photon detection technology, particularly in photo-sensors and readout electronics, to yield ever higher precision and richer detection information. The measurement of the energy of neutrinos, referred to as calorimetry, can be achieved in two distinct approaches: photon-counting, where single-photon can be counted digitally, and photon-integration, where multi-photons are aggregated and estimated via analogue signals. The energy is pursued today to reach permille level systematics control precision in ever-vast volumes, exemplified by experiments like JUNO. The unprecedented precision brings to the foreground the systematics due to calorimetric response entanglements in energy, position and time that were negligible in the past, thus driving further innovation in calorimetry. This publication describes a novel articulation that detectors can be endowed with multiple photon detection systems. This multi-calorimetry approach opens the notion of dual-calorimetry detector, consisting of both photon-counting and photon-integration systems, as a cost-effective evolution from the single-calorimetry setups used over several decades for most experiments so far. The dual-calorimetry design exploits unique response synergies between photon-counting and photon-integration systems, including correlations and cancellations in calorimetric responses, to maximise the mitigation of response entanglements, thereby yielding permille-level high-precision calorimetry.

Abstract Kidney organoids are connected to the host circulation and mature after transplantation. However, they are still immature compared to the adult kidneys, and their precise maturation stages remain unclear. By transplanting the mouse embryonic kidney as a model system for organoid transplantation, we report here the maturation defects of the graft, especially in the medulla. Single cell profiling of the developing kidneys in vivo identified gene sets associated with the maturation of the collecting duct epithelium and medullary stroma. These data revealed an upregulation of genes associated with channel/transporter functions and immune defense, as well as a downregulation of neuronal genes. Using these marker genes, we found that the maturation of the collecting duct and medullary stroma in the grafts barely corresponds to the perinatal stage, which was confirmed histologically by using representative genes. Thus, the gene sets obtained serve as maturation coordinates for the renal medulla and will be helpful in analyzing its maturation defects after transplantation. They will also provide a useful basis for further maturation of transplanted kidney organoids.

Abstract There is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in humans. The gut MPS/Fluid3D-X model was constructed using a newly developed flow-controllable and dimethylpolysiloxane-free MPS device (Fluid3D-X®). Human induced pluripotent stem cells-derived small intestinal epithelial cells were employed in this model, which exhibited key characteristics of the human absorptive epithelial cells of the small intestine, including the expression of key gene transcripts responsible for drug transport and metabolism, and the presence of dome-like protrusions in the primary intestinal epithelium under air-liquid interface culture conditions. Functional studies of transporters in the constructed model demonstrated basal-to-apical directional transport of sulfasalazine and quinidine, substrates of the active efflux transporters breast cancer resistance protein and P-glycoprotein, respectively, which were diminished by inhibitors. Furthermore, a cytochrome P450 (CYP) 3A inhibitor increased the apical-to-basal transport of midazolam, a typical CYP3A4 substrate, and reduced metabolite formation. These results suggest that gut MPS/Fluid3D-X has the potential to assess the intestinal absorption of small-molecule drugs.

Abstract The functional significance of the morphological and genetic changes that occurred in the brain during evolution is not fully understood. Here we show the relationships between evolutionary changes of the brain and glymphatic circulation. We establish a mathematical model to simulate glymphatic circulation in the cerebral hemispheres, and our results show that cortical neurons accumulate in areas of the cerebral hemispheres where glymphatic circulation is highly efficient. We also find that cortical folds markedly enhance the efficiency of glymphatic circulation in the cerebral hemispheres. Furthermore, our in vivo study using ferrets reveals sulcus-dominant cerebrospinal fluid (CSF) influx, which enhances the efficiency of glymphatic circulation in the enlarged cerebral hemispheres of gyrencephalic brains. Sulcus-dominant CSF influx is mediated by preferential expression of aquaporin-4 in sulcal regions, and similar expression patterns of aquaporin-4 are also found in human cerebral hemispheres. These results indicate that evolutionary changes in the cerebral hemispheres are related to improved efficiency of glymphatic circulation. It seems plausible that the efficiency of glymphatic circulation is an important factor determining the evolutionary trajectory of the cerebral hemispheres.

Abstract Beta-catenin is essential for diverse biological processes, such as body axis determination and cell differentiation, during metazoan embryonic development. Beta-catenin is thought to exert such functions through complexes formed with various proteins. Although β-catenin complex proteins have been identified in several bilaterians, little is known about the structural and functional properties of β-catenin complexes in early metazoan evolution. In the present study, we performed a comparative analysis of β-catenin sequences in nonbilaterian lineages that diverged early in metazoan evolution. We also carried out transphyletic function experiments with β-catenin from nonbilaterian metazoans using developing Xenopus embryos, including secondary axis induction in embryos and proteomic analysis of β-catenin protein complexes. Comparative functional analysis of nonbilaterian β-catenins demonstrated sequence characteristics important for β-catenin functions, and the deep origin and evolutionary conservation of the cadherin–catenin complex. Proteins that co-immunoprecipitated with β-catenin included several proteins conserved among metazoans. These data provide new insights into the conserved repertoire of β-catenin complexes.

ABSTRACT Aim Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear. Materials and Methods This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure. Results At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time. Conclusions The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes.

ABSTRACT Aims/Introduction We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic β‐cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the β‐cell mass and function of long‐term high‐fat, high‐sucrose (HFHS) diet‐fed mice. Materials and Methods Four‐week‐old male glucokinase haploinsufficient (Gck+/−) mice and 4‐week‐old male wild‐type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet‐fed group and a normal chow‐fed group, and the four groups were followed until 16, 40 or 60 weeks‐of‐age. Their glucose tolerance, glucose‐stimulated insulin secretion and β‐cell mass were evaluated. In addition, islets were isolated from 40‐week‐old mice, and the expression of key genes was compared. Results Gck+/−HFHS mice had smaller compensatory increases in β‐cell mass and glucose‐stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks‐of‐age. However, their β‐cell mass and glucose‐stimulated insulin secretion did not decrease between 40 and 60 weeks‐of‐age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in β‐cell function, was high in Gck+/+HFHS mice, but not in Gck+/−HFHS mice. Conclusions Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic β‐cell mass/function and glucose tolerance in long‐term HFHS diet‐fed mice.

ABSTRACT Aims/Introduction The 2023 Delphi consensus recommended the use of new term, metabolic dysfunction‐associated steatotic liver disease (MASLD), aiming conceptual shift from the conventional non‐alcoholic fatty liver disease (NAFLD). The association between NAFLD and type 2 diabetes mellitus (T2DM) development is well known. This study aimed to examine the correlation between MASLD and T2DM development, comparing their utility as predictors. Materials and Methods This retrospective cohort study obtained data from a medical health checkup program conducted at Asahi University Hospital, Japan, between 2004 and 2021. Logistic regression analysis was used to assess the association between MASLD and incident T2DM over 5 years. To compare the predictive utility of NAFLD and MASLD, receiver operating characteristic curves were drawn, followed by area under the curve (AUC) comparisons. Results In total, 15,039 participants (59.6% males; median [interquartile range {IQR}] age, 44 [38, 50] years) were included. Out of 2,682 participants meeting the criteria for MASLD, 234 individuals (8.7%) developed T2DM. Multivariate analysis revealed a significantly elevated risk of T2DM in MASLD compared with the reference healthy group (without steatotic liver disease or cardiometabolic risk), presenting an OR of 127.00 (95% CI 40.40–399.00, P

ABSTRACT Aims Despite the reported success of low‐carbohydrate diets in improving glycemic control in the Western countries, no studies have investigated the effects of such diets in Asians. We aimed to conduct a systematic review and meta‐analysis of randomized controlled trials to examine the effects of low‐carbohydrate diets on glycemic control in East Asian adults. Materials and Methods We systematically searched the PubMed, Cochrane Library, and Embase databases from inception to June 28, 2023, to identify randomized controlled trials examining the efficacy of low‐carbohydrate diets in patients with type 2 diabetes (PROSPERO number CRD 42023453007). The primary outcome was the difference in glycated hemoglobin levels between the low‐carbohydrate diet and control groups. The secondary outcome was the difference in body mass index, fasting blood glucose level, blood pressure, and lipid profile. Results Six randomized controlled trials met the eligibility criteria. The study duration ranged from 3 to 18 months, with five studies conducted within 6 months. The results showed that low‐carbohydrate diets were more beneficial in lowering glycated hemoglobin levels and body mass index than control diets. The risk of bias for the six studies was minimal for two and moderate for four. The heterogeneity among the studies was low. Conclusions Low‐carbohydrate diets improved glycated hemoglobin levels and body mass index in East Asians compared with control diets. Therefore, carbohydrate restriction may be effective for glycemic management in East Asians with type 2 diabetes for at least 6 months.

The TGF‐β superfamily plays a pivotal role in the regulation of adipogenesis, but little is known about the potential differential role of the three isoforms of TGF‐β, TGF‐β‐1~3. To further elucidate their role, two‐dimensionally (2D) and three‐dimensionally (3D) cultured 3T3‐L1 mouse preadipocytes were subjected to the following analyses: (a) qPCR analysis of adipogenesis‐related factors and major extracellular matrix protein (2D and /or 3D), (b) lipid staining by Oil Red O (2D) or BODIPY (3D), (c) Seahorse cellular metabolic measurement (2D), and (d) size and stiffness measurements of 3D 3T3‐L1 spheroids. In the 2D cultured 3T3‐L1 cells, mRNA expression levels of adipogenesis‐related genes and Oil Red O lipid staining intensity were significantly increased by adipogenesis and they were substantially decreased following treatment with 0.1 nm TGF‐β isoforms, with TGF‐β2 having the greater effects. Consistent with these results, treatment with TGF‐β2 resulted in suppression of mitochondrial and glycolytic functions in 2D cultured 3T3‐L1 cells. However, the inhibitory effect of TGF‐β on adipogenesis decreased under 3D spheroid culture conditions and TGF‐β isoforms did not affect adipogenesis‐induced (a) enlargement and downsizing of 3T3‐L1 spheroids, (b) increase in BODIPY lipid staining intensity, and (c) up‐regulation of the mRNA expression of adipogenesis‐related genes. The findings presented herein suggest that the three TGF‐β isoforms have different suppressive effects on adipogenesis‐related cellular properties of 2D cultured 3T3‐L1 cells and that their effects decrease under 3D spheroid culture conditions.

Abstract Aim Overweight is associated with low‐grade systemic inflammation. However, its effect on neuroinflammation remains unclear. We examined the possible association between overweight and neuroinflammation using cerebrospinal fluid (CSF) in a nonclinical adult population in Japan. Methods CSF and plasma levels of interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), plasma levels of C‐reactive protein (CRP), and leptin were measured in nonclinical adult participants (35 males and 34 females) who had no current or past history of neuropsychiatric diseases. We performed partial correlation analyses with sex and age as covariates between the body mass index (BMI) and the inflammatory markers and compared them between overweight and nonoverweight participants. Results The BMI significantly correlated with CSF levels of IL‐6 (rs = 0.32, p = 0.009), plasma levels of CRP (rs = 0.30, p = 0.016), IL‐1β (rs = 0.29, p = 0.019), IL‐6 (rs = 0.25, p = 0.042), TNF‐α (rs = 0.43, p

Objective: The risk factors for residual liver recurrence after resection of colorectal cancer liver metastases were analyzed separately for synchronous and metachronous metastases. Methods: This retrospective study included 236 patients (139 with synchronous and 97 with metachronous lesions) who underwent initial surgery for colorectal cancer liver metastases from April 2010 to December 2021 at the Fujita Health University Hospital. We performed univariate and multivariate analyses of risk factors for recurrence based on clinical background. Results: Univariate analysis of synchronous liver metastases identified three risk factors: positive lymph nodes (p = 0.018, HR = 2.067), ≥3 liver metastases (p

Migratory birds carry ticks harboring various pathogens, including the zoonotic Yezo virus. In Hokkaido, Japan, we collected ticks from migratory birds during 2020–2021. Eight of 385 pools, comprising 2,534 ticks, tested positive for Yezo virus RNA, suggesting Yezo virus might be spread through the flyways of migratory birds.

Despite the global implementation of COVID-19 mitigation measures, the disease continues to maintain transmission. Although mask wearing became one of the key measures for preventing the transmission of COVID-19 early in the pandemic period, many countries have relaxed the mandatory or recommended wearing of masks. The objective of the present study was to estimate the epidemiological impact of removing the mask-wearing recommendation in Japan. We developed a model to assess the consequences of declining mask-wearing coverage after the government revoked its recommendation in February 2023. The declining mask-wearing coverage was estimated using serial cross-sectional data, and a mathematical model was devised to determine the age-specific incidence of COVID-19 using the observed case count in Tokyo from week of October 3, 2022 to October 30, 2023. We explored model-based counterfactual scenarios to measure hypothetical situations in which the mask-wearing coverage decreases or increases relative to the observed coverage. The results show that mask-wearing coverage declined from 97% to 69% by the week of October 30, 2023, and that if the mask-wearing recommendation had continued, 427 lives could have been saved in Tokyo. If the mask-wearing coverage had declined to 25% of the observed level, the model suggests there might have been 1587 additional deaths. Thus, revoking the mask-wearing recommendation had a substantial epidemiological impact. In future pandemics, our proposed approach could provide a real-time quantification of the effects of relaxing countermeasures.

Acetic acid is a common inhibitor present in lignocellulose hydrolysate, which inhibits the ethanol production by yeast strains. Therefore, the cellulosic ethanol industry requires yeast strains that can tolerate acetic acid stress. Here we demonstrate that overexpressing a yeast native arginase-encoding gene, CAR1, renders Saccharomyces cerevisiae acetic acid tolerance. Specifically, ethanol yield increased by 27.3% in the CAR1-overexpressing strain compared to the control strain under 5.0 g/L acetic acid stress. The global intracellular amino acid level and compositions were further analyzed, and we found that CAR1 overexpression reduced the total amino acid content in response to acetic acid stress. Moreover, the CAR1 overexpressing strain showed increased ATP level and improved cell membrane integrity. Notably, we demonstrated that the effect of CAR1 overexpression was independent of the spermidine and proline metabolism, which indicates novel mechanisms for enhancing yeast stress tolerance. Our studies also suggest that CAR1 is a novel genetic element to be used in synthetic biology of yeast for efficient production of fuel ethanol.

ABSTRACTFruits from five wild edible berries that grow in the eastern region of Shizuoka (Japan) were collected, and their antioxidant activities were evaluated using the ORAC, DPPH, FRAP, and ABTS assays to obtain basic scientific knowledge of these species. Among the Shizuoka wild berries tested, Rubus microphyllus L. fil. exhibited the highest antioxidant activity, which is equivalent to that of commercial raspberry (Rubus idaeus L.). Furthermore, anthocyanins from these wild berries were analyzed using quantitative 1H NMR spectroscopy. Cyanidin-3-glucoside and pelargonidin-3-glucoside were detected in Shizuoka wild berries, with the latter identified as the characteristic anthocyanin. The present study revealed that Shizuoka wild berries are rich in natural antioxidants and pigments and are therefore potentially beneficial for reducing the risks of associated with lifestyle-related diseases in consumers.

Introduction: Administration of adipose-derived stem cells (ADSCs) into the joint cavity has been shown to alleviate the symptoms of knee osteoarthritis (OA) by releasing exosomes and anti-inflammatory cytokines. However, the therapeutic effect of these cells is limited by their rapid disappearance after administration. Thus, it is necessary to prolong cell survival in the joint cavity. This study aimed to investigate the potential application of ADSCs adhered to atelocollagen microspheres (AMSs) for cell therapy of knee OA. Methods: ADSCs were cultured for 2, 4, and 7 days in AMS suspension or adherent culture dishes. The supernatants were analyzed for IL-10 and exosome secretion via enzyme-linked immunosorbent assay and Nanosight. The effect of AMS was compared with that of adherent-cultured ADSCs (2D-cultured ADSCs) using transcriptome analysis. Moreover, the solubility of AMS and viability of ADSCs were evaluated using synovial fluid (SF) from patients with knee OA. Results: Compared with 2D-cultured ADSCs, AMS-cultured ADSCs exhibited a significant increase in secretion of exosomes and IL-10, and the expression of several genes involved in extracellular matrix and immune regulation were altered. Furthermore, when AMS-cultured ADSCs were cultured in SF from knee OA patients to mimic the intra-articular environment, the SF dissolved the AMSs and released viable ADSCs. In addition, AMS-cultured ADSCs showed significantly higher long-term cell viability than 2D-cultured ADSCs. Conclusion: Increased survival of AMS-adhered ADSCs was observed in the intra-articular environment, and AMSs were found to gradually dissipate. These results suggest that AMS-adhered ADSCs are promising source for cell therapy of knee OA.

Dental and oral management (DOM) is a long-established treatment modality. This scoping review aimed to narratively review previous studies, examine the effects of perioperative DOM, and identify the available evidence. A literature search was conducted using the PubMed electronic database for studies published between January 1, 2000, and March 8, 2022. The search yielded 43 studies, most of which were published in the last 10 years. The results of this study confirmed that improved perioperative oral hygiene is effective in preventing postoperative pneumonia. Our results also suggested that preoperative DOM is effective in preventing postoperative surgical site infections. Perioperative DOM is effective in reducing the incidence of postoperative pneumonia, SSI, and postsurgical complications. Further studies are needed to elucidate the various mechanism of DOM and to examine efficient intervention methods and timing.

Background This study aimed to evaluate VE of primary, first, and second booster ancestral-strain monovalent mRNA COVID-19 vaccination against symptomatic infections and severe diseases in Japan.Methods We conducted a test-negative case-control study. We included medically attended episodes and hospitalizations involving individuals aged [Formula: see text]16 with signs and symptoms from July to November 2022, when Omicron BA.5 was dominant nationwide. To evaluate VE, we calculated adjusted ORs of vaccination among test-positive versus test-negative individuals using a mixed-effects logistic regression.Results For VE against symptomatic infections among individuals aged 16 to 59, VE of primary vaccination at > 180 days was 26.1% (95% CI: 10.6–38.8%); VE of the first booster was 58.5% (48.4–66.7%) at [Formula: see text]90 days, decreasing to 41.1% (29.5–50.8%) at 91 to 180 days. For individuals aged [Formula: see text]60, VE of the first booster was 42.8% (1.7–66.7%) at [Formula: see text]90 days, dropping to 15.4% (−25.9–43.2%) at 91 to 180 days, and then increasing to 44.0% (16.4–62.5%) after the second booster. For VE against severe diseases, VE of the first and second booster was 77.3% (61.2–86.7%) at [Formula: see text]90 days and 55.9% (23.4–74.6%) afterward.Conclusion mRNA booster vaccination provided moderate protection against symptomatic infections and high-level protection against severe diseases during the BA.5 epidemic in Japan.

Introduction: Minimally invasive surgical treatment of myelopathy caused by central thoracic disc herniation (TDH) is challenging to carry out because reaching the herniation site is difficult and the thoracic spinal cord is fragile. In this study, using the posterior-lateral approach for central TDH with myelopathy, we present a novel procedure of transcostal microendoscopic discectomy (TCMED). Technical Note: The patient was operated in a prone position under general anesthesia. At a preoperatively determined distance from the midline, an 18-mm-long longitudinal incision was conducted, and using a 25-degree microendoscope, the operation was carried out. The endoscope was placed at an inward angle of approximately 50 degrees in the vertical direction. The ribs adjacent to the disc were identified, and the disc was exposed by resecting the ribs using a surgical high-speed drill while preserving the cortical bone of the ribs on the pleural side. The herniation was identified by drilling the ventral side of the disc and was then successfully removed. After discectomy, the dura mater expanded ventrally. Three male patients (mean age, 47.3 years) were treated, with 20 weeks of follow-up on average, 237.7-min mean operative time, and 26.7-mL mean blood loss. The average preoperative modified Japanese Orthopedic Association score was 5.2/11, which improved to 9.5/11 postoperatively, with a 75.6% average recovery rate. The 10-s step test score improved from an average of eight times preoperatively to 20 times postoperatively. No serious perioperative or postoperative complications or residual rib pain were observed. Conclusions: The proposed TCMED approach for treating central TDH that causes myelopathy allows for safe access to the level of the posterior vertebral wall using the rib as a landmark for resecting the rib head without opening the chest. Using the angled microendoscope and curved surgical instruments, the central TDH, located ventral to the spinal canal, can then be safely and effectively resected without spinal cord retraction.

Introduction: Elderly patients have a higher frequency of upper cervical fractures caused by minor trauma; nevertheless, the clinical differences between mid- and lower-cervical (C6-C7) injuries are unclear. The aim of this study was to compare the epidemiology of lower- and mid-cervical injuries in the elderly. Methods: This multicenter, retrospective study included 451 patients aged 65 years or older who had mid- or lower-cervical fractures/dislocations. Patients' demographic and treatment data were examined and compared based on mid- and lower-cervical injuries. Results: There were 139 patients (31%) with lower-cervical injuries and 312 (69%) with mid-cervical injuries. High-energy trauma (60% vs. 47%, p=0.025) and dislocation (55% vs. 45%, p=0.054) were significantly experienced more often by elderly patients with lower-cervical injuries than by patients with mid-cervical injuries. Although the incidence of key muscle weakness at the C5 to T1 levels were all significantly lower in patients with lower-cervical injuries than those with mid-cervical injuries, impairments at C5 occurred in 49% of them, and at C6, in 65%. No significant differences were found in the rates of death, pneumonia, or tracheostomy requirements, and no significant differences existed in ambulation or ASIA impairment scale grade for patients after 6 months of treatment. Conclusions: Elderly patients with lower-cervical fractures/dislocations were injured by high-energy trauma significantly more often than patients with mid-cervical injuries. Furthermore, half of the patients with lower-cervical injuries had mid-cervical level neurological deficits with a relatively high rate of respiratory complications.

Introduction: Preoperative estimations of blood loss are important when planning surgery for cervical spine injuries in older adults. The association between ankylosis and blood loss in perioperative management is of particular interest. This multicenter database review aimed to evaluate the impact of ankylosis on surgical blood loss volume in elderly patients with cervical spine injury. Methods: The case histories of 1512 patients with cervical spine injury at among 33 institutions were reviewed. After the exclusion of patients without surgery or whose blood loss or ankylosis status was unclear, 793 participants were available for analysis. Differences in blood loss volume were compared between the Ankylosis (+) group with ankylosis at the cervical level and the Ankylosis (−) group without by the inverse probability of treatment weighting (IPTW) method using a propensity score. Results: Of the 779 patients (mean age: 75.0±6.3 years) eligible for IPTW calculation, 257 (32.4%) had ankylosis at the cervical level. The mean blood loss volume was higher in Ankylosis (+) patients than in Ankylosis (−) patients (P

Background/Aims To validate endoscopic ultrasound-guided tissue acquisition (EUS-TA) used in conjunction with stereomicroscopic on-site evaluation (SOSE) as a preoperative diagnostic tool for resectable pancreatic cancer (R-PC) and borderline resectable PC (BR-PC). Methods Seventy-eight consecutive patients who underwent EUS-TA for suspected R-PC or BR-PC were enrolled. The primary endpoint was the sensitivity of EUS-TA together with SOSE based on the stereomicroscopically visible white core (SVWC) cutoff value. One or two sites were punctured by using a 22-gauge biopsy needle for EUS-TA, based on the SOSE findings. Results We collected 99 specimens from 56 and 22 patients with R-PC and BR-PC, respectively. Based on the SOSE results, we performed 57 procedures with one puncture. The SVWC cutoff values were met in 73.7% and 73.1% of all specimens and in those obtained during the first puncture, respectively. The final diagnoses were malignant and benign tumors in 76 and two patients, respectively. The overall sensitivity, specificity, and accuracy of EUS-TA for the 78 lesions were 90.8%, 100%, and 91.0%, respectively. The sensitivity for malignant diagnosis based on the SVWC cutoff value were 89.5% and 90.4% for the first puncture and all specimens, respectively. Conclusions The sensitivity of EUS-TA in conjunction with SOSE for malignancy diagnosis in patients with suspected R-PC or BR-PC was 90.4%.

Abstract Flexibility has been pursued enthusiastically in the field of porous crystals for enhancing their adsorption and separation performances. However, flexibility has never been observed among porous crystals sustained thoroughly by van der Waals interactions since flexible motions readily lead to the collapse of the porous architecture. Here we report a van der Waals crystal featuring conformational flexibility as well as permanent microporosity. The single-crystal structure and its structural transition in response to the adsorption of water molecules were unambiguously disclosed by means of electron and X-ray crystal structure analyses. The peripheral aromatic rings of the constituent molecule rotated as increasing the ambient humidity, while the connectivity of the pores was maintained throughout the structural transition. The transformative pores allowed the guest water molecules to move exceedingly quickly through the pores with a time constant of 490 μs. We demonstrated that the quick release of water induced by photothermal heating induced a significant upward bending of a film set above the crystalline powder compared to conventional porous materials. This finding contributes to the future crystal engineering based on van der Waals interactions rather than cohesive bonds.

Abstract This study employs Conversation Analysis to create a recursive model that improves the quality of human-robot interaction. Our research goal is to create a dialogue robot that offers pleasant experiences for users, so they are willing to engage in repeated interactions in daily lives. While there has been dramatic progress in the performance of dialogue robots, there has been less attention to the importance of users’ interactional experience compared to the “specs” of the dialogue system. Employing Goffmanian insights and using research in Conversation Analysis (CA), the present study develops a dialogue closing system to exit the interaction. We then experimentally verified that the robot with the dialogue closing system performs better in the user’s perception of the robot (i.e. likeability, politeness, and dialogue satisfaction) than the control group. Further, by analyzing the dialogue between the human and the robot through CA, we propose to build a recursive, reflective model to improve the dialogue model design. A constructive approach urges us to reproduce complicated social phenomena in human-robot interaction so that we can investigate the underlying cognitive mechanisms of humans and create robots that can convey human-like cognition functions and coexist with humans. Taking such a constructive approach, we posit that our recursive model for dialogue systems that uses CA insights and then qualitatively analyzes conversational data can enhance the quality of dialogue systems because the model elucidates which properties of a conversation humans need to experience a conversational robot as human-like. Our study suggests that interactional morality - particularly conversational closings - is one property of human interactions that humans likely require social robots to adhere to.

Abstract Sea ice is regarded as a temporal sink and carrier of microplastics (MPs). Nevertheless, knowledge and understanding of MPs in sea ice remain sparse. This study investigated the abundance, composition, size (> 30 μm), and shape of MPs in four sea-ice cores retrieved at the southern end of the Sea of Okhotsk. Nine microplastic (MP) types, mostly with fragmentary shapes, were detected among ice-core sections. Most fragmentary MPs were smaller than 120 μm, but all fiber MPs were in the largest size class (> 210 μm). MP concentrations were 0–60 particles/L, with an average of 21 particles/L. Higher occurrences of MPs observed in the lower ice layers are attributable to heavier MP contamination in the southern part of the sea and/or relocation of MPs in the ice matrix. No significant correlation was found between the distributions of MP and inorganic particle (sediment) abundances, implying difference in their kinetics of suspension freezing. Taken together, these findings suggest important implications for elucidating the nature and distribution of MPs in sea ice.

Abstract We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital capacity percentage/diffusing capacity of the lungs for carbon monoxide percentage> 1.6 and met criteria for high risk of PAH. Identification of elevated plasma proteins in SSc patients with high risk of PAH, followed by upstream regulator analysis, predicted interleukin (IL)-17A as a major upstream molecule. Furthermore, we performed in vitro neutralization study using MT-6194, a bispecific antibody targeting both IL-17A and IL-6 receptor. We found that MT-6194 broadly suppressed the increased expression of downstream molecules of IL-17A including IL-17A-related cytokines/chemokines, IL-17A-driven NF $$\kappa$$ B pathway and IL-6-driven JAK/STAT pathway which were shown to be increased in SSc patients with high risk of PAH by the proteomics. Consequently, it is revealed that IL-17A is a promising target for early intervention in SSc patients with high risk for PAH.

Abstract Human gut microbiota plays a crucial role in health and disease. Infancy is a critical period for gut microbiota maturation and immune system development and has the potential to affect long-term health. Understanding the development of gut microbiota in Japanese children is essential because of regional differences and the long-term health effects of the early gut microbiota. However, while several longitudinal studies in Japan have explored the development of the gut microbiota after birth, more extended follow-up periods are still needed. In this study, we aimed to analyze the gut microbiota of 106 Japanese mother–child pairs from the Chiba Study of Mother and Child Health, Japan, over 3.5 years. The results showed that the alpha diversity of the gut microbiota in children increased with age, and its composition began to resemble that of adults. We identified four distinct clusters of gut microbiota that reflected different maturation stages. The similarity between the maternal and child gut microbiota appeared to follow a bimodal-like distribution, suggesting that the presence of older siblings may enhance this similarity. This study highlights the dynamic nature of gut microbiota development in Japanese children and deepens our understanding of the similarities between maternal and child gut microbiota.

Abstract In present investigation, the effort is done to enhance the grain quality in brewer’s rice cultivar Yamadanishiki with the plasma treatment of caryopsis (rice fruit) on ripening process. Seedlings transplanted from a paddy field into pots were grown in a greenhouse, and each caryopsis was treated with plasma on 1, 5, 10 and 15 days after flowering (DAF). The ratio of white-core grains to total number of grains was decreased in the grains treated on DAF1, same level on DAF5, and increased on DAF10 and 15, respectively, compared with control grains. Moreover, same treatment test was conducted with seedlings transplanted from a paddy field into pots and grown in growth chambers equipped with a sensing system to monitor environmental and growth conditions, referred to the climatic conditions of paddy fields. The ratio of white-core grains to total number of grains was decreased in the grains treated on DAF1, and increased on DAF5, 10 and 15, respectively. We demonstrated that plasma treatment of caryopsis affected the formation of white core, and that environmental conditions in the growth chamber were simulated to a paddy field. We would advocate the next-generation agriculture using ICT and plasma, “Smart Agriculture System”, for producing high-quality crops.

Abstract Lipidomics and metabolomics communities comprise various informatics tools; however, software programs handling multimodal mass spectrometry (MS) data with structural annotations guided by the Lipidomics Standards Initiative are limited. Here, we provide MS-DIAL 5 for in-depth lipidome structural elucidation through electron-activated dissociation (EAD)-based tandem MS and determining their molecular localization through MS imaging (MSI) data using a species/tissue-specific lipidome database containing the predicted collision-cross section values. With the optimized EAD settings using 14 eV kinetic energy, the program correctly delineated lipid structures for 96.4% of authentic standards, among which 78.0% had the sn-, OH-, and/or C = C positions correctly assigned at concentrations exceeding 1 μM. We showcased our workflow by annotating the sn- and double-bond positions of eye-specific phosphatidylcholines containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs), characterized as PC n-3-VLC-PUFA/FA. Using MSI data from the eye and n-3-VLC-PUFA-supplemented HeLa cells, we identified glycerol 3-phosphate acyltransferase as an enzyme candidate responsible for incorporating n-3 VLC-PUFAs into the sn1 position of phospholipids in mammalian cells, which was confirmed using EAD-MS/MS and recombinant proteins in a cell-free system. Therefore, the MS-DIAL 5 environment, combined with optimized MS data acquisition methods, facilitates a better understanding of lipid structures and their localization, offering insights into lipid biology.

Abstract Background Despite surgery intervention for femoral neck fractures is recommended within 48 h of admission, achieving timely surgery presents challenges for patients with severe comorbidities, or in resource-limited settings. Preoperative rehabilitation (prehabilitation) reduces bedridden time, enhances mobility, and improves postoperative outcomes for patients scheduled for hip arthroplasty due to femoral neck fractures. However, prehabilitation is hindered by insufficient pain control. The pericapsular nerve group (PENG) block provides effective analgesia while preserving motor function. We designed a study to assess the efficacy of PENG block in facilitating prehabilitation for patients with femoral neck fractures who are scheduled for hip arthroplasty. Methods This prospective randomized placebo-controlled double-blinded trial aims to enroll 100 patients with Garden 3 or 4 femoral neck fractures who are scheduled for hip arthroplasty. Participants will be randomly assigned to receive a PENG block with 0.375% ropivacaine (PENG group) or with normal saline (placebo group) before the initial prehabilitation session. The prehabilitation program comprises five items: Bed-sitting, Edge-sitting, Stand-up, Maintaining-standing, and Wheelchair-transfer, performed with the assistance of a single physical therapist. The primary outcome is the percentage of patients completing the entire prehabilitation program. Secondary outcomes during the initial prehabilitation session are the achievement of each program item and the Numerical Rating Scale (NRS) pain score. Other secondary outcomes include intraoperative bleeding amounts, thromboembolic events during postoperative day 0 to 7, postoperative 3-day cumulative Cumulated Ambulation Score (CAS), and discharge destination. The postoperative outcomes will be compared between subgroups of patients undergoing surgery within 48 h of admission and those undergoing surgery more than 48 h of admission. Discussion This is the first study aiming to assess the efficacy of PENG block in prehabilitation for patients with femoral neck fractures who are scheduled for hip arthroplasty. PENG block could be beneficial, especially for patients facing delayed surgery, providing a potential treatment option during the waiting period. Trial registration Japan Registry of Clinical Trials, jRCT1031220294, registered on August 26, 2022.

Abstract Background Oral frailty is proposed as a new concept defined as an age-related gradual loss of oral functions accompanied by a decline in cognitive and physical functions in older adults. Additionally, the participants with ≥ 20 remaining teeth are associated with a lower risk of cognitive frailty in older adults. Herein, we aimed to examine the correlations between the high risk of oral frailty and oral conditions or health behavior in community-dwelling 80-year-old adults in Japan. Additionally, our secondary aim was to investigate the factors associated with ≥ 20 remaining teeth. Methods The present investigation was designed as a cross-sectional study using data from an adult dental health field study. This study included participants only aged 80 years in Japan. Oral frailty was evaluated using the Oral Frailty Index-8, and ≥ 4 points were defined as high risk. Oral examination was performed, and data on oral health behavior and frailty were also collected by using a self-administered questionnaire. The logistic regression analysis was conducted, with the objective variable being the risk of oral frailty groups or remaining teeth. Results Overall, 3,222 participants ( 1,911 female and 1,311 men) were included. Among the participants, 1,217 (37.8%) had a high risk of oral frailty. The risk of oral frailty was significantly affected by smoking status, number of remaining teeth, dental plaque, oral malodor, family dental clinic, oral concerns, osteoporosis, and shrinking body weight. Logistic regression analysis revealed that a high risk of oral frailty was significantly associated with

Abstract The histaminergic system plays a key role in modulating learning and memory, wakefulness, and energy balance. Histamine H3 receptors constitutively inhibit the synthesis and release of histamine and other neurotransmitters. Therefore, H3 receptor inverse agonists/antagonists increase the synthesis and release of these neurotransmitters, enhancing cognitive functions, including memory consolidation and retrieval. Spontaneous neural activity across the cerebral cortex is essential for cognitive function, including memory consolidation. Abnormal spontaneous activity has, in fact, been associated with cognitive dysfunctions and psychiatric disorders. Given the cognitive improvement achieved with the use of H3 receptor inverse agonists/antagonists, we examined the effects of two inverse agonists/antagonists – thioperamide and pitolisant – on spontaneous cortical activity, using in vivo wide-field Ca2+ imaging. Changes in cortical activity, across multiple cortical regions and in inter-regional connectivity, from pre- to post-administration were evaluated using a linear support vector machine decoder. Thioperamide and pitolisant both modified the amplitude distribution of calcium events across multiple cortical regions, including a reduction in the frequency of low-amplitude calcium events in the somatosensory cortex. Graph theory analysis revealed increases in centrality measures in the somatosensory cortex with the use of both thioperamide and pitolisant, indicative of their importance in the organization of cortical networks. These findings indicate that H3 receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization of activity in the cerebral cortex during the resting state.

Tamibarotene is a synthetic retinoid that inhibits tumor cell proliferation and promotes differentiation. We previously reported on the safety and tolerability of tamibarotene in patients with recurrent or refractory solid tumors. Therefore, in this study, we aimed to evaluate the pharmacokinetic properties of tamibarotene and construct a precise pharmacokinetic model. We also conducted a non-compartmental analysis and population pharmacokinetic (popPK) analysis based on the results of a phase I study. Targeted pediatric and young adult patients with recurrent or refractory solid tumors were administered tamibarotene at doses of 4, 6, 8, 10, and 12 g/m2/day. Serum tamibarotene concentrations were evaluated after administration, and a popPK model was constructed for tamibarotene using Phoenix NLME. During model construction, we considered the influence of various parameters (weight, height, body surface area, and age) as covariates. Notably, 22 participants were included in this study, and 109 samples were analyzed. A two-compartment model incorporating lag time was selected as the base model. In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory.

Abstract Background To describe a rare case of infiltrative optic neuropathy (ION) caused by vitreoretinal lymphoma (VRL) with hyperreflective deposits in the intraretinal and subretinal pigment epithelial (RPE) layers before the disease onset. Case presentation An 87-year-old Japanese female, previously treated for unexplained uveitis in the right eye, was referred for further evaluation. Despite the absence of intraocular inflammation or vitreous opacification (VO), yellowish-white deposits were noted in the macula, and OCT revealed hyperreflective deposits in the intraretinal and sub-RPE layers. One month later, she returned with acute visual deterioration. Optic disc swelling and disc hemorrhage were observed without VO or intraocular inflammation. Magnetic resonance imaging (MRI) showed no abnormalities. One week later, VO developed and we performed a 25-gauge vitrectomy. Cytology, flow cytometry, and gene rearrangement confirmed malignant B-cell lymphoma. The diagnosis of ION secondary to VRL was made, and intravitreal methotrexate injections were administered a total of 6 times. Six months postoperatively, VO and optic disc swelling resolved, and visual acuity improved to 20/50, with no recurrence on MRI. Conclusions Although there were reports on VRL advanced from hyperreflective deposits in the intraretinal or sub-RPE layers, there have been no studies that these OCT findings has progressed to ION with VRL. When differentiating optic neuropathy, OCT may assist in the diagnosis by evaluating intraretinal and sub-RPE findings.

Abstract We describe a case of RAS-associated autoimmune leukoproliferative disease with primary ciliary dyskinesia (PCD)-like symptoms, such as recurrent pneumonia, sinusitis, and otitis media, that occurred 7 years after hematopoietic cell transplantation. Whole-exome sequencing revealed a heterozygous CFAP43 nonsense variant. Environmental factors related to hematopoietic cell transplantation may have led to PCD symptoms in this patient with this variant. Genetic screening can help avoid subsequent complications during patient management.