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Abstract Traumatic brain injury (TBI) has been found to be associated with certain peripheral organ injuries; however, a few studies have explored the chronological influences of TBI on multiple organs and the systemic effects of therapeutic interventions. Particularly, high-mobility group box 1 (HMGB1) is a potential therapeutic target for TBI; however, its effects on peripheral organs remain unclear. Therefore, this study aimed to determine whether severe TBI can lead to multiple organ injury and how HMGB1 inhibition affects peripheral organs. This study used a weight drop-induced TBI mouse model and found that severe TBI can trigger short-lived systemic inflammation, in the lungs and liver, but not in the kidneys, regardless of the severity of the injury. TBI led to an increase in circulating HMGB1 and enhanced gene expressions of its receptors in every organ. Anti-HMGB1 antibody treatment reduced neuroinflammation but increased inflammation in peripheral organs. This study also found that HMGB1 inhibition appears to have a beneficial role in early neuroinflammation but could lead to detrimental effects on peripheral organs through decreased peripheral immune suppression. This study provides novel insights into the chronological changes in multiple organs due to TBI and the unique roles of HMGB1 between the brain and other organs.

Abstract: Almost all mutations of ITGA2B or ITGB3 identified in congenital macrothrombocytopenia induce constitutive activation of αIIbβ3. However, whether concomitant αIIbβ3 activation is essential for macrothrombocytopenia development remains unknown. Recently, we identified the β3(R760C) mutation that does not induce αIIbβ3 activation in a patient with macrothrombocytopenia. The family study showed that macrothrombocytopenia with reduced expression of αIIbβ3 and glycoprotein IV (GPVI) appeared to be associated with patients heterozygous for β3(R760C). We generated β3(R760C) knockin (KI) mice and investigated the effects of the mutation on platelet/megakaryote biology. Macrothrombocytopenia was decreased to 76% and 40% of platelet counts in heterozygous (Hetero) and homozygous (Homo) KI mice, respectively, when compared with the wild-type mice. Platelet αIIbβ3 and GPVI expression were decreased in KI mice, and αIIbβ3 activation was not detected in nonstimulated KI platelets. Thus, the hetero KI mice reproduced the phenotype of the human participant, indicating that the β3(R760C) mutation is responsible for the macrothrombocytopenia. Platelet aggregation, agonist-induced JON/A binding, and P-selectin expression were impaired in KI mice. Platelet spreading on fibrinogen was also impaired in Homo mice with adenosine 5′-diphosphate or thrombin stimulation. Filopodia and lamellipodia formation was impaired in fibrinogen-adhered megakaryocytes of Homo mice with significantly impaired RhoA activation. Proplatelet formation in Homo mice was impaired with abnormal morphology. In addition, platelet life span was shortened in Homo mice. These data indicate that the β3(R760C) mutation impairs the inside-out and outside-in signaling of αIIbβ3, and abnormal actin rearrangement and impaired RhoA activation may play major roles in macrothrombocytopenia.

Third-person perspectives in virtual reality (VR) based public speaking training enable trainees to objectively observe themselves through self-avatars, potentially enhancing their public speaking skills. Taking a job interview as a case study, this study investigates the influence of perspective on the training effects in VR public speaking training and explores the relationship between training effects and the sense of embodiment (SoE) and presence, as these concepts are central to virtual experiences. In the experiment, VR job interview training was conducted under three conditions: a first-person perspective (1PP), a typical third-person perspective from behind the avatar (Back), and a third-person perspective from the front of the avatar (Front). The results indicate that participants trained in the Front condition received higher evaluations from others in terms of verbal communication skills and the overall impression of the interview compared to those trained in the other conditions, highlighting the advantages of training while observing a self-avatar. Furthermore, it was confirmed that training effects correlated with the subcomponents of SoE and presence, suggesting that these trends may vary depending on perspective.

Ultrafine-grained (UFG) high-Mn austenitic steel exhibited unusual discontinuous yielding on its stress-strain curve, characterized by a yield drop followed by a stress plateau, indicative of Lüders deformation. Utilizing the digital image correlation (DIC) technique, a strain-localized region known as a Lüders band was observed to propagate during Lüders deformation. Following microstructural observations using state-of-the-art techniques such as in-situ synchrotron XRD measurement during the tensile test and ex-situ S/TEM and SEM-ECCI, dislocation multiplication, rather than twinning, was theoretically identified as the primary deformation mechanism responsible for the unusual Lüders deformation in UFG high-Mn austenitic steel.

Good syndrome (GS) is a combined immunodeficiency that is associated with thymomas. The cause of the reduction in B-cells in patients with GS may be multifactorial and may include dysregulated T-cell responses. It has been proposed that tumorigenesis in a normal thymus alters thymic epithelial cell function, which leads to attenuated elimination of T-cells autoreactive to B-cells. Although the comprehensive genetic analysis of thymoma has been performed and reported in many articles, the comprehensive genetic analysis specified for GS-related thymoma has not been reported. Herein, we report comprehensive genetic analysis of a thymoma taken from a patient with GS. Oncogenesis-associated genes that may contribute to thymoma development were detected. Additionally, alteration of VCAM1, which is required in the interaction between T-cells and thymic epithelial cells, was observed. Aberrantly expressed VCAM1 in thymic epithelial cells may decrease the efficacy of negative of selection autoreactive T-cells and contribute to autoimmunity to B-cells.

BackgroundNewborn screening (NBS) for severe combined immunodeficiency (SCID) has improved the prognosis of SCID. In Japan, NBS testing (measurement of the T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC)) was launched in 2017 and has expanded nationwide in recent years. In this study, we report a Japanese patient with X-linked SCID with a novel IL2RG variant identified through NBS. The patient underwent cord blood transplantation (CBT).CaseThe patient had no siblings or family history of inborn errors of immunity. He was born at 38 weeks of gestation and weighed 3,072 g. His NBS results revealed TREC 0 copies/105 cells (normal value: >565 copies/105 cells), which was considered suggestive of SCID. The patient was referred to our hospital. Although his lymphocyte count was 1,402/μL, naïve T cells and CD56+ natural killer (NK) cells were decreased to 0% and 0.05% of the total lymphocytes, respectively. Flow cytometric measurement testing revealed a decrease in γc protein expression in the B lymphocytes and NK lymphocytes. We identified a hemizygous novel missense variant (c.256A>C, p.Thr86Pro) of IL2RG. Both in silico and structural analyses revealed that this variant is likely pathogenic. At 3 months of age, he underwent CBT from a human leukocyte antigen-full-matched unrelated donor. The conditioning regimen included fludarabine (180 mg/m2) and targeted busulfan (35 mg×h/L). The patient achieved high-level donor chimerism and immune reconstitution, including B-cell function, at 13 months.ConclusionUsing NBS, the patient was diagnosed as having X-linked SCID with a novel missense variant of IL2RG. Early diagnosis using NBS tests enables safe hematopoietic stem cell transplantation without complications such as infection. We also found that even SCID with novel variants can be accurately diagnosed using the NBS program. In Japan, the test uptake rate is approximately 80% due to the high number of self-funded screening tests, and it is hoped that the uptake rate will increase in the future.

IntroductionResearch supporting the presence of diverse motor impairments, including impaired balance coordination, in children with autism spectrum disorder (ASD) is increasing. The one-legged standing test (OLST) is a popular test of balance. Since machine learning is a powerful technique for learning predictive models from movement data, it can objectively evaluate the processes involved in OLST. This study assesses machine learning’s effectiveness in evaluating movement in OLST for predicting high autistic trait.MethodsIn this study, 64 boys and 62 girls participated. The participants were instructed to stand on one leg on a pressure sensor while facing the experimenter. The data collected in the experiment were time-series data pertaining to pressure distribution on the sole of the foot and full-body images. A model to identify the participants belonging to High autistic trait group and Low autistic trait group was developed using a support vector machine (SVM) algorithm with 16 explanatory variables. Further, classification models were built for the conventional, proposed, and combined explanatory variable categories. The probabilities of High autistic trait group were calculated using the SVM model.ResultsFor proposed and combined variables, the accuracy, sensitivity, and specificity scores were 1.000. The variables shoulder, hip, and trunk are important since they explain the balance status of children with high autistic trait. Further, the total Social Responsiveness Scale score positively correlated with the probability of High autistic trait group in each category of explanatory variables.DiscussionResults indicate the effectiveness of evaluating movement in OLST by using movies and machine learning for predicting high autistic trait. In addition, they emphasize the significance of specifically focusing on shoulder and waist movements, which facilitate the efficient predicting high autistic trait. Finally, studies incorporating a broader range of balance cues are necessary to comprehensively determine the effectiveness of utilizing balance ability in predicting high autistic trait.

Abstract Background Providing medical care on isolated islands can be challenging in several ways. Telepsychiatry can potentially offer a solution for accessible psychiatric services on isolated islands. When video conferencing is used in telepsychiatry, the psychiatry specialist, who is remotely located, may find it difficult to establish trust. To address this, we developed a teleoperated robot system termed “Sota 100,” which is equipped to convey various elements of nonverbal communication, such as eye contact, in remote settings. Case Presentation In this report, we introduce the case of a patient with alcohol use disorder who lived on an isolated island and received medical care from a primary care physician at the island's medical clinic and from Sota 100 teleoperated by a psychiatry specialist. Using this system, the patient admitted that he had developed a physical illness and had damaged his relationships partly because of alcohol abuse. At the conclusion of the three‐way conversation, the patient understood that stopping drinking alcohol was the only way to prevent worsening his physical condition and damaging his relationships further. Concurrently, the primary care physician gained a deeper understanding of the etiology of alcohol use disorder and of how to support patients with alcohol dependency. Conclusion These case findings suggest that our system is helpful for patients with alcohol use disorder who need to receive telepsychiatry services. Future studies should include single‐case experimental designs with regular measurements of key outcome variables and other relevant variables over time.

Abstract Background Childcare leave extensions can sometimes negatively affect the professional clinical training of early‐career psychiatrists in Japan. During childcare leave, being able to learn in the examination room while staying at home would be useful. Therefore, we developed a training system using a teleoperated robot (Sota) for young psychiatrists who wanted to participate in the examination room during childcare leave while remaining at home. Case Presentation We report the case of a patient with autism spectrum disorder (ASD) comorbid with Tourette's disorders (P). A young female psychiatrist (D) used the training system to learn from a board‐certified psychiatrist. In this case, the board‐certified psychiatrist, P, and the robot were placed in the examination room. D teleoperated Sota from home, allowing her to talk to the board‐certified psychiatrist and P. She learned about the clinical features of Tourette's syndrome by observing the examination of the board‐certified psychiatrist and hearing the patient's distress. P was satisfied with the fact that he was seen not only by a board‐certified psychiatrist but also by D. Conclusion These case findings suggest that our system is helpful for young psychiatrists who want to study in the examination room during childcare leave while staying at home. Future studies should include a single‐case experimental design with information regarding key outcome variables and other relevant variables gathered regularly over time.

Abstract The intensive study of electrochemical CO2 reduction reaction (CO2RR) has resulted in numerous highly selective catalysts, however, most of these still exhibit uncontrollable selectivity. Here, it is reported for the first time the controllable CH4/C2H4 selectivity by modulating the electronic states of Cu incorporated in metal‐organic frameworks with different functional ligands, achieving a Faradaic efficiency of 58% for CH4 on Cu‐incorporated UiO‐66‐H (Ce) composite catalysts, Cu/UiO‐66‐H (Ce) and that of 44% for C2H4 on Cu/UiO‐66‐F (Ce). In situ measurements of Raman and X‐ray absorption spectra revealed that the electron‐withdrawing ability of the ligand side group controls the product selectivity on MOFs through the modulation of the electronic states of Cu. This work opens new prospects for the development of MOFs as a platform for the tailored tuning of selectivity in CO2RR.

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) tends to involve central nervous system (CNS) infiltration at diagnosis. However, cases of residual CNS lesions detected at the end of induction and post early intensification have not been recorded in patients with T-ALL. Also, the ratio and prognosis of patients with residual intracranial lesions have not been defined. Case presentation A 9-year-old boy with T-ALL had multiple intracranial tumors, which were still detected post early intensification. To investigate residual CNS lesions, we used 11C-methionine (MET)-positron emission tomography. Negative MET uptake in CNS lesions and excellent MRD status in bone marrow allowed continuing therapies without hematopoietic cell transplantation. Conclusions In cases with residual lesions on imaging studies, treatment strategies should be considered by the systemic response, direct assessment of spinal fluid, along with further development of noninvasive imaging methods in CNS. Further retrospective or prospective studies are required to determine the prognosis and frequency of cases with residual intracranial lesions after induction therapy.

Human sapovirus (HuSaV) is a significant cause of gastroenteritis. This study aims to analyze the evolutionary dynamics of the RNA-dependent RNA polymerase (RdRp) and capsid (VP1) genes of the HuSaV GI.1 and GI.2 genotypes between 1976 and 2020. Using bioinformatics tools such as the Bayesian phylogenetics software BEAST 2 package (v.2.7.6), we constructed time-scale evolutionary trees based on the gene sequences. Most of the recent common ancestors (MRCAs) of the RdRp region and VP1 gene in the present HuSaV GI.1 diverged around 1930 and 1933, respectively. The trees of the HuSaV GI.1 RdRp region and VP1 gene were divided into two clusters. Further, the MRCAs of the RdRp region and VP1 gene in HuSaV GI.2 diverged in 1960 and 1943, respectively. The evolutionary rates were higher for VP1 gene in HuSaV GI.1 than that in HuSaV GI.2, furthermore, were higher in GI.1 Cluster B than GI.1 Cluster A. In addition, a steep increase was observed in the time-scaled genome population size of the HuSaV GI.1 Cluster B. These results indicate that the HuSaV GI.1 Cluster B may be evolving more actively than other genotypes. The conformational B-cell epitopes were predicted with a higher probability in RdRp for GI.1 and in VP1 for GI.2, respectively. These results suggest that the RdRp region and VP1 gene in HuSaV GI.1 and GI.2 evolved uniquely. These findings suggest unique evolutionary patterns in the RdRp region and VP1 gene of HuSaV GI.1 and GI.2, emphasizing the need for a ‘One Health’ approach to better understand and combat this pathogen.

Human norovirus (HuNoV) is a major causative agent of foodborne illness and causes acute viral gastroenteritis. This study aimed to compare the virucidal efficacies of alcohol-based disinfectants against HuNoV and its surrogates for murine norovirus and feline calicivirus using a cell culture infectivity assay. Additionally, the study evaluated the validity of estimating virucidal efficacy on HuNoV from the results of virucidal efficacy on the surrogate virus. All disinfectants decreased the titer of each virus by >3 log10 and >4 log10 for an exposure duration of 30 s against murine norovirus and feline calicivirus, respectively. However, acidic alcohol-based disinfectants completely inactivated the HuNoV GII.17 strain for 30 or 60 s, whereas an alkaline alcohol-based disinfectant did not inactivate HuNoV GII.17 for 60 s. This finding indicates that the pH of alcohol disinfectants affects their virucidal effects against HuNoV, and acidity has a higher virucidal efficacy against HuNoV than alkalinity. Disinfectants showing virucidal efficacy against surrogates were not effective against HuNoV. Few studies have used cell culture infectivity assays to test the inactivating effects of hand sanitizers on HuNoV and its surrogates. Our study provides useful information for the development of disinfectants that are effective against HuNoV.

To better understand the phylogenomics of the hemagglutinin-neuraminidase (HN) gene and HN protein in human parainfluenza virus type 4 (HPIV4), we performed phylogenomic analyses using various bioinformatics methods. The main bioinformatics analyses included a time-scaled phylogeny, genetic distance assessments, and three-dimensional (3D) structure mapping of the HN protein with conformational epitope and selective pressure analyses. The time-scaled phylogenetic tree indicated that the most recent common ancestor of the HN gene emerged approximately 100 years ago. Additionally, the tree revealed two distinct clusters corresponding to HPIV4a and HPIV4b. The divergence times for the most recent common ancestors of the HN gene in HPIV4a and HPIV4b strains were estimated to be around 1993 and 1986, respectively. The evolutionary rates of the gene varied significantly between clusters, ranging from approximately 1.2 × 10−3 to 8.7 × 10−4 substitutions per site per year. Genetic distances within each cluster were relatively short (less than 0.04). Phylodynamic analyses demonstrated an increase in the genome population size around the year 2000. Structural analyses revealed that the active sites of the HN protein were located at the protein’s head. Furthermore, the most conformational epitopes were located in adjacent active sites of the protein. These results suggested that reinfection may be unlikely to occur in the case of most HPIV4. Together, the HN gene and protein of HPIV4 strains isolated in Japan have undergone unique evolutionary changes. In addition, antibodies targeting the conformational epitopes of the HPIV4 HN protein may contribute to protection against the virus.

Human parainfluenza virus type 2 (HPIV2) is a clinically significant respiratory pathogen, which highlights the necessity of studies on its molecular evolution. This study investigated the evolutionary dynamics, phylodynamics, and structural characteristics of the HPIV2 fusion (F) gene using a comprehensive dataset spanning multiple decades and geographic regions. Phylogenetic analyses revealed two distinct clusters of HPIV2 F gene sequences, which were estimated to have diverged from a common ancestor approximately a century ago. Cluster 1 demonstrated a higher evolutionary rate and genetic diversity compared to the more stable cluster 2. Bayesian Skyline Plot analyses indicated a significant increase in the effective population size of the F gene between 2005 and 2015; potentially linked to enhanced diagnostic and surveillance capabilities. Structural modeling identified conserved conformational epitopes predominantly in the apex and stalk regions of the F protein. These findings underscore the evolutionary constraints and antigenic landscape of the HPIV2 F protein.

The purpose of the present study is to contribute to the establishment of a standard method for evaluating the adverse effects of nanomaterials by intratracheal administration. Low and high doses of multi-walled carbon nanotubes (MWCNTs) were administered to rats in a single administration or the same final dose as the single administration but divided over four administrations. Bronchoalveolar lavage examination on day 14 showed an inflammatory reaction and cytotoxicity in the lung, generally greater at the higher dose, and tending to be greater in the rats with four administrations at both the low and high doses. Histopathologic findings showed increased alveolar macrophages and MWCNT deposition (fibers phagocytosed by alveolar macrophages and fibers that were not phagocytosed) in the alveolar space, granulomatous changes, and MWCNT deposition in bronchus-associated lymphoid tissue (BALT) and lung-related lymph nodes on days 14, 28, and 91. In addition, alveolar type II epithelial hyperplasia was observed on day 91, and fibrosis of the alveolar wall was observed on days 28 and 91. Fewer alveolar macrophages with phagocytosed MWCNTs were present at day 91 compared to day 28. MWCNT deposition tended to be higher in the BALT after a single administration, whereas deposition was higher in the lung-related lymph nodes after four administrations. MWCNTs were considered to be transported from the lungs or BALT to the lymph nodes over time. There were no significant differences in MWCNT deposition in the lung after the single administration compared with four administrations at either the low or high doses, and the histopathological findings were similar after single and four administrations, at both the low and high doses. Based on the above findings, a toxicity evaluation of the nanomaterials can be sufficiently performed by intratracheal administration, even with a single intratracheal administration.

Numerous host factors function as intrinsic antiviral effectors to attenuate viral replication. MARCH8 is an E3 ubiquitin ligase that has been identified as a host restriction factor that inhibits the replication of various viruses. This study elucidated the mechanism by which MARCH8 restricts respiratory syncytial virus (RSV) replication through selective degradation of the viral small hydrophobic (SH) protein. We demonstrated that MARCH8 directly interacts with RSV-SH and catalyzes its ubiquitination at lysine 13, leading to SH degradation via the ubiquitin-lysosomal pathway. Functionally, MARCH8 expression enhances RSV-induced apoptosis through SH degradation, ultimately reducing viral titers. Conversely, an RSV strain harboring the SH-K13R mutation exhibited prolonged SH protein stability and attenuated apoptosis in infected cells, even in the presence of MARCH8. Targeted depletion of MARCH8 enhances cellular survival and potentially increases viral persistence. These findings demonstrate that MARCH8 promotes the early elimination of virus-infected cells by abrogating the anti-apoptotic function of SH, thereby reducing viral transmission. Our study provides novel insights into the interplay between host restriction factors and viral evasion strategies, potentially providing new therapeutic approaches for RSV infections.

Abstract The study investigates the thermal expansion and superconducting properties of a CuAl2‐type (tetragonal) superconductor CoZr2 under high pressures. High‐pressure synchrotron X‐ray diffraction is performed in a pressure range of 2.9 GPa < P < 10.4 GPa, and it is discovered that CoZr2 exhibits volumetric negative thermal expansion (NTE) under high pressures. Although uniaxial positive thermal expansion (PTE) along the a‐axis is observed under ambient pressure, it is suppressed by pressure, whereas a large uniaxial NTE along the c‐axis is maintained under the pressure regime. Because of the combination of the suppressed uniaxial PTE along the a‐axis and uniaxial NTE along the c‐axis, volumetric NTE is achieved under high pressure in CoZr2. The volumetric NTE mechanism is based on the flexible crystal structure caused by the soft Co–Co bond, as observed in the isostructural compound FeZr2, which exhibits a uniaxial NTE along the c‐axis. High‐pressure electrical resistance measurements of CoZr2 are performed and confirm superconductivity at 0.03 GPa < P < 41.9 GPa. Because of the coexistence of the two phenomena, volumetric NTE and superconductivity, in CoZr2 under high pressure, coexistence can be achieved under ambient pressure by tuning the chemical composition after the present observation.

Background: Deteriorated sinusitis and increased adiposity relative to muscle mass may affect quality of life in patients with asthma. However, whether these effects are observed regardless of intrapulmonary pathology is unknown. Objectives: We evaluated the correlation of the cross-sectional ratio of abdominal visceral fat (VF) to erector spinae muscle (ESM) and sinus findings based on Lund-Mackey scoring system (LMS) on computed tomography (CT) with the impaired score of the Asthma Quality of Life Questionnaire (AQLQ), regardless of airway and parenchymal disease, in patients with asthma. Methods: We recruited participants from the Hokkaido-based severe asthma cohort who had completed AQLQ and CT examination at the entry. The participants were divided into high (highest) and low (other quartiles) groups on the bases of the extrapulmonary indices. Multivariate analysis examined the association of VF/ESM for the adiposity-to-muscle ratio and LMS with AQLQ after adjusting for the airway fractal dimension for airway index and percentage of low attenuation volume to lung volume for parenchymal index. Results: No significant differences were observed in VF/ESM and LMS in terms of sex. The AQLQ score in the high VF/ESM group and high LMS group was lower than those in low VF/ESM group and low LMS group (63 male and 100 female subjects). High VF/ESM (estimate [95% confidence interval] (−0.43 [−0.61, −0.25]) and high LMS scores (−0.22 [−0.41, −0.03]) were associated with low AQLQ scores when adjusted for age, body mass index, smoking status, blood eosinophil count, and intrapulmonary CT indices. Conclusions: Increased VF relative to ESM mass and high LMS may deteriorate asthma-related quality of life, regardless of presence of intrapulmonary disease.

Abstract Multiple myeloma (MM) is an incurable B‐cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL‐18 and M‐CSF levels showed significantly shorter progression‐free survival and overall survival (OS). In contrast, patients with high PDGF‐BB levels had longer survival. Moreover, low levels of G‐CSF, IL‐7, IL‐8, and SDF‐1α were associated with shorter OS after Ld therapy. During Ld therapy, pro‐inflammatory cytokines such as IL‐2Rα, IL‐18, and TNF‐α were decreased, while IFN‐γ was increased. IL‐4 and IL‐6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy.

Echinococcus multilocularis is a cestode that causes human alveolar echinococcosis, a lethal zoonotic disease distributed in the northern hemisphere. The life cycle of this parasite is maintained in nature by voles as intermediate hosts and foxes as definitive hosts in Hokkaido, Japan. Although dogs are also susceptible to the parasite, the infection has been considered typically asymptomatic. We report the detection of E. multilocularis eggs in the diarrheal feces of a dog with chronic gastrointestinal signs, which disappeared after anthelmintic treatment. The mitochondrial genome sequence constructed by sequencing of the overlapping PCRs using DNA from the eggs was identical to the most predominant haplotype previously reported in red foxes in Hokkaido. This case highlights that Echinococcus infection should be considered as a differential diagnosis for diarrheal dogs in the disease endemic areas. Further efforts are needed to accumulate parasite genotypes in domestic dogs as well as humans to assess the risk of human infection from dogs.

Introduction Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series.Methods and analysis This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over.Ethics and dissemination This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians.Trial registration number jRCTs041210027.

Abstract Human placental villi have essential roles in producing hormones, mediating nutrient and waste exchange, and protecting the fetus from exposure to xenobiotics. Human trophoblast organoids that recapitulate the structure of villi could provide an important in vitro tool to understand placental development and the transplacental passage of xenobiotics. However, such organoids do not currently exist. Here we describe the generation of trophoblast organoids using human trophoblast stem (TS) cells. Following treatment with three kinds of culture medium, TS cells form spherical organoids with a single outer layer of syncytiotrophoblast (ST) cells that display a barrier function. Furthermore, we develop a column-type ST barrier model based on the culture condition of the trophoblast organoids. The bottom membrane of the column is almost entirely covered with syndecan 1-positive ST cells. The barrier integrity and maturation levels of the model are confirmed by measuring transepithelial/transendothelial electrical resistance (TEER) and the amount of human chorionic gonadotropin. Further analysis reveals that the model can be used to derive the apparent permeability coefficients of model compounds. In addition to providing a suite of tools for the study of placental development, our trophoblast models allow the evaluation of compound transfer and toxicity, which will facilitate drug development.

Convolution is the inner product of the neighborhood signal and weights and plays a fundamental role in image processing; thus, acceleration of convolution is essential. Among convolutions, variable-weighted convolution is used in adaptive filters and edge-preserving smoothing to realize various applications. Some weights are replaced with lookup tables (LUTs) to accelerate these filters. LUT reference is a classical acceleration method. However, the difference between the growth rate in computing speed and memory I/O speed has limited the scope of utilization of LUT references. Speedup would be possible if registers could be used as LUTs, but their small size makes them difficult to utilize. Therefore, this study proposes a downsampling method to fit LUTs into SIMD registers, which are relatively large and an efficient reference method for register-LUTs. Experimental results show that the proposed method can reproduce an accuracy in PSNR of 65.52 (+25.11) dB, while a simple full-size LUT in the register size can only reproduce 40.41 dB. Using a wider register width, the PSNR was 78.63 (+38.22) dB with AVX-512 and 84.5 (+44.09) dB with bfloat16. The fastest proposed method was on average 4.82/3.72 times faster than direct vector computing, 2.99/3.10 times faster than vector addressing, and 3.79/7.80 times faster than scalar addressing on the AVX2/AVX-512 computers while exceeding the display limit of 60 dB for 8-bit displays. Taking into account these speed/accuracy trade-offs, the performance of the proposed method was superior. This paper shows that LUT references can be realized with small SIMD registers in convolution. The proposed method is expected to be extended to adaptive filters, convolutional neural networks, and other image processing applications by accelerating the approximation with this register-LUT. Our code is available at https://fukushimalab.github.io/registerLUT4conv/.

Hericium mushrooms are a group of rare medicinal mushrooms that have attracted considerable attention worldwide. In order to gain insight into the current trends and frontiers of Hericium research, we conducted a comprehensive search of the Web of Science (WOS) database to identify relevant literature on Hericium research. Following an optimised search strategy and careful removal of duplicate entries, a total of 839 documents were selected from the core WOS database for bibliometric analysis. We used VOSviewer to visualize the co-occurrence network between publishing organizations, while CiteSpace allowed us to visualize and analyse the national co-occurrence network, author co-occurrence network, keyword co-linearity, keyword clustering and co-citation mapping. Our analysis revealed a significant and continuous increase in the number of publications related to Hericium mushrooms, with a peak observed in 2021. Examination of publication statistics by country (region) and institution identified China and Universiti Malaysia as the leading contributors in their respective fields, with active collaboration with other countries and institutions. The analysis of author co-occurrence suggests that inter-author communications and collaborations may be geographically limited by the research institutions to which they belong. Various keyword-based analyses highlighted the structural diversity and bioactivities of small molecule compounds derived from Hericium mushrooms, underscoring their potential health-protective effects as rare food and medicinal mushrooms. Through co-citation analysis, we identified J. Agr. Food Chem. as the most cited journal for Hericium mushroom research results, while Yoko Kawagishi of Shizuoka University (Japan) emerged as the most cited researcher in the field. Overall, our findings suggest that research into the potential anti-neurodegenerative properties of Hericium mushrooms is a promising area of investigation, with a focus on elucidating the underlying mechanisms of action.

Abstract Background Immune checkpoint inhibitors (ICIs) can cause severe immune‐related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. Methods Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti‐PD‐1, anti‐PD‐L1, or anti‐CTLA‐4 plus anti‐PD‐1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non‐irAE group). Eosinophils were examined before the two‐course treatment. Results Patients in the irAE group who received anti‐PD‐1 or anti‐CTLA‐4 plus anti‐PD‐1 therapy had higher eosinophils before the two‐course treatment than those in the non‐irAE group (p

In the original publication [...]

Background/Objectives: A retrospective study was conducted to clarify the clinical characteristics of taste disorder cases at the Department of Oral Medicine of Hokkaido University Hospital. The subjects were 322 taste disorder patients (86 male, 236 female, average age: 66 (13.1) years, mean duration of disorder: 15.2 (20.0) months) who were treated at our department from 2007 to 2018. Methods: Associations between symptoms and classification were examined. Results: When looking at the taste symptoms, 154 cases of quantitative taste disorder were observed as taste loss, abscission, and dissociative taste disorder, and 168 cases of qualitative taste disorder were observed as spontaneous abnormal taste, dysgeusia, and maltaste. There was no relationship between sex and quantitative/qualitative taste disorders at V = 0.08. When looking at the causes of taste disorders, the majority were psychogenic, idiopathic, and oral diseases. Conclusions: Approximately 20% of taste disorders are caused by oral diseases, so it should be noted that oral diseases such as oral candidiasis and xerostomia can cause taste disorders and that many of them can be improved with oral treatment.

To better understand the molecular genetics of the Shiga toxin type 2 subunit A gene (stx2A gene), we collected many subtypes of stx2A genes and performed detailed molecular evolutionary analyses of the gene. To achieve the aim of the study, we used several bioinformatics technologies, including time-scaled phylogenetic analyses, phylogenetic distance analyses, phylodynamics analyses, selective pressure analyses, and conformational epitope analyses. A time-scaled phylogeny showed that the common ancestor of the stx2A gene dated back to around 18,600 years ago. After that, the gene diverged into two major lineages (Lineage 1 and 2). Lineage 1 comprised the stx2a–2d subtypes, while Lineage 2 comprised the stx2e, 2g, 2h, and 2o subtypes. The evolutionary rates of the genes were relatively fast. Phylogenetic distances showed that the Lineage 2 strains had a wider genetic divergence than Lineage 1. Phylodynamics also indicated that the population size of the stx2A gene increased after the 1930s and spread globally. Moreover, negative selection sites were identified in the Stx2A proteins, and these sites were diffusely distributed throughout the protein. Two negative selection sites were located adjacent to an active site of the common Stx2A protein. Many conformational epitopes were also estimated in these proteins, while no conformational epitope was found adjacent to the active site. The results suggest that the stx2A gene has uniquely evolved and diverged over an extremely long time, resulting in many subtypes. The dominance of the strains belonging to Lineage 1 suggests that differences in virulence may be involved in the prosperity of the offspring. Furthermore, some subtypes of Stx2A proteins may be able to induce effective neutralizing antibodies against the proteins in humans.

Abstract Immune thrombocytopenia (ITP) is a common childhood acute autoimmune bleeding disorder caused by numerous viruses and characterized by isolated thrombocytopenia. Although cases of ITP caused by coronavirus disease 2019 (COVID‐19) infection have been reported in adults, pediatric reports are limited. We present the case of a 1‐year‐old girl who developed COVID‐19‐infection‐related ITP with a very low platelet count (0.0 × 104/μL). We searched for COVID‐19‐related pediatric ITP cases and found 10 other cases, with the majority having platelet counts of

AbstractActivated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.

Abstract Background High-flow nasal cannula (HFNC) therapy is an important non-invasive respiratory support in acute respiratory failure, including coronavirus disease (COVID-19) pneumonia. Although the respiratory rate and oxygenation (ROX) index is a simple and useful predictor for HFNC failure and mortality, there is limited evidence for its use in patients with COVID-19 pneumonia. We aimed to evaluate the ROX index as a predictor for HFNC failure in patients with COVID-19 pneumonia. We also evaluated the ROX index as a predictor for 28-day mortality. Methods In this single-center, retrospective, cohort study, 248 patients older than 18 years of age with COVID-19 pneumonia received HFNC therapy for acute respiratory failure. The ROX index was evaluated within 4 h from the start of HFNC therapy. Past medical history, laboratory data, and the ROX index were evaluated as predictors for HFNC failure and 28-day mortality. Results The ROX index

Abstract High serum levels of triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of coronary heart disease in humans. Herein, we first reported that the C3H/HeNSlc (C3H-S) mouse, a C3H/HeN-derived substrain, is a novel model for dyslipidemia. C3H-S showed hypertriglyceridemia and low total cholesterol (TC), HDL-C, and phospholipid (PL) concentrations. To identify the gene locus causing dyslipidemia in C3H-S, we performed genetic analysis. In F2 intercrosses between C3H-S mice and strains with normal serum lipids, the locus associated with serum lipids was identified as 163–168 Mb on chromosome 2. The phospholipid transfer protein (Pltp) gene was a candidate gene within this locus. Pltp expression and serum PLTP activity were markedly lower in C3H-S mice. Pltp expression was negatively correlated with serum TG and positively correlated with serum TC and HDL-C in F2 mice. Genome sequencing analysis revealed that an endogenous retrovirus (ERV) sequence called intracisternal A particle was inserted into intron 12 of Pltp in C3H-S. These results suggest that ERV insertion within Pltp causes aberrant splicing, leading to reduced Pltp expression in C3H-S. This study demonstrated the contribution of C3H-S to our understanding of the relationship between TG, TC, and PL metabolism via PLTP.

Background: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. Methods: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (

Abstract Background The recently developed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). Methods We retrospectively measured serum SARS‐CoV‐2 antibodies against the spike protein (S‐IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S‐IgG titers ≥300 antibody units/mL). Results Although active anti‐myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B‐cell maturation antigen‐targeted therapy. Dose 3 (booster vaccination) led to significantly higher S‐IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine‐induced cellular immune response in patients using T‐spot Discovery SARS‐CoV‐2 kit, revealed an enhanced cellular immune response after Dose 3. Conclusions This study highlighted the significance of booster SARS‐CoV‐2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine‐induced humoral immune response.

The human parainfluenza virus type 4 (HPIV4) can be classified into two distinct subtypes, 4a and 4b. The full lengths of the fusion gene (F gene) of 48 HPIV4 strains collected during the period of 1966–2022 were analyzed. Based on these gene sequences, the time-scaled evolutionary tree was constructed using Bayesian Markov chain Monte Carlo methods. A phylogenetic tree showed that the first division of the two subtypes occurred around 1823, and the most recent common ancestors of each type, 4a and 4b, existed until about 1940 and 1939, respectively. Although the mean genetic distances of all strains were relatively wide, the distances in each subtype were not wide, indicating that this gene was conserved in each subtype. The evolutionary rates of the genes were relatively low (4.41 × 10−4 substitutions/site/year). Moreover, conformational B-cell epitopes were predicted in the apex of the trimer fusion protein. These results suggest that HPIV4 subtypes diverged 200 years ago and the progenies further diverged and evolved.

The leading-edge erosion of a wind turbine blade was tested using a whirling arm rain erosion tester, whose rotation rate is considerably higher than that of a full-scale wind turbine owing to the scale effect. In this study, we assessed the impact pressure of droplets on a wet surface of wind turbine blades using numerical simulation of liquid droplet impact by solving the Navier–Stokes equations combined with the volume-of-fluid method. This was conducted in combination with an estimation of liquid film thickness on the rotating blade using an approximate solution of Navier–Stokes equations considering the centrifugal and Coriolis forces. Our study revealed that the impact pressure on the rain erosion tester exceeded that on the wind turbine blade, attributed to the thinner liquid film on the rain erosion tester than on the wind turbine blade caused by the influence of centrifugal and Coriolis forces. This indicates the importance of correcting the influence of liquid-film thickness in estimating the impact velocity of droplets on the wind turbine blade. Furthermore, we demonstrated the correction procedure when estimating the impact velocity of droplets on the wind turbine blade.

The relationships among bacterial flora, diseases, and diet have been described by many authors. An operational taxonomic units (OTUs) are the result of clustering the 16S rRNA gene sequences at a certain cutoff value, and they are considered compositional data. As Pearson’s correlation coefficient is difficult to interpret, Aitchison’s ratio analysis was used to develop a method to handle compositional data. Multivariate analysis was developed because univariate analysis can be subject to large biases. Simulations regarding absolute abundance based on certain assumptions and some analyses, such as nonparametric multidimensional scaling (NMDS), principal component analysis (PCA), and ratio analysis, were conducted in this study. The same content as a 100% stacked bar graph could be expressed in low dimensions using PCA. However, the relative diversity was not reproducible with NMDS. Various assumptions were made regarding absolute abundance based on the relative abundance. However, which assumptions are true could not be determined. In summary, ratio analysis and PCA are useful for analyzing compositional data and the gut microbiota.

BackgroundRobots offer many unique opportunities for helping individuals with autism spectrum disorders (ASD). Determining the optimal motion of robots when interacting with individuals with ASD is important for achieving more natural human-robot interactions and for exploiting the full potential of robotic interventions. Most prior studies have used supervised machine learning (ML) of user behavioral data to enable robot perception of affective states (i.e., arousal and valence) and engagement. It has previously been suggested that including personal demographic information in the identification of individuals with ASD is important for developing an automated system to perceive individual affective states and engagement. In this study, we hypothesized that assessing self-administered questionnaire data would contribute to the development of an automated estimation of the affective state and engagement when individuals with ASD are interviewed by an Android robot, which will be linked to implementing long-term interventions and maintaining the motivation of participants.MethodsParticipants sat across a table from an android robot that played the role of the interviewer. Each participant underwent a mock job interview. Twenty-five participants with ASD (males 22, females 3, average chronological age = 22.8, average IQ = 94.04) completed the experiment. We collected multimodal data (i.e., audio, motion, gaze, and self-administered questionnaire data) to train a model to correctly classify the state of individuals with ASD when interviewed by an android robot. We demonstrated the technical feasibility of using ML to enable robot perception of affect and engagement of individuals with ASD based on multimodal data.ResultsFor arousal and engagement, the area under the curve (AUC) values of the model estimates and expert coding were relatively high. Overall, the AUC values of arousal, valence, and engagement were improved by including self-administered questionnaire data in the classification.DiscussionThese findings support the hypothesis that assessing self-administered questionnaire data contributes to the development of an automated estimation of an individual’s affective state and engagement. Given the efficacy of including self-administered questionnaire data, future studies should confirm the effectiveness of such long-term intervention with a robot to maintain participants’ motivation based on the proposed method of emotion estimation.

Abstract Background Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low‐dose fluconazole (FLCZ) prophylaxis (100 mg/day). Methods We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low‐dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post‐transplant. Results Of the 107 patients, 70 received low‐dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection‐related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44–8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02–4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. Conclusion Low‐dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.

Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover event occurred from fruits bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is an effective tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, displayed a prominent antiviral effect on PRV. Secondly, the antiviral effects of micafungin on PRV infected human cell lines (HEK293T and A549), and their transcriptome changes by PRV infection were investigated, compared to four different bat-derived cell lines (FBKT1 (Ryukyu flying fox), DEMKT1 (Leschenault's rousette), BKT1 (Greater horseshoe bat), YUBFKT1 (Eastern bent-wing bats)). In two human cell lines, unlike bat cells that induce an IFN-γ response pathway, an endoplasmic reticulum stress response pathway was commonly activated. Additionally, micafungin inhibits viral release rather than suppressing PRV genome replication in human cells, although it was disturbed in Vero cells. The target of micafungin's action may vary depending on the animal species, but it must be useful for human purposes as a first choice of medical care.

IntroductionGrowing anecdotal evidence suggests the feasibility of robotic intervention for people who suffer from disorders related to state anxiety. Few studies have been conducted on utilizing robots for persons who stutter (PWS). The present study examines the feasibility of using a robot for speech therapy for PWS.MethodsWe prepared four settings (i.e., interviews with unfamiliar persons, interviews with unfamiliar communication robots, reading sentences aloud with a tandem robot that can utter the same words as a user by repeating the user’s voice after a short delay, and reading sentences aloud while being alone). We assessed the potential of the robots as both interlocutors and practice partners in training with delayed auditory feedback (DAF) for PWS. Moreover, we assessed the relationship between the trait of stuttering and the participants’ affinity to the robots.ResultsEleven PWS participated in the study. Eight (72.7%) participants had fewer stuttering-related psychological symptoms when they communicated with robots than when they communicated with humans. Spearman’s rank correlation analysis revealed that there was a significant negative correlation between the Modified Erickson Communication Attitude scale (S-24) and the difference between the scores for stuttering-related psychological symptoms pertaining to the communication robot and humans (p

Key Clinical Message Negative myoclonus may present in the early stages of cefepime neurotoxicity. Cefepime neurotoxicity typically presents as reduced consciousness, myoclonus, and seizures; however, negative myoclonus is uncommon. This video shows an older woman with cefepime neurotoxicity that presented as a negative myoclonus of the upper limbs.