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Sequential optimization is one of the promising approaches in identifying the optimal candidate(s) (molecules, reactants, drugs, etc.) with desired properties (reaction yield, selectivity, efficacy, etc.) from a large set of potential candidates, while minimizing the number of experiments required. However, the high dimensionality of the feature space (e.g., molecular descriptors) makes it often difficult to utilize the relevant features during the process of updating the set of candidates to be examined. In this article, we developed a new sequential optimization algorithm for molecular problems based on reinforcement learning, multi-armed linear bandit framework, and online, dynamic feature selections in which relevant molecular descriptors are updated along with the experiments. We also designed a stopping condition aimed to guarantee the reliability of the chosen candidate from the dataset pool. The developed algorithm was examined by comparing with Bayesian optimization (BO), using two synthetic datasets and two real datasets in which one dataset includes hydration free energy of molecules and another one includes a free energy difference between enantiomer products in chemical reaction. We found that the dynamic feature selection in representing the desired properties along the experiments provides a better performance (e.g., time required to find the best candidate and stop the experiment) as the overall trend and that our multi-armed linear bandit approach with a dynamic feature selection scheme outperforms the standard BO with fixed feature variables. The comparison of our algorithm to BO with dynamic feature selection is also addressed. [ABSTRACT FROM AUTHOR]

We present a new food processing method to increase the content of polyphenols, which are a type of health-promoting food component, in harvested onions using atmospheric-pressure low-temperature plasma technologies. Harvested onions were locally irradiated for different times with a low-temperature air plasma jet generated near atmospheric pressure and stored in the dark for various periods. The plasma-irradiated area was 7 mm2. The plasma irradiation was performed without removing the onion peel. After storage following plasma irradiation, the onion was peeled and cut into the outer, middle, and inner parts, analysing polyphenol content at each edible onion part, namely the bulb. The polyphenol content in the onions irradiated for 30 min and stored for 3 d increased over that of unirradiated onions stored for the same period. This increase occurred regardless of the bulb parts. Neither the plasma-irradiated onions without storage nor the air gas-irradiated onions without air plasma irradiation exhibited a higher polyphenol content. In particular, quercetin aglycone, quercetin 4′-O-glucoside, quercetin 3-O-glucoside, and quercetin 3,4′-O-glucoside were increased in the polyphenol content, contributing to an increase in the antioxidative activity. NO3− and NO2− were introduced into water under an onion peel by air plasma irradiation for 30 min and decreased after 3 d of storage but remained. However, no H2O2 was introduced. The plasma-introduced NO3− was distributed throughout the onion owing to the plasmodesmata serving as channels for cell-to-cell transports of molecules. These results suggest that the increased polyphenol content originates from the transcriptional factors acting in stress responses to the plasma-introduced NO3− and NO2−, not the electric field-induced electroporation, in onion cells. The present study provides valuable insights into interactions between low-temperature air plasma jets and onion cells. [ABSTRACT FROM AUTHOR]

This study proposes a method for determining the appropriate harvesting order for densely growing wood ear mushrooms by recognizing their growth stages and harvesting priorities from depth images obtained from a stereo camera. We aim to minimize crop damage and improve the quality of harvested crops during the harvesting of densely growing crops using a robot arm. The proposed two-stage method consists of two models—one of the models to recognize priority harvest regions, and the other model to identify individual wood ear mushroom regions and growth stages. The final harvesting order is determined based on the outputs of these models. The models were trained using simulated CGI data of wood ear mushroom growth. The experimental results show that the appropriate harvesting order can be outputted in 57.5% of the cases for the 40 sets of test data. The results show that it is possible to determine the harvesting order of dense wood ear mushrooms based solely on depth images. However, there is still room for improvement in operations in actual environments. Further work is needed to enhance the method's robustness and accuracy. [ABSTRACT FROM AUTHOR]

In Japan, little is known about the approaches to medical care for older patients with multimorbidity used by physicians either at patients' homes or in hospitals. A questionnaire survey was conducted to understand the current approaches to older patients with multimorbidity. The questionnaire was sent to 3300 people, including 1650 geriatric specialists and 1650 primary care specialists, were enrolled. A four-point Likert-type scale was used to score the following items: diseases that cause difficulties in treatment (diseases), patient backgrounds that cause difficulties in treatment (backgrounds), important clinical factors, and important clinical strategies. We used the Tukey–Kramer test to examine the differences between scores across 3 groups: physicians providing only home care (the "home" group), physicians providing only inpatient care (the "hospital" group), and physicians providing both home care and inpatient care (the "home and hospital" group). Out of 836 valid responses, those from 587 physicians were included in the analysis. The overall score for diseases was significantly higher in the "hospital" group than in either the "home" or "home and hospital" groups. The overall score for important clinical strategies was significantly higher in the "home and hospital" group than in the "hospital" group. In conclusion, physicians' approaches to treating older people with multimorbidity may vary by practice setting, and particularly whether they provide care only to patients at home or in hospital or to both. To improve the quality of transition of care between hospital and home, a support system that considers differences in physician practice should be developed. [ABSTRACT FROM AUTHOR]

Background: Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. Methods: Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. Results: Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. Conclusions: Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs. [ABSTRACT FROM AUTHOR]

Lacrimal punctal agenesis is an extremely rare condition with an unclear genetic basis. Here, we report a 3‐year‐old male patient harboring a hemizygous variant in glypican 4 (GPC4), which causes Keipert syndrome, who presented with complete lacrimal punctal agenesis, distinctive craniofacial features, mild developmental delay, mild intellectual disability, and autism. The craniofacial features included a prominent forehead, epicanthus, depressed and broad nasal bridge, hypoplastic columella, midface hypoplasia, tented upper lip, and low‐set ears. Proband exome sequencing identified a hemizygous variant in GPC4: NM_001448.3:c.1051C > T (p.Arg351*). The GPC4 variant was inherited from his heterozygous mother; X‐inactivation followed a skewed pattern in his mother. This patient demonstrated clinical features consistent with Keipert syndrome including craniofacial features, brachydactyly, broad distal phalanx, broad first toe, and mild developmental delay; however, agenesis of the lacrimal puncta has not been reported previously in Keipert syndrome. Our findings suggest that GPC4, which encodes a heparan‐sulfate proteoglycan, may play an important role in lacrimal morphogenesis. Our observations also suggest that Keipert syndrome should be considered in patients with lacrimal punctal agenesis. [ABSTRACT FROM AUTHOR]

Techniques for triggering neural differentiation of embryonic and induced pluripotent stem cells into neural stem cells and neurons have been established. However, neural induction of mesenchymal stem cells, including dental pulp stem cells (DPSCs), has been assessed primarily based on neural-related gene regulation, and detailed studies into the characteristics and differentiation status of cells are lacking. Therefore, this study was aimed at evaluating the cellular components and differentiation pathways of neural lineage cells obtained via neural induction of human DPSCs. Human DPSCs were induced to neural cells in monolayer culture and examined for gene expression and mechanisms underlying differentiation using microarray-based ingenuity pathway analysis. In addition, the neural lineage cells were subjected to single-cell RNA sequencing (scRNA-seq) to classify cell populations based on gene expression profiles and to elucidate their differentiation pathways. Ingenuity pathway analysis revealed that genes exhibiting marked overexpression, post-neuronal induction, such as FABP7 and ZIC1, were associated with neurogenesis. Furthermore, in canonical pathway analysis, axon guidance signals demonstrated maximum activation. The scRNA-seq and cell type annotations revealed the presence of neural progenitor cells, astrocytes, neurons, and a small number of non-neural lineage cells. Moreover, trajectory and pseudotime analyses demonstrated that the neural progenitor cells initially engendered neurons, which subsequently differentiated into astrocytes. This result indicates that the aforementioned neural induction strategy generated neural stem/progenitor cells from DPSCs, which might differentiate and proliferate to constitute neural lineage cells. Therefore, neural induction of DPSCs may present an alternative approach to pluripotent stem cell-based therapeutic interventions for nervous system disorders. [ABSTRACT FROM AUTHOR]

Background: Sub-phenotyping of acute respiratory distress syndrome (ARDS) could be useful for evaluating the severity of ARDS or predicting its responsiveness to given therapeutic strategies, but no studies have yet investigated the heterogeneity of patients with severe ARDS requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO). Methods: We conducted this retrospective multicenter observational study in adult patients with severe ARDS treated by V-V ECMO. We performed latent class analysis (LCA) for identifying sub-phenotypes of severe ARDS based on the radiological and clinical findings at the start of ECMO support. Multivariate Cox regression analysis was conducted to investigate the differences in mortality and association between the PEEP setting of ≥ 10 cmH2O and mortality by the sub-phenotypes. Results: We identified three sub-phenotypes from analysis of the data of a total of 544 patients with severe ARDS treated by V-V ECMO, as follows: Dry type (n = 185; 34%); Wet type (n = 169; 31%); and Fibrotic type (n = 190; 35%). The 90-days in-hospital mortality risk was higher in the patients with the Fibrotic type than in those with the Dry type (adjusted hazard ratio [95% confidence interval] 1.75 [1.10–2.79], p = 0.019) or the Wet type (1.50 [1.02–2.23], p = 0.042). The PEEP setting of ≥ 10 cmH2O during the first 3 days of ECMO decreased the 90-days in-hospital mortality risk only in patients with the Wet type, and not in those with the Dry or Fibrotic type. A significant interaction effect was observed between the Wet type and the PEEP setting of ≥ 10 cmH2O in relation to the 90-day in-hospital mortality (pinteraction = 0.036). Conclusions: The three sub-phenotypes showed different mortality rates and different relationships between higher PEEP settings in the early phase of V-V ECMO and patient outcomes. Our data suggest that we may need to change our management approach to patients with severe ARDS during V-V ECMO according to their clinical sub-phenotype. [ABSTRACT FROM AUTHOR]

Solute carrier family 37 member 4 (SLC37A4) is known to regulate glucose-6-phosphate transport from cytoplasm to the lumen of the endoplasmic reticulum, which serves to maintain glucose homeostasis. Glycogen storage disease type 1b (GSD1b) is caused by a mutation of SLC37A4, leading to a glycogenolysis defect. Although GSD1b cases are known to be complicated by periodontitis, the etiological molecular basis remains unclear. The present study investigated the effects of SLC37A4 on gingival barrier function. Examinations of immortalized human gingival epithelial (IHGE) cells showed SLC37A4 localized in the endoplasmic reticulum. SLC37A4 knockout decreased expression of JAM1, a tight junction-related protein, in IHGE cells. Using in silico analysis to investigate potential transcription factor binding sites, H6 family homeobox 3 (HMX3) was shown to be related to JAM1 expression. In HMX3-knockdown IHGE cells, JAM1 expression was markedly suppressed. Furthermore, HMX3 was scarcely detected in SLC37A4-knockout cells, while HMX3 overexpression restored JAM1 expression in those cells. Finally, using a three-dimensional multilayered gingival epithelial tissue model, knockout of SLC37A4 was also found to increase permeability to lipopolysaccharide and peptidoglycan, which was dependent on JAM1 expression. Specific downregulation of HMX3 by SLC37A4 and the consequent decrease in JAM1 expression provides findings indicating a molecular basis for the reduction in barrier function of gingival epithelial tissues in GSD1b cases. [ABSTRACT FROM AUTHOR]

Background: Periodontal health in men with HIV remains understudied, despite suggestions of associations between HIV infection and gingival pocketing, periodontal attachment loss, and gingival inflammation. As antiretroviral therapy (ART) has improved the quality of life for people living with HIV (PLWH), aging-related risk factors and comorbidities, including periodontitis, have emerged. This study aims to assess alveolar bone height, gingival crevicular fluid (GCF) cytokines, and periodontal disease activity in men with and without HIV. Methods: Ninety-three men (50 HIV+, 43 HIV-) aged 35–70 years were recruited from Columbia University Irving Medical Center clinics. Periodontal examination, GCF collection, and intraoral radiographs were collected. Statistical analysis was conducted with t-tests for continuous variables and chi-squared tests for categorical variables. Results: While no significant differences were observed in bleeding on probing, clinical attachment loss and pocket depths, men with HIV exhibited significantly greater alveolar crestal height on radiographs compared to men without HIV (HIV + 3.41+/-1.35 mm, HIV- 2.64+/-1.01 mm; p = 0.004), reflecting greater alveolar bone loss. Conclusions: Men living with HIV demonstrate increased alveolar bone loss compared to those without HIV, possibly mediated by elevated IL6 levels. These results underscore the importance of comprehensive oral health management in PLWH and highlight the need for further research understanding the mechanisms linking HIV infection, cytokine dysregulation, and periodontal health. [ABSTRACT FROM AUTHOR]

Cellulose acetate (CA), synthesized by solid–liquid acetylation of low crystalline cellulose (LCCell) obtained by cold shearing in a short time under environmentally benign conditions, effectively enhanced the crystallization of poly(lactic acid) (PLA). The composite of PLA compounded with CA from LCCell exhibited higher crystallinity of PLA and flexural modulus than those from pristine PLA. CAs obtained from crystalline and recrystallized cellulose also improved the mechanical strength of PLA by compounding, but their effects were weaker than that of CA from LCCell. The factor of the effectiveness of CA obtained from LCCell is the higher miscibility with PLA originating from the sufficiently released interchain hydrogen bonds in the cellulose fibrils by cold shearing, which allows the dissolution of macroscopic aggregation of the CA chains in the composite. [ABSTRACT FROM AUTHOR]

Background: Error-corrected next-generation sequencing (ecNGS) technologies have enabled the direct evaluation of genome-wide mutations after exposure to mutagens. Previously, we reported an ecNGS methodology, Hawk-Seq™, and demonstrated its utility in evaluating mutagenicity. The evaluation of technical transferability is essential to further evaluate the reliability of ecNGS-based assays. However, cutting-edge sequencing platforms are continually evolving, which can affect the sensitivity of ecNGS. Therefore, the effect of differences in sequencing instruments on mutation data quality should be evaluated. Results: We assessed the performance of four sequencing platforms (HiSeq2500, NovaSeq6000, NextSeq2000, and DNBSEQ-G400) with the Hawk-Seq™ protocol for mutagenicity evaluation using DNA samples from mouse bone marrow exposed to benzo[a]pyrene (BP). The overall mutation (OM) frequencies per 106 bp in vehicle-treated samples were 0.22, 0.36, 0.46, and 0.26 for HiSeq2500, NovaSeq6000, NextSeq2000, and DNBSEQ-G400, respectively. The OM frequency of NextSeq2000 was significantly higher than that of HiSeq2500, suggesting the difference to be based on the platform. The relatively higher value in NextSeq2000 was a consequence of the G:C to C:G mutations in NextSeq2000 data (0.67 per 106 G:C bp), which was higher than the mean of the four platforms by a ca. of 0.25 per 106 G:C bp. A clear dose-dependent increase in G:C to T:A mutation frequencies was observed in all four sequencing platforms after BP exposure. The cosine similarity values of the 96-dimensional trinucleotide mutation patterns between HiSeq and the three other platforms were 0.93, 0.95, and 0.92 for NovaSeq, NextSeq, and DNBSeq, respectively. These results suggest that all platforms can provide equivalent data that reflect the characteristics of the mutagens. Conclusions: All platforms sensitively detected mutagen-induced mutations using the Hawk-Seq™ analysis. The substitution types and frequencies of the background errors differed depending on the platform. The effects of sequencing platforms on mutagenicity evaluation should be assessed before experimentation. [ABSTRACT FROM AUTHOR]

Extractives, which naturally evolve as fundamental defense mechanisms in wood against environmental stresses, hold an essential place in the field of wood conservation science. Despite their low content in woody substrates, extractives are chemically complex and can be extracted accurately by solvents with different polarities, covering key components such as aliphatic, terpenoid, and phenolic compounds. The application of solvent extraction allows for the effective recovery of these extracts from forestry waste, thereby creating new opportunities for their reuse in wood modification and enhancing the economic value and potential applications of forestry waste. In the wood industry, extractives not only act as efficient preservatives and photo-stabilizers, significantly improving the decay resistance and photodegradation resistance of wood, but also serve as ideal dyes for fast-growing wood due to their abundant natural colors, which lend the product a distinct aesthetic appeal. The aim of this paper is to provide a comprehensive review of the origin and distribution characteristics of wood extractives and to examine the impact of solvent selection on extraction efficiency. At the same time, the mechanism of extractives in enhancing wood decay resistance and slowing down photodegradation is deeply analyzed. In addition, specific examples are presented to illustrate their wide utilization in the wood industry. This is intended to provide references for research and practice in related fields. [ABSTRACT FROM AUTHOR]

In this study, we investigated the spatial distribution and homogeneity of gold nanoparticles (AuNPs) on an alumina (Al2O3; AAO) substrate for potential application as surface-enhanced Raman scattering (SERS) sensors. The AuNPs were synthesized through thermal treatment at 450 °C at varying times (5, 15, 30, and 60 min), and their distribution was characterized using field-emission scanning electron microscopy (FE-SEM) and scanning transmission electron microscopy (STEM). The FE-SEM and STEM analyses revealed that the size and interparticle distance of the AuNPs were significantly influenced by the duration of thermal treatment, with shorter times promoting smaller and more closely spaced nanoparticles, and longer times resulting in larger and more dispersed particles. Raman spectroscopy, using Rhodamine 6G (R6G) as a probe molecule, was employed to evaluate the SERS enhancement provided by the AuNPs on the AAO substrate. Raman mapping (5 µm × 5 µm) was conducted on five sections of each sample, demonstrating improved homogeneity in the SERS effect across the substrate. The topological features of the AuNPs before and after R6G incubation were analyzed using atomic force microscopy (AFM), confirming the correlation between a decrease in surface roughness and an increase in R6G adsorption. The reproducibility of the SERS effect was quantified using the maximum intensity deviation (D), which was found to be below 20% for all samples, indicating good reproducibility. Among the tested conditions, the sample synthesized for 15 min exhibited the most favorable characteristics, with the smallest average nanoparticle size and interparticle distance, as well as the most consistent SERS enhancement. These findings suggest that AuNPs on AAO substrates, particularly those synthesized under the optimized condition of 15 min at 450 °C, are promising candidates for use in SERS-based sensors for detecting cancer biomarkers. This could be attributed to temperature propagation promoted at the time of synthesis. The results also provide insights into the influence of thermal treatment on the spatial distribution of AuNPs and their subsequent impact on SERS performance. [ABSTRACT FROM AUTHOR]

Purpose: Some patients who undergo anterior cruciate ligament (ACL) reconstruction experience abnormal mechanical stress in the meniscus. Medial meniscal extrusion (MME) is reflected in the pathological condition of the meniscus, which expands owing to repetitive mechanical stress. Thus, the effect of the reconstructed ACL on increasing MME under weight-bearing conditions remains unclear. This study investigated the effect of ACL reconstruction on meniscal extrusion under non-weight-bearing and weight-bearing conditions. Methods: Seventeen patients who underwent unilateral ACL reconstruction (ACL group) and 20 age-matched healthy volunteers (control group) were enrolled. Ultrasonography was performed in the supine, standing, and walking positions in preoperative and postoperative ACL patients. MME during walking was evaluated based on the dynamic behavior of extrusion, and kinetic and kinematic data were synchronously obtained. Moreover, the ACL group underwent magnetic resonance imaging (MRI) evaluation at two points: preoperatively and 12 months postoperatively, and the ultrasound findings were compared. Results: MME in the supine position measured using both ultrasonography and MRI was not significantly different preoperatively and postoperatively in the ACL group. However, postoperative MME and dynamic behavior of extrusion under standing and walking conditions were significantly higher than those in the preoperative state (dynamic behavior: 0.9 ± 0.4 mm preoperatively, 1.2 ± 0.4 mm postoperatively). Moreover, the deficits in knee extension during walking persisted postoperatively and were significantly higher than those in the control group. Conclusion: MME in patients with ACL reconstruction including meniscus repair was different under mechanical stress compared to the non-weight bearing condition. [ABSTRACT FROM AUTHOR]

Summary: Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra‐terminal motif (BET) inhibitor on iPSC‐derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment. [ABSTRACT FROM AUTHOR]

Solvent extraction behaviors of Se (VI) from nitric acid solutions were investigated with multiple extractants used for uranium, plutonium, minor actinides, and rare earth elements separation processes from high-level liquid waste. During the processes, Se remained in the residual aqueous solutions, as all extractants showed distribution ratios < 1. In contrast, Se showed distribution ratios > 1 with o-phenylenediamine in dilute nitric acid (< 2 M HNO3), octanol as the organic phase, and concentrated nitric acid (8 M HNO3) for back extraction, suggesting a potential new single separation process and recovery of Se. [ABSTRACT FROM AUTHOR]

Members of the T-cell immunoglobulin and mucin (TIM) family, which is crucial for T-cell function, are implicated in autoimmunity. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. Zymosan A was used to induce arthritis in female SKG mice. The arthritis scores, histology, mRNA expression, cytokine levels, micro-computed tomography, and flow cytometry results were obtained. The application of RMT1-10 reduced the arthritis scores, histological damage, and CD4+ T-cell infiltrations, and it suppressed interleukin (IL)-6 and -17A and reduced TIM-3 mRNA expressions. RMT3-23 also lowered arthritis severity, improved histology, and reduced serum levels of tumor necrosis factor (TNF)-α and IL-17A. RMT3-23 inhibited intracellular TNF-α and IL-6 and early apoptosis. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis. Graphical Abstract [ABSTRACT FROM AUTHOR]

This article provides a historical overview of the period from 1853 to 1889, during which Okinawa transitioned from the Ryūkyū Kingdom to Okinawa prefecture. It examines the political process of integrating Okinawa into the modern Japanese state, considering both international and domestic challenges faced by the Meiji regime. The article also explores the unique position of Okinawa within Japanese society, its historical relations with China, and the resistance movements that emerged during the integration process. Additionally, the document discusses the negotiations between Japan and China regarding the division of the Ryūkyū archipelago, which ultimately failed to reach an agreement. It also delves into the Meiji government's decision to station a military detachment in Okinawa for national defense purposes, despite objections from China. [Extracted from the article]

The following section includes an introduction to the work of Okinawan historian Gabe Masao by Wendy Matsumura and Tze M. Loo, along with translations of two of his articles that were previously available only in the original Japanese. First, Matsumura and Loo's introduction situates Gabe's work within the historiographical literature on the Ryūkyū kingdom's annexation by the Japanese state, arguing that although he eschews the word "colonialism" to describe the process through which the newly formed Okinawa prefecture is incorporated into the empire, his work provides compelling evidence to support the application of a colonial framework to understand Japan's rule of the prefecture. Next is Gabe's essay "From Ryūkyū to Okinawa," as excerpted and translated by Matsumura. Last is Loo's excerpt and translation of Gabe's "Actions toward Modern Japanese National Consciousness: The Case of Ryūkyū-Okinawa." [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that prenatal maternal smoking and maternal secondhand smoke exposure during pregnancy were associated with an increased risk of wheezing and asthma development. However, few studies have examined the influence of different sources of tobacco exposure in different perinatal timeframes (preconception, prenatal, and postnatal) on wheezing phenotypes in children. Using national survey data from Japan, we investigated the effects of exposure to tobacco smoke during pregnancy on wheezing phenotypes in children before the age of 3 years. Methods: Pregnant women who lived in the 15 regional centers in the Japan Environment and Children's Study were recruited. We obtained information on prenatal and postnatal exposure to active and secondhand smoke (SHS) and wheeze development up to 3 years of age. Multiple logistic regression analysis was performed to determine the association between tobacco smoke exposure and wheezing phenotypes in children. Results: We analyzed 73,057 singleton births and identified four longitudinal wheezing phenotypes: never wheezing; early transient wheezing (wheezing by age 1 year but not thereafter); late-onset wheezing (wheezing by age 2–3 years but not beforehand); and persistent wheezing. Maternal smoking during pregnancy was significantly associated with early transient and persistent wheezing in children compared with no maternal smoking [early transient wheezing: 1–10 cigarettes per day, adjusted odds ratio (aOR) 1.43, 95% confidence interval (CI) 1.23–1.66; ≥ 11 cigarettes per day, aOR 1.67, 95% CI 1.27–2.20; persistent wheezing: 1–10 cigarettes per day, aOR 1.64, 95% CI 1.37–1.97; ≥ 11 cigarettes per day, aOR 2.32, 95% CI 1.70–3.19]. Smoking cessation even before pregnancy was also significantly associated with increased risk of early transient wheezing, late-onset wheezing, and persistent wheezing in children. Moreover, maternal exposure to SHS during pregnancy was significantly associated with increased risk of early transient and persistent wheezing compared with no such exposure. Conclusions: Maternal smoking before and throughout pregnancy was associated with wheeze development in children up to 3 years of age. It appears that smoking is detrimental compared to never smoking, regardless of whether individuals quit smoking before or after becoming aware of the pregnancy. [ABSTRACT FROM AUTHOR]

Background: Accurate implant placement in the optimal position is important to obtain favourable clinical outcomes and prevent complications in total joint arthroplasty. We aimed to assess the accuracy of implant placement based on three-dimensional (3D) preoperative planning for unlinked total elbow arthroplasty (TEA) and to clarify the effect of implant placement on clinical outcomes. Methods: This study included 20 patients (22 elbows, 17 with rheumatoid arthritis and 5 with osteoarthritis, with a mean follow-up period of 47 months) who underwent TEA with an unlinked-type implant after computed tomography (CT)-based 3D preoperative planning. Implant placement was planned preoperatively and several parameters were set to reflect it intraoperatively. TEA was performed based on the plan, and postoperative CT was conducted to evaluate differences in implant placement by comparing the preoperative plan and postoperative implant placement. Furthermore, we evaluated the relationship between implant placement differences and postoperative clinical outcomes, including range of motion, Visual Analogue Scale, Mayo Elbow Performance Score 1 year after surgery and complications at the last follow-up. Results: The mean absolute translation was within 2 mm, the mean absolute tilt was within 4°, the mean absolute rotation of the humeral component was within 4° and the mean absolute rotation of the ulnar component was 10.2° ± 6.8°. In the ulnar components, 15/22 (68%) cases were externally rotated, and the mean external rotation was 7.1° ± 10.2°. We defined the absolute ulnar component's rotational difference of more than 10° as a 'malrotation' group (n = 8) and 10° or less as a 'control' group (n = 14). We compared the clinical outcomes between both groups, however, no significant differences were observed in clinical outcomes and complications. Conclusions: We observed notable malrotation in the postoperative positioning of the ulnar component. Intraoperative support devices may be necessary to accurately reproduce the preoperative plan in the surgical field. Level of Evidence: Level IV (Therapeutic) [ABSTRACT FROM AUTHOR]

Botulism is a deadly neuroparalytic condition caused by the botulinum neurotoxin (BoNT) produced by Clostridium botulinum and related species. Toxin‐neutralizing antibodies are the most effective treatments for BoNT intoxication. We generated human monoclonal antibodies neutralizing type B botulinum neurotoxin (BoNT/B), designated M2 and M4. The combination of these antibodies exhibited a strong neutralizing effect against BoNT/B toxicity. In this study, we analyzed the mechanisms of action of these antibodies in vitro. M4 binds to the C‐terminus of the heavy chain (the receptor‐binding domain) and inhibits BoNT/B binding to neuronal PC12 cells. Although M2 recognized the light (L) chain (the metalloprotease domain), it did not inhibit substrate (VAMP2) cleavage in the cleavage assay. M2 increased the surface localization of BoNT/B in PC12 cells at a later time point, suggesting that M2 inhibits the translocation of the L chain from synaptic vesicles to the cytosol. These results indicate that M2 and M4 inhibit the different processes of BoNT/B individually and that multistep inhibition is important for the synergistic effect of the combination of monoclonal antibodies. Our findings may facilitate the development of effective therapeutic antibodies against BoNTs. [ABSTRACT FROM AUTHOR]

Objectives: The osteological paradox recognizes that the presence of lesions is not always directly related with increased mortality. When combined with the clinical, historical, and epidemiological literature on scurvy, survivorship analysis, a form of statistical analysis to assess the relationship between the presence of diseases in the archeological record and survival, helps determine the overall burden of the disease both in terms of morbidity and mortality. This article explores the relationship between scurvy and survivorship in 26 adults from Man Bac, a Neolithic site from northern Vietnam together with prepublished evidence of scurvy in the nonadult population (n = 44). Methods: Diagnosis of scurvy included differential diagnosis combined with the Snoddy, A. M. E., Buckley, H. R., Elliott, G. E., Standen, V. G., Arriaza, B. T., & Halcrow, S. E. (2018). Macroscopic features of scurvy in human skeletal remains: A literature synthesis and diagnostic guide. American Journal of Physical Anthropology, 167(4), 876–895. https://doi.org/10.1002/ajpa.23699 threshold criteria and the Brickley, M. B., & Morgan, B. (2023). Assessing diagnostic certainty for scurvy and rickets in human skeletal remains. American Journal of Biological Anthropology, 181, 637–645 diagnostic certainty approaches. Kaplan–Meier survival curves were produced to assess the relationship between the presence of probable scurvy and age‐at‐death. Results: The prevalence of probable scurvy in adults (35%) was considerably lower than reported for the nonadults (80%). Almost all lesions observed in the adults were in a mixed stage of healing. Kaplan–Meier analysis demonstrated no difference in survivorship between infants and children (<15 years) with or without probable scurvy, whereas a meaningful difference was observed for the adults and adolescents (15+ years). Conclusions: The findings demonstrate that scurvy considerably decreased survivorship to older age categories. The degree of lesion remodeling, however, indicates that scurvy was not necessarily the direct cause of death but contributed to an overall disease burden that was ultimately fatal. [ABSTRACT FROM AUTHOR]

Background: Recently, the incidence of achalasia has been increasing, but its cause remains unknown. This study aimed to examine the initial symptoms and the course of symptoms and to find new insights into the cause and course of the disease. Methods: Altogether, 136 patients diagnosed with achalasia by high-resolution manometry (HRM) were enrolled. Questionnaires and chart reviews were conducted to investigate the initial symptoms, time from onset to diagnosis, and comorbidities, as well as the relationship between HRM results, time to diagnosis, and symptom severity. Results: In total, 67 of 136 patients responded to the questionnaire. The median ages of onset and diagnosis were 42 and 58 years, respectively. The median time from onset to diagnosis was 78.6 months, with 25 cases (37.3%) taking > 10 years to be diagnosed. The symptom onset was gradual and sudden in 52 (77.6%) and 11 (16.4%) patients, respectively. Of the 11 patients with acute onset, three (27.3%) developed anhidrosis at the same time. There was no correlation between the time from onset to diagnosis and esophageal dilatation, resting LES pressure, or mean integrated relaxation pressure (IRP). No correlation was also found between the degree of symptoms and resting LES pressure or IRP. Conclusion: Esophageal achalasia can have acute or insidious onsets. This finding may help to elucidate the cause of achalasia. [ABSTRACT FROM AUTHOR]

A gaseous mixture of CO2 and C5F10O has been widely investigated as one of the alternative gases for SF6. Due to the better electron attachment ability of oxygen molecule O2, it is generally expected that adding of O2 gas would improve the dielectric strength of arc quenching and insulating gas for electric power equipment. Therefore, in this paper, the dielectric breakdown properties of hot CO2/O2/C5F10O gas mixture were numerically estimated. The calculation results revealed that the critical electric field strength of the CO2/C5F10O gas mixture is disappointingly decreased by the addition of O2 gas, especially in the temperature range of 3000 K to 1000 K. This is brought about by the increase of ionization reaction of CO2 molecules with an increase in the O2 concentration in the arc‐quenching gas of CO2/O2/C5F10O. © 2024 Institute of Electrical Engineers of Japan and Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

The activation level of the JAEA-Tokai tandem accelerator facility was investigated experimentally in advance of the future decommissioning. JAEA-Tokai tandem accelerator facility has a higher terminal voltage of 18 MV and a larger total floor area, Compared to other electrostatic accelerators with terminal voltage of 1 MV to 6 MV. Therefore, determination for 'where,' 'what,' and 'how many' nuclides are produced in the facility is crucial. Thermal neutrons generated by beam losses associated with accelerator operations contribute significantly to the activation of equipment and facilities. The accumulated activities of60Co and152Eu; the most considerable radionuclides at the decommissioning, can be deduced by the thermal neutron fluence rate during the accelerator operation. In this study, thermal neutron fluence measurement on the surface of the pressure vessel and concrete building was conducted with conventional methods using dosimeters and metal foil detectors as well as a new method using a portable γ-ray detector. The thermal neutron fluence in the facility during the accelerator operation ranges from 101 to 104 n/cm2/s. The sum of deduced activities of60Co and152Eu in 50 years is much lower than the clearance level of 0.1 Bq/g in all areas except in the irradiation room. [ABSTRACT FROM AUTHOR]

Objective: We aimed to establish a practical diagnostic index for Lewy body diseases (LBD), such as Parkinson's disease and dementia, with Lewy bodies in outpatient settings and criteria for exempting patients from late imaging. Methods: We acquired early and late 123I-metaiodobenzylguanidine (MIBG) images from 108 consecutive patients with suspected LBD and standardized heart-to-mediastinum (H/M) ratios for collimator conditions. Exclusions included young-onset Parkinson's disease (age < 50 years) and genetic transthyretin-type amyloidosis. We developed logistic models incorporating H/M ratios with or without age (n = 92). The sympathetic MIBG index for LBD (SMILe index), categorized LBD likelihood from 0 (lowest) to 1 (highest). Diagnostic accuracy was assessed as the area under the receiver operating characteristic (ROC) curve (AUC). The characteristics of the new index were compared with H/M ratios. The need for late imaging was explored using the SMILe index. Results: Early or late SMILe indexes using a single H/M ratio variable discriminated LBD from non-LBD. The AUC values for early and late SMILe indexes were 0.880 and 0.894 (p < 0.0001 for both), identical to those for early and late H/M ratios. The sensitivity and the specificity of early SMILe indexes with a 0.5 threshold were 76% and 90%, achieving accuracy of accuracy 86%. Similarly, the late SMILe index demonstrated a sensitivity of 76% and specificity of 87%, with an accuracy of 84%. Early SMILe indexes < 0.3 or > 0.7 (representing 84% patients) indicated a diagnosis without a late MIBG study. Conclusion: The 123I-MIBG-derived SMILe indexes provide likelihood of LBD, and those with a 50% threshold demonstrated optimal diagnostic accuracy for LBD. The index values of either < 0.3 or > 0.7 accurately selected patients who do not need late imaging. [ABSTRACT FROM AUTHOR]

Background: Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. Methods: We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS ≥ 12 months). Results: Fifty patients (76.9%) received ≥ 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36–5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04–0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of ≥ 1 dose of pegfilgrastim, or either ≥ 5 doses of filgrastim or ≥ 1 dose of pegfilgrastim). Conclusions: G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. Methods: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. Results: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1–36.8) and 63.8% (95% CI, 48.0–75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. Conclusion: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases. [ABSTRACT FROM AUTHOR]

In compression ignition engines, the urea selective catalytic reduction (SCR) system is used to reduce NOX in the exhaust gas. However, under low exhaust gas temperature conditions, the urea is not decomposed completely, leading to a decreased NOx purification rate. In this study, the temperature of the urea water solution (UWS) was controlled to promote atomization, evaporation, and the chemical reaction of the UWS spray. To understand the effect of the degree of superheat on UWS spray characteristics, the urea SCR nozzle tip was electrically heated, and the UWS spray was optically measured at different temperatures. The Super High Spatial Resolution Photography (SHSRP) method, which allows for whole spray imaging while maintaining the spatial resolution of small droplets, was applied, and the UWS droplet size distribution in quiescent conditions was analyzed. By applying a phase change model of flash boiling with energy balance, the vapor mass fraction at the nozzle outlet of the heated UWS spray was analyzed. Assuming a low-temperature exhaust gas flow field, the mass fraction of UWS spray droplets following the gas flow, the adhesion mass on the wall, and the location of water evaporation were estimated. The efficiency of UWS heating in urea SCR systems was discussed. [ABSTRACT FROM AUTHOR]

In compression ignition engines, the urea selective catalytic reduction system is used to reduce NOX in the exhaust gas. However, under low exhaust gas temperature conditions, the urea water solution (UWS) film forms on the wall where the spray impinges and changes chemically to the solid deposit. Since this solid deposit prevents the NH3 formation and its homogeneous dispersion, it is necessary to understand the detailed chemical reaction process under actual engine conditions. In this study, the chemical reaction process of the UWS film was measured by Raman spectroscopy in an experimental system simulating the actual exhaust system. As a result, the UWS film evaporated and decomposed at all gas temperatures, and finally solid deposits remained on the wall, with different mass and composition at each gas temperature. Immediately after the UWS was put in, the urea mass decreased, and the wall surface temperature also decreased due to the vaporization latent heat. Thereafter, the rate of decrease of urea mass becomes smaller as the surface temperature of the wall surface decreases. [ABSTRACT FROM AUTHOR]

Ash formation in post-injection is considered to be caused by the splashing of lubricant oil due to the impingement of the spray on the lubricant oil film. In this paper, the mixing ratio of diesel fuel and lubricating oil in droplets splashed from the oil crown was measured using the laser-induced fluorescence method. By measuring the droplet diameter and the number of droplets, the experimental equation to predict the amount of lubricant dispersed is calculated. As a result, it was shown that the amount of lubricant splashed from the oil crown decreased as the K-factor increased, and the amount of lubricant splashed increased as the non-dimensional film thickness δnon increased. [ABSTRACT FROM AUTHOR]

In port fuel injection (PFI) gasoline engines, combustion fluctuations are caused by the interaction of various factors during ignition. Variations in the fuel deposition on the intake port walls cause fluctuations in the fuel supply to the combustion chamber and in the fuel concentration distribution, which causes knocking. In addition, when a large amount of fuel deposition occurs, it flows into the cylinder in liquid form without vaporizing, generating unburned hydrocarbons. In the previous report, we confirmed that the fuel adhesion amount on the port wall can be reduced by increasing the fuel injection pressure. In this paper, we investigated fuel atomization under even higher injection pressure conditions than the injection pressure range commonly used in intake port injection, with the aim of further reducing the amount of adhesion. In this paper, shadowgraph photography and Super High Spatial Resolution Photography were used to visualize and measure the free-spray jet morphology and atomization characteristics. The effect of high injection pressure to like direct injection, which on the Jet configuration and atomization characteristics of the spray. The results showed that the droplet diameter changed significantly from 1 to 3 MPa (Wavy region) to 4 MPa (Spray region), but no significant change was observed after 8 MPa (Spray region, Spray region with secondary breakup), and that the droplet diameter did not decrease after 8 MPa. [ABSTRACT FROM AUTHOR]

We synthesized a "cyborg protein," wherein a synthetic molecule partially substitutes the main peptide chain by linking 2 protein domains with a synthetic oligomer. Green fluorescent protein (GFP) served as the model for constructing the cyborg proteins. We prepared circularly permuted GFP (cpGFP) with new termini between β10 and β11, where the original N- and C-termini were linked by a cleavable peptide loop. The cyborg GFP was constructed from cpGFP by linking the β10 and β11 with oligo(ethylene glycol) (OEG) using maleimide-cysteine couplings, followed by the enzymatic cleavage of the N- and C-termini linking loop by thrombin. With the help of machine learning, we were able to obtain the cpGFP mutants that significantly alter the fluorescence intensity (53% increase) by thrombin treatment, which splits cpGFP into 2 fragments (fragmented GFP), and by heat shock. When the cyborg GFP was constructed using this mutant, the fluorescence intensity increased by 13% after heat treatment, similar to cpGFP (33% increase), and the behavior was significantly different from that of the fragmented GFP. This result suggests the possibility that the OEG chain in the cyborg protein plays a similar role to the peptide in the main chain of the protein. [ABSTRACT FROM AUTHOR]

The present paper is concerned with an inviscid limit problem of radially symmetric stationary solutions for an exterior problem in R n (n ≥ 2) to compressible Navier–Stokes equation, describing the motion of viscous barotropic gas without external forces, where boundary and far field data are prescribed, in particular, the flow velocity at the far field is assumed to be zero. For both inflow and outflow problems, the inviscid limit is considered in a suitably small neighborhood of the far field state. For the outflow problem, we prove the uniform convergence of the Navier–Stokes flow toward the corresponding Euler flow in the inviscid limit. On the other hand, for the inflow problem, we show that the Navier–Stokes flow uniformly converges toward a linear superposition of the corresponding boundary layer profile and the Euler flow in the inviscid limit. The estimates of algebraic rate toward the inviscid limit are also obtained. [ABSTRACT FROM AUTHOR]

Many animal species have movement abilities. Behavior is important for evolutionary ecology because animal movement leads to dispersal, migration, search for food and mates, and escaping from enemies. However, individual differences in movement activity are found within a population. This phenomenon can be affected by various factors, one of which is suggesting that higher moving activity has fitness cost, whereas lower moving activity has benefits. Animal movement may also affect reproduction (e.g., resource allocation tradeoff between movement and reproduction as well as intra‐ and intersexual selection). Although many previous studies have investigated the relationship between movement and reproduction, less attention has been paid to walking movement. In this study, previous studies that investigated the relationship between movement and reproduction were reviewed using the flour beetle Tribolium castaneum, a model insect in behavioral ecology and genetics. Several previous studies suggest that beetle walking is strongly associated with male and female reproductive traits. In recent years, empirical studies on the correlation between walking and other traits have increased, particularly in T. castaneum. Although this species can fly and walk, the movement is often discussed without discriminating between flight and walk. Differences in modes of movement may affect the correlation between movement and other traits; thus, discussing each mode of movement separately is necessary. [ABSTRACT FROM AUTHOR]

Aim Congenital nasolacrimal duct obstruction (CNLDO) is the most common cause of epiphora and mucous discharge in the newborn. We conducted a multicentre randomised controlled trial to determine whether Crigler massage promotes the resolution of CNLDO in infants under 1 year of age. Methods A total of 102 infants aged 3-11 months with unilateral CNLDO were enrolled in the study. Patients were randomly assigned to the massage and non-massage groups (n=51/group). As an allocation adjustment factor, the patients were divided into age groups of 3-5, 6-8 and 9-11 months. In the massage group, the guardian performed 10 strokes two times per day for each day until resolution or 1 month. The primary endpoint was a comparison of the 1-month resolution rate in the massage and non-massage groups. Results This study included 49 male and 53 female patients with a mean age of 6.4±2.4 months. Overall, in this study, the resolution rate was not significantly different between the massage and non-massage groups (31.4% and 33.3%, respectively). However, the resolution rate was higher in the massage group in the 3-5 months age group among the protocol-compliant patients after excluding those with insufficient massage frequency (the massage group, 68.8% and the non-massage group, 28.6%, p=0.022). Conclusions There was no increase in the resolution rate after 1 month of lacrimal sac massage in patients 3-11 months old with unilateral CNLDO. However, in protocol-compliant younger age groups, Crigler massage may be effective. [ABSTRACT FROM AUTHOR]

Background and Aim: The measurement of esophageal acid exposure time (AET) using combined multichannel intraluminal impedance–pH (MII‐pH) tests is the gold standard for diagnosing gastroesophageal reflux disease (GERD). However, this catheter‐based 24‐h test can cause considerable patient discomfort. Our aim is to identify factors affecting AET and to develop a scoring model for predicting AET abnormalities before conducting the MII‐pH test. Methods: Of the 366 patients who underwent MII‐pH test at two facilities in Japan and Vietnam, 255 patients who also had esophagogastroduodenoscopy and high‐resolution manometry were included in this study. Logistic regression analysis was conducted using risk factors for AET > 6% identified from a derivation cohort (n = 109). A scoring system predicting AET > 6% was then constructed and externally validated with a separate cohort (n = 146). Results: Three variables were derived from the prediction model: male gender, Hill grades III–IV, and weak mean distal contractile integrals. Based on these scores, patients were classified into low (0 point), intermediate (1–3 points), and high (4 points) risk groups. The probabilities of having an AET > 6% were 6%, 34%, and 100% for these groups, respectively. A score of < 1 excluded patients with abnormal AET, with a negative predictive value of 93.8% in the derivation cohort and 80.0% in the validation cohort. Conclusions: We derived and externally validated a prediction model for abnormal AET. This system could assist in guiding the appropriate treatment strategies for GERD. [ABSTRACT FROM AUTHOR]

Aims Coronary computed tomography angiography provides non-invasive assessment of coronary stenosis severity and flow impairment. Automated artificial intelligence (AI) analysis may assist in precise quantification and characterization of coronary atherosclerosis, enabling patient-specific risk determination and management strategies. This multicentre international study compared an automated deep learning-based method for segmenting coronary atherosclerosis in coronary computed tomography angiography (CCTA) against the reference standard of intravascular ultrasound (IVUS). Methods and results The study included clinically stable patients with known coronary artery disease from 15 centres in the USA and Japan. An AI-enabled plaque analysis was utilized to quantify and characterize total plaque (TPV), vessel, lumen, calcified plaque (CP), non-calcified plaque (NCP), and low-attenuation plaque (LAP) volumes derived from CCTA and compared with IVUS measurements in a blinded, core laboratory-adjudicated fashion. In 237 patients, 432 lesions were assessed; mean lesion length was 24.5 mm, and mean IVUS-TPV was 186.0 mm3. AI-enabled plaque analysis on CCTA showed strong correlation and high accuracy when compared with IVUS; correlation coefficient, slope, and Y intercept for TPV were 0.91, 0.99, and 1.87, respectively; for CP volume 0.91, 1.05, and 5.32, respectively; and for NCP volume 0.87, 0.98, and 15.24, respectively. Bland–Altman analysis demonstrated strong agreement with little bias for these measurements. Conclusion AI-enabled CCTA quantification and characterization of atherosclerosis demonstrated strong agreement with IVUS reference standard measurements. This tool may prove effective for accurate evaluation of coronary atherosclerotic burden and cardiovascular risk assessment. [ABSTRACT FROM AUTHOR]

Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF. [ABSTRACT FROM AUTHOR]

Asciminib is a first-in-class BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket (STAMP). It is approved worldwide and in Japan for chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to previous tyrosine kinase inhibitor (TKI) therapy. In the Phase 3 ASCEMBL study, patients with CML-CP who received ≥ 2 prior ATP-competitive TKIs were randomized (2:1) to asciminib 40 mg twice-daily or bosutinib 500 mg once-daily. Here, we report the 96-week results of the subgroup analysis of Japanese patients (asciminib, n = 13; bosutinib, n = 3) in the ASCEMBL study. The MMR rate at Week 96 was 46.2% in asciminib-treated patients, increasing from Weeks 24 and 48. Patients who achieved MMR at Week 24 remained in MMR up to the Week 96 cutoff. While a high proportion of patients treated with asciminib remained on treatment at cutoff, none randomized to bosutinib were on treatment at Week 96. Despite the longer duration of exposure to asciminib, its safety and tolerability continued to be favorable with no new or worsening safety findings. Overall, the efficacy and safety outcomes in the Japanese subgroup were comparable with the ASCEMBL global study population, which supports the use of asciminib in Japanese patients with previously treated CML-CP. [ABSTRACT FROM AUTHOR]

Objectives: We characterized blood glucose fluctuations in patients with myotonic dystrophy type 1 (DM1). After confirming the incretin secretion capacity of patients with DM1, we intended to clarify whether dipeptidyl peptidase 4 (DPP-4) inhibitor administration was appropriate in cases of DM1 with diabetes mellitus. Methods: A 48 h continuous glucose monitoring (CGM) was performed in 29 Japanese patients with DM1. An oral glucose tolerance test (OGTT) was performed in patients with DM1 and five disease controls, and levels of blood glucose, insulin, and incretin (glucagon-like peptide-1 and gastric inhibitory polypeptide) were measured. DPP-4 inhibitors were administered to patients with diabetes mellitus complicated by DM1, and the CGM results were compared. Results: The CGM showed distinct patterns of blood glucose variability among patients classified by an OGTT pattern with significant differences in glucose parameters such as time above 140 mg/dL and mean amplitude of glycemic excursions between the groups. High sensor glucose values were observed in a certain number of patients who were classified as having normal or impaired glucose tolerance by the OGTT. The CGM confirmed the presence of low glucose levels in several patients. Incretin secretion, the target of DPP-4 inhibitors, was preserved in patients with DM1. DPP-4 inhibitor treatment resulted in lower glucose levels and improved insulin secretion in some patients. Conclusions: This is the first CGM study for DM1 patients. The CGM identified potential early abnormalities in glucose metabolism in DM1. In the future, it will be crucial to explore effective methods for harnessing CGM and assessing it quantitatively in DM1. [ABSTRACT FROM AUTHOR]

Background This study evaluated the effect of an artificial intelligence (AI)-based clinical decision support system on the performance and diagnostic confidence of endoscopists in their assessment of Barrett's esophagus (BE). Methods 96 standardized endoscopy videos were assessed by 22 endoscopists with varying degrees of BE experience from 12 centers. Assessment was randomized into two video sets: group A (review first without AI and second with AI) and group B (review first with AI and second without AI). Endoscopists were required to evaluate each video for the presence of Barrett's esophagus-related neoplasia (BERN) and then decide on a spot for a targeted biopsy. After the second assessment, they were allowed to change their clinical decision and confidence level. Results AI had a stand-alone sensitivity, specificity, and accuracy of 92.2%, 68.9%, and 81.3%, respectively. Without AI, BE experts had an overall sensitivity, specificity, and accuracy of 83.3%, 58.1%, and 71.5%, respectively. With AI, BE nonexperts showed a significant improvement in sensitivity and specificity when videos were assessed a second time with AI (sensitivity 69.8% [95%CI 65.2%–74.2%] to 78.0% [95%CI 74.0%–82.0%]; specificity 67.3% [95%CI 62.5%–72.2%] to 72.7% [95%CI 68.2%–77.3%]). In addition, the diagnostic confidence of BE nonexperts improved significantly with AI. Conclusion BE nonexperts benefitted significantly from additional AI. BE experts and nonexperts remained significantly below the stand-alone performance of AI, suggesting that there may be other factors influencing endoscopists' decisions to follow or discard AI advice. [ABSTRACT FROM AUTHOR]

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo‐electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population. [ABSTRACT FROM AUTHOR]