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Abstract Arthropathy is a common complication in haemophilia and decreases quality of life. It has been known that concentrations of β-hydroxybutyrate (BHB) in blood are increased by a ketogenic diet, and elevated levels of circulating BHB restricts the progression of inflammation-mediated joint pathological changes. We hypothesized that elevation of blood BHB concentrations could be effective for reducing the progression of bleeding-induced arthropathy by moderating the inflammatory responses of macrophages. In this study, we investigated whether BHB alleviates the arthropathy caused by repeated intra-articular blood injection in rats. To increase blood BHB levels, rats were fed with ketogenic diet. Repeated intra-articular blood injection induced significant joint swelling, whereas ketogenic diet intake significantly increased blood BHB concentrations and ameliorated the joint swelling. The periarticular tissue-fibrosis observed in the control diet intake group appeared to be significantly alleviated in the ketogenic diet intake group. In addition, the IL-1β, which is involved in the progression of arthropathy, levels in the supernatants of blood-exposed macrophages derived from THP-1 cell line were significantly suppressed by BHB supplementation. In summary, BHB moderated the pathological joint changes caused by intra-articular blood exposure.

Abstract We carried out a retrospective observational investigation to explore the association of endotheliopathy with coagulofibrinolytic reactions and the progression of disseminated intravascular coagulation (DIC) in adult trauma patients. We measured syndecan-1 (SDC-1), an indicator of endotheliopathy, and biomarkers of coagulofibrinolysis in 100 trauma patients immediately transferred to Ehime University Hospital. We evaluated the correlations between the coagulofibrinolytic parameters and SDC-1. We also investigated the association between SDC-1 elevations and the development of DIC, and determined the discriminators of DIC development. The median SDC-1 concentration was 82.7 (43.5–178.1) ng/mL. DIC developed in 16 patients (16.0%), and SDC-1 concentrations were significantly higher in DIC patients than in non-DIC patients (218.8 [134.5–798.2] ng/mL vs. 67.2 [39.6–114.5] ng/mL, p 92.5 ng/mL was significantly correlated with DIC progression (odds ratio [OR], 31.67; 95%CI: 3.97–252.31, p = 0.001). Many coagulofibrinolytic parameters were significantly correlated with SDC-1. Estimating the discriminators of DIC development by the least absolute shrinkage and selection operator (LASSO) and elastic-net regression analysis identified markers of coagulofibrinolytic activation, such as thrombin-antithrombin complex (TAT) and tissue plasminogen activator (tPA). A multivariate logistic regression model using TAT, tPA, and SDC-1 demonstrated that TAT and tPA, but not SDC-1, were independent factors predicting the development of DIC (TAT per 10 µg/L: OR, 1.14, 95%CI: 1.05–1.24, p = 0.003; tPA per 100pg/mL: OR, 1.03, 95%CI: 1.01–1.05, p = 0.003; SDC-1 per 10ng/mL: OR, 1.00, 95%CI: 0.99–1.01, p = 0.973). Mediation analysis showed that SDC-1 elevation was predominantly associated with the development of DIC indirectly through the increase in TAT (proportion mediated = 96.1%, p

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

Abstract Trichosporon asahii, a dimorphic fungus, causes bloodstream infections in immunocompromised patients with neutropenia. Biofilms are formed on the surfaces of medical devices such as catheters as T. asahii transitions morphologically from yeast to hyphae in the host environment. Oxidative stress tolerance and morphological changes of T. asahii are regulated by Hog1, a mitogen-activated protein kinase. The role of Hog1 in the biofilm formation by T. asahii, however, has remained unknown. In the present study, we demonstrated that a hog1 gene-deficient T. asahii mutant formed excess biofilm under a rich medium in vitro, but did not form biofilm in an in vivo evaluation system using silkworms. The hog1 gene-deficient T. asahii mutant formed a greater amount of biofilm than the parent strain in vitro. Under an oxidative stress condition in vitro, however, lower amounts of biofilm were formed by the hog1 gene-deficient T. asahii mutant than by the parent strain. In an in vivo evaluation system using silkworms, lower amounts of biofilm were formed by the hog1 gene-deficient T. asahii mutant than by the parent strain. Our findings suggest that Hog1 regulates biofilm formation by T. asahii in response to host environmental conditions, including oxidative stress.

Abstract The environmental realm has been acknowledged as a pivotal arena for the emergence and propagation of antimicrobial resistance. To further explore insight into antimicrobial resistance dynamics beyond clinical and veterinary settings, we embarked on an environmental surveillance initiative targeting the prevalence of antibiotic-resistant bacteria within the bustling confines of an international airport in Japan. Our findings illuminate a high prevalence of methicillin-resistant staphylococci (46.3%) on frequently contacted surfaces in the public domain. Notably, Staphylococcus haemolyticus and S. epidermidis emerged as the preeminent carriers of the mecA gene. Intriguingly, we encountered a virulent strain of livestock-associated MRSA harboring a PVL-positive ST1232 clone, CC398 lineage. Further scrutiny unveiled a repertoire of resistance mechanisms, the methicillin-resistant isolates exhibited two or more resistance genes conferring resistance against different types of antibiotics, including beta-lactams, macrolides, lincosamides, aminoglycosides, chloramphenicol, and fosfomycin. Revealing multidrug-resistant CoNS and a LA-MRSA across various surfaces in urban public areas unearths a looming public health hazard. Thus, implementation of molecular surveillance is imperative, augmenting our capacity for early detection and mitigation of the insidious spread and potential transfer of antibiotic resistance genes and virulence factors amidst urban settings, notably within pivotal nodes such as airports.

Abstract Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120 h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option. Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020.

Abstract Our research focuses on elucidating the crystallographic structure of Japanese swords in a nondestructive manner using the neutron imaging instrument RADEN at the Materials and Life Science Experimental Facility of the Japan Proton Accelerator Research Complex (J-PARC). We developed an analysis method combining wavelength-resolved Bragg-edge imaging and wavelength-selective neutron tomography with a new strategy and applied it to an approximately 45-cm blade length Japanese sword signed by Bishu Osafune Norimitsu. Computed tomography was performed, and the three-dimensional analysis captured the characteristic internal structure of Kobuse. Kobuse is the most famous steel-combining structure of Japanese swords, where an outer steel with high-carbon content (Kawagane) covers a core steel with low-carbon content (Shingane). The crystallite size distribution obtained through Bragg-edge analysis could consistently explain the internal structure of two steels observed in neutron tomograms. Our nondestructive imaging revealed deep hardening, forming a wavy pattern more than 5 mm from the cutting edge.

Abstract Copper oxide high-temperature superconductors, such as Bi2Sr2CaCu2O8+ δ (Bi2212), have garnered extensive research interest due to their high critical temperatures (T c) surpassing the Bardeen–Cooper–Schrieffer (BCS) limit. The two-dimensional CuO₂ plane is widely regarded as the most crucial element of high-T c cuprate superconductors. The anisotropy of this CuO₂ layer remains a topic of ongoing interest. Although a few experimental results have reported strong optical anisotropy in both ab and ac-planes of Bi2212 through optical “reflectivity” measurements, there is a lack of studies focusing on the optical anisotropy of these materials using optical “transmittance” measurements by utilizing ultraviolet and visible light. Using a generalized high-accuracy universal polarimeter, we observed significant linear birefringence and linear dichroism peaks in the UV region at room temperature. To investigate the origin of the significant optical anisotropy, single crystals of Bi2− x Pb x Sr2CaCu2O8+ δ with different lead contents (x = 0, 0.4, and 0.6) were grown using the floating zone method, and the wavelength dependencies of linear birefringence and linear dichroism along the c axis were measured. The insights gained into the optical anisotropy of Bi2− x Pb x Sr2CaCu2O8+ δ from this study are significant for discussing its origin of the mechanism of high-T c superconductivity.

Abstract This report is of a systematic review and meta-analysis evaluating the efficacy and safety of transcatheter arterial embolization (TAE) for nonvariceal gastrointestinal bleeding (GIB) with n-butyl cyanoacrylate (NBCA) or coils as the primary embolic agent. The primary outcome was the clinical success rate. The secondary outcomes were technical success rates, 30-day rebleeding rates, major complication rates, and 30-day overall mortality rates. A systematic search was performed in PubMed, Embase, and Cochrane Library. Articles included had been published in English from January 2000 to August 2023 and assessed patients with nonvariceal upper and lower GIB (UGIB and LGIB) who received TAE with NBCA or coils. Single-arm meta-analyses were performed for these outcomes. Subgroup analyses comparing NBCA and coils were conducted if there were more than 10 articles selected for each outcome. Thirty-seven articles were selected for analysis. The pooled rates of TAE for UGIB and LGIB were clinical success 73.0% and 76.5%, technical success 94.9% and 91.4%, 30-day rebleeding 25.0% and 17.1%, major complications 3.5% and 10.0%, and 30-day overall mortality 20.7% and 11.4%, respectively. The subgroup analysis showed a significant difference only for the technical success rates of LGIB between NBCA and the coils (p

Abstract Endothelial dysfunction exacerbates hypertension and other vascular complications in diabetes mellitus (DM). Circulating microparticles (MPs) and extracellular vesicles released in patients with DM have emerged as novel regulators of endothelial dysfunction. The obstruction of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications. Their impact on the obstruction of MRs on circulating MPs and endothelial dysfunction in DM remains unclear. DM was induced in mice through a single intravenous dose of streptozotocin (STZ; 200 mg/kg). Esaxerenone (ESAX; 3 mg/kg/day), a MR blocker was administered via diet for 8 weeks. In this study, the aortas of the DM group showed the endothelial dysfunction and the administration of ESAX ameliorated the endothelial-dependent responses. Moreover, ESAX influences the impaired endothelial-dependent responses of DM-derived MPs. Interestingly, MP levels increased in DM whereas decreased after ESAX administration. In the aorta, the DM-derived MPs increased the expression of intercellular adhesion molecule-1 (ICAM-1). ESAX inhibited the adhesion of DM-derived MPs. Moreover, the ICAM-1 inhibitor A205804 shows similar effects as ESAX. These results indicate that the release and adhesion properties of MPs can be partially obstructed by ESAX via the ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of ESAX.

Abstract Injury recurrence in young children is a significant public health concern, as it may indicate an unfavorable home environment. This study evaluates whether infantile injuries increase recurrence during preschool years, contributing to more effective prevention strategies for vulnerable families. The study included 20,191 children from “The Longitudinal Survey of Babies in the 21st Century,” a representative sample of infants born in Japan between May 10 and 24, 2010. We conducted a logistic regression analysis to compare injury recurrence risk between children aged 18 months to seven years with and without infantile injury histories. The study revealed that infants with a history of injuries had a higher risk of subsequent hospital visits for injuries during preschool years (crude Odds Ratio (cOR) 1.52, 95% CI, 1.41–1.64, adjusted OR (aOR) 1.48, 95% CI 1.37–1.60). Specific injuries, such as falls (aOR 1.34, 95% CI, 1.26–1.43), pinches (aOR 1.22, 95% CI, 1.15–1.29), drowning (aOR 1.29, 95% CI, 1.19–1.40), ingestion (aOR 1.35, 95% CI, 1.17–1.55), and burns (aOR 1.47, 95% CI, 1.31–1.65), independently increased the risk of future injuries. Our findings highlight the necessity of universal safety measures in the home environment and targeted interventions for families with a history of high-risk injuries.

Abstract Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) infection has forced social changes worldwide. Development of potent antiviral agents is necessary to prevent future pandemics. Titanium oxide, a photocatalyst, is a long-acting antiviral agent; however, its effects are weakened in the dark. Therefore, new antiviral substances that can be used in the dark are needed. Two types of nitroxyl radicals, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) and 2-azaadamantane N-oxyl (AZADO), are commonly used as oxidation catalysts utilizing oxygen in the air as the terminal oxidant. Therefore, in this study, we aimed to evaluate the potential of these radicals as antiviral compounds with sustained activity even in the dark. We evaluated the antiviral effects of oxoammonium salts corresponding to TEMPO and AZADO (TEMPO-Oxo and AZADO-Oxo, respectively), which are the active forms of nitroxyl radicals in oxidation reactions. TEMPO-Oxo and AZADO-Oxo inhibited the binding of SARS-CoV2 spike protein receptor-binding domain (S-RBD) to angiotensin-converting enzyme 2. Notably, AZADO-Oxo exhibited a 10-fold stronger inhibitory effect than TEMPO-Oxo. TEMPO-Oxo and AZADO-Oxo also denatured S-RBD; however, effects of AZADO-Oxo were 10-fold stronger than those of TEMPO-Oxo and did not change in the dark. Some S-RBD peptides treated with AZADO-Oxo were cleaved at the N-terminal side of tyrosine residues. TEMPO-Oxo and AZADO-Oxo exhibited concentration-dependent antiviral effects against feline coronavirus. In conclusion, active forms of the nitroxyl radicals, TEMPO-Oxo and AZADO-Oxo, exerted antiviral effects by denaturing S-RBD, regardless of the presence or absence of light, suggesting their potential as novel antiviral agents.

Abstract Patients with coronavirus disease 2019 (COVID-19) often experience acute kidney injury, linked to disease severity or mortality, along with renal tubular dysfunction and megalin loss in proximal tubules. Megalin plays a crucial role in kidney vitamin D metabolism. However, the impact of megalin loss on vitamin D metabolism during COVID-19 is unclear. This study investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reduces megalin expression in proximal tubules and its subsequent effect on vitamin D metabolism in mice expressing human angiotensin converting enzyme 2 (K18-hACE2 mice). Histological and immunohistochemical staining analyses revealed glomerular and capillary congestion, and elevated renal neutrophil gelatinase-associated lipocalin levels, indicative of acute kidney injury in K18-hACE2 mice. In SARS-CoV-2-infected mice, immunohistochemical staining revealed suppressed megalin protein levels. Decreased vitamin D receptor (VDR) localization in the nucleus and increased mRNA expression of VDR, CYP27B1, and CYP24A1 were observed by quantitative PCR in SARS-CoV-2-infected mice. Serum vitamin D levels remained similar in infected and vehicle-treated mice, but an increase in tumor necrosis factor-alpha and a decrease in IL-4 mRNA expression were observed in the kidneys of the SARS-CoV-2 group. These findings suggest that megalin loss in SARS-CoV-2 infection may impact the local role of vitamin D in kidney immunomodulation, even when blood vitamin D levels remain unchanged.

Abstract We propose a simple tool for liquid static culture using a copolymer film with high gas permeability. The film bags were successfully used to culture microorganisms Escherichia coli, Komagataella phaffii (methylotrophic) and Bacillus sp. (biofilm-forming), with cells cultured under physical stress-free conditions with sufficient oxygen supply. Similar growth curves and plasmid productivity were observed for liquid shake and film bag E. coli cultures. The early growth response of the film bag culture following colony inoculation of liquid media differed from conventional shake cultures. Our results indicate that a gas-permeable film bag is a promising liquid culture tool and provides novel microbiology materials.

Abstract We recently reported a method for recovering and quantifying residual proteins bound to surfaces of various medical instruments via thermal coagulation under neutral pH and room temperature. The method effectively recovered and solubilised coagulated proteins at high temperatures in dry and humid conditions, with a protein recovery rate of > 90%. This study validated the previous method by comparing residual protein recovery from test samples using a conventional extraction solution (1% SDS, [pH 11.0]) and proposed solution (1% SDS, 10 mM TCEP, and 10 mM HEPES [pH 7.0]). To mimic soiled medical equipment, pseudo-blood-contaminated stainless steel plates were prepared. Residual protein was recovered using conventional and proposed solutions under varying temperature and humidity conditions. Quantitative protein recovery limits were determined at nine facilities. Compared with the conventional solution, the proposed solution recovered proteins more effectively from samples processed at temperatures > 60 °C. However, low recovery rates were observed for samples processed at 95 °C, possibly owing to differences in protein adhesion due to sample and plate-surface properties. Our findings present a method for quantifying residual proteins on medical instruments exposed to high temperatures during use or disinfection. Further studies should standardise test soiling conditions, materials, and solutions to evaluate cleaning methods.

Abstract Baicalin is a flavonoid extracted from Scutellaria baicalensis Georgi. As it has significant antitumor and apoptosis-inducing effects, baicalin may be useful as a lead compound in new antitumor drug development. However, as the pharmacological actions of baicalin have yet to be elucidated, we isolated its target protein, which was successfully identified as Annexin A2. Annexin A2 forms a heterotetramer with S100A10 protein, which plays an important role in the plasminogen activator system. The heterotetramer bound to tissue plasminogen activator (tPA) activates the conversion of plasminogen to plasmin and promotes the expression of STAT-3 and NF-κB, which are target genes involved in the development of cancer. Moreover, NF-κB and STAT-3 induce the expression of cell inhibitors of apoptotic proteins and inhibit apoptosis. To examine whether these antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2, we prepared Annexin A2 knockdown HepG2 cells. We compared mRNA expression by RT-qPCR and apoptosis by caspase-3 activity assays in Annexin A2 knockdown HepG2 cells. The results showed that the antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2. The results of this study suggest that agents capable of inhibiting Annexin A2 may be useful candidates for the development of novel antitumor agents.

Abstract Y-box binding protein 1 (YBX1) promotes oncogenic transformation and tumor growth. YBX1 plays a role in regulation of cell cycle promotion via upregulation of cell cycle-related genes. In ovarian cancer, YBX1 also promotes tumor growth, but the mechanisms of YBX1 in cell growth and cell cycle in ovarian cancer remain not to be fully understood. Here, we investigated whether YBX1-dependent cancer cell proliferation was specifically associated with expression of cell cycle related genes in ovarian cancer. Protein and mRNA expression levels of YBX1 and cell cycle-related genes in ovarian cancer cell lines and tissues were determined by western blot analysis, immunohistochemical analysis and reverse transcription-quantitative PCR. Cell cycle analysis was performed by flow cytometry. Luciferase assay and Chromatin immunoprecipitation assay were used to investigate a transcriptional function of YBX1. YBX1 silencing induced marked growth suppression in 4 cell lines (group A), moderate suppression in 5 cell lines (group B), and no suppression in 3 cell lines (group C) among 12 ovarian cancer cell lines in culture. The YBX1 silencing induced cell cycle arrest at G2/M phase and suppressed expression of cyclin A1 gene in group A and B cell lines, but not in group C cell lines. Cyclin A1 silencing specifically suppressed cell proliferation in group A cell lines and partially in group B cell lines, but not at all in group C cell lines. YBX1 mRNA levels were significantly correlated with cyclin A1 mRNA levels in patients with high-grade serous carcinoma. Augmented YBX1 expression plays a key role in tumor growth promotion in ovarian cancer in its close association with cyclin A1.

Abstract Rapid on-site cytopathology evaluation (ROSE) has been considered an effective method to increase the diagnostic ability of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA); however, ROSE is unavailable in most institutes worldwide due to the shortage of cytopathologists. To overcome this situation, we created an artificial intelligence (AI)-based system (the ROSE-AI system), which was trained with the augmented data to evaluate the slide images acquired by EUS-FNA. This study aimed to clarify the effects of such data-augmentation on establishing an effective ROSE-AI system by comparing the efficacy of various data-augmentation techniques. The ROSE-AI system was trained with increased data obtained by the various data-augmentation techniques, including geometric transformation, color space transformation, and kernel filtering. By performing five-fold cross-validation, we compared the efficacy of each data-augmentation technique on the increasing diagnostic abilities of the ROSE-AI system. We collected 4059 divided EUS-FNA slide images from 36 patients with pancreatic cancer and nine patients with non-pancreatic cancer. The diagnostic ability of the ROSE-AI system without data augmentation had a sensitivity, specificity, and accuracy of 87.5%, 79.7%, and 83.7%, respectively. While, some data-augmentation techniques decreased diagnostic ability, the ROSE-AI system trained only with the augmented data using the geometric transformation technique had the highest diagnostic accuracy (88.2%). We successfully developed a prototype ROSE-AI system with high diagnostic ability. Each data-augmentation technique may have various compatibilities with AI-mediated diagnostics, and the geometric transformation was the most effective for the ROSE-AI system.

Abstract The objective of this study was to assess radiolucent lines (RLLs) and to determine their effect on clinical outcomes of the newly introduced cementless mobile-bearing total knee arthroplasty (TKA) system. This was prospective, multicentre study. Seventy-eight patients with knee osteoarthritis who underwent primary TKA were enrolled. Patient-reported outcome measures (PROMs) and radiographic assessments were evaluated at preoperative baseline and at 6 weeks, 1 year, and 2 years after surgery. KOOS, PKIP, 2011KSS, EQ-5D-3L and SKO improved from preoperative baseline to all postoperative timepoints, with no loosening of components. No RLLs were detected at 6 weeks after surgery. However, RLLs ≥ 1 mm developed in 2.8% of the patients for the femur and 9.7% for the tibia at 1 year after surgery, and values were 5.7% and 10.9%, respectively, at 2 years after surgery. RLL incidence was not correlated with PROMs. Age, sex, body mass index, range of motion knee flexion, posterior cruciate ligament treatment and β angle did not impact the occurrence of RLLs. There were no intraoperative complications, revisions or reoperations. This TKA system improved PROMs and showed less incidence of RLLs compared to the previous reported TKA without implant-related complications.

Abstract The coronavirus disease (COVID-19) pandemic negatively affected the diagnosis and treatment of several cancer types. However, this pandemic’s exact impact and extent on bone and soft tissue sarcomas need to be clarified. We aimed to investigate the effect of the COVID-19 pandemic and emergency declaration by the local government on consultation behavior and clinical stage at diagnosis of bone and soft tissue sarcoma. A total of 403 patients diagnosed with bone and soft tissue sarcoma who initially visited three sarcoma treatment hospitals between January 2018 and December 2021 were included. The monthly number of newly diagnosed soft tissue sarcoma patients was reduced by 25%, and the proportion of soft tissue patients with stage IV disease at diagnosis significantly increased by 9% during the COVID-19 pandemic compared to before the COVID-19 pandemic. Furthermore, the monthly number of new primary bone and soft tissue sarcoma patients significantly decreased by 43% during the state of emergency declaration. The COVID-19 pandemic had a negative impact on soft tissue sarcoma patients’ consultation behavior and increased the proportion of advanced-stage patients at initial diagnosis. An emergency declaration by the local government also negatively affected primary bone and soft tissue sarcoma patients’ consultation behavior.

Abstract This study aims to investigate the influence of lumbar spine disorders on the development of asymmetric hallux valgus (HV). Data from the fifth survey of the Osteoarthritis/Osteoporosis Against Disability (ROAD) study, a nationwide prospective study in Japan, were analyzed. HV severity was categorized into 4 grades based on the radiographic HV angle, and asymmetric HV was defined as having at least one HV on either side, with a difference of two or more severity grades between the left and right. Controls were matched from both the Normal group (without HV on both sides) and the Symmetric group (HV on at least one side with a difference of one or less severity grades). Univariate analysis assessed lumbar conditions, and multinomial logistic regression analysis explored the association between lumbar spine disorders and asymmetric HV. Among 1997 participants, 27 had asymmetric HV. Univariate analysis revealed a higher incidence of L5 spondylolisthesis and scoliosis in the Asymmetric group. Multinomial logistic regression analysis revealed that scoliosis independently increased the likelihood of asymmetrical HV (Odds ratio [OR] = 3.586, 95%Confidence interval [CI] 1.111–11.582), but showed no significant impact on symmetrical HV (OR 0.910, 95% CI 0.355–2.334). Asymmetric HV is rare but may be associated with lumbar spine disorders, particularly scoliosis.

Abstract Macular edema is a known side effect of taxane-based anticancer drugs. We retrospectively investigated data from 11 centers between January 2016 and December 2021. Among 14,260 patients, 30 (0.21%) developed macular edema; from these, the number of cases associated with nab-paclitaxel was 16 (0.43%), significantly higher than the number of cases associated with paclitaxel or docetaxel (P

Abstract Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl4-injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury.

Abstract Change in mucosal microbiome is associated with various types of cancer in digestive tract. We hypothesized that microbial communities in the esophageal endoscopic wash fluids reflects resident flora in esophageal mucosa that is associated with esophageal carcinoma (EC) risk and/or directly correlates microbiome derived from EC tumor tissue. Studying microbial communities in esophageal endoscopic wash samples would be therefore useful to predict the incidence or risk of EC. We examined microbial communities of the endoscopic wash samples from 45 primary EC and 20 respective non-EC controls using 16S rRNA V3-V4 amplicon sequencing. The result was also compared with microbial communities in matched endoscopic biopsies from EC and non-cancerous esophageal mucosa. Compared with non-EC controls, 6 discriminative bacterial genera were detected in EC patients. Among them, relative abundance ratio of Prevotella and Shuttlewarthia, as well as decrease of genus Prevotella presented good prognostic performance to discriminate EC from controls (area under curve, 0.86, 0.82, respectively). Multivariate analysis showed occurrence of EC was an independent factor associated with decrease of this bacteria. Abundance of genus Prevotella in the esophageal endoscopic wash samples was significantly correlated with the abundance of this bacteria in the matched endoscopic biopsies from non-cancerous esophageal mucosa but not in the EC tissues. Our findings suggest that microbiome composition in the esophageal endoscopic wash samples reflects resident flora in the esophagus and significantly correlates with the incidence of EC.

Abstract General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.

Abstract Dogs diagnosed with chronic enteropathy (CE) or small-cell lymphoma (SCL) exhibit marked differences in faecal microbiota and organic acid profiles compared with healthy dogs, as well as immune abnormalities in intestinal mucosal tissue. However, few studies have analysed trace organic acids, such as succinic acid, which have been suggested to be associated with IBD in humans. Therefore, in this study, we compared the faecal microbiota and organic acid profiles as well as serum inflammatory markers between dogs with disease (n = 11; 6 with CE and 5 with SCL) and healthy controls (n = 16). We also performed machine learning and correlation analysis to obtain more detailed insights into the characteristics of affected dogs. These results revealed that dogs with CE and SCL had lower levels of Erysipelotrichaceae (e.g. Turicibacter and Allobaculum), exhibited abnormalities in the succinic acid metabolism (i.e. succinic acid accumulation and decreased levels of Phascolarctobacterium as succinic acid-utilising bacteria) and increased levels of pathobiont bacteria such as Escherichia-Shigella. Additionally, the presence of Dubosiella was significantly negatively correlated with Canine Inflammatory Bowel Disease Activity Index scores. These findings are expected to aid the development of microbiome-based medications and/or supplements, although further verification is needed.

Abstract The usefulness of the derived neutrophil-to-lymphocyte ratio (dNLR) and its dynamics before/after durvalumab consolidation therapy to predict safety or efficacy remains unclear. We retrospectively reviewed patients with locally advanced non-small cell lung cancer treated with durvalumab consolidation therapy after chemoradiotherapy (D group) or chemoradiotherapy alone (non-D group) at multiple institutions. We investigated the association between dNLR, or its dynamics, and pneumonitis, checkpoint inhibitor-related pneumonitis (CIP), irAEs, and efficacy. Ninety-eight and fifty-six patients were enrolled in the D and non-D groups, respectively. The dNLR at baseline was significantly lower in patients who experienced irAEs or CIP than in those who did not. The low dNLR group, 28 days following durvalumab consolidation therapy (dNLR28 ≤ 3), demonstrated longer progression-free survival (PFS) and overall survival (OS) than the high dNLR group (dNLR28 > 3) (PFS, hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22–0.88, p = 0.020; OS, HR 0.39, 95% CI 0.16–0.94, p = 0.037). Among patients with high dNLR at baseline (dNLR > 3), the dNLR28 ≤ 3 group showed longer PFS than the dNLR28 > 3 group (p = 0.010). The dNLR is a predictive factor for irAEs and CIP in patients receiving durvalumab consolidation therapy. The dNLR at 28 days after durvalumab consolidation therapy and its dynamics predict favorable outcomes.

Abstract EBUS-guided transbronchial mediastinal cryobiopsy (TBMC) has emerged as a promising biopsy tool for diagnosing hilar and mediastinal pathologies. However, several fundamental technical aspects of TBMC remain unexplored. This study aims to determine the optimal number of cryo-passes and freezing time of the ultrathin cryoprobe in EBUS-TBMC concerning specimen size and procedural diagnostic yield. We conducted a retrospective chart review of patients with mediastinal and hilar lesions who underwent EBUS-TBMC between January 2021 and April 2023 across three hospitals in Malaysia. A total of 129 EBUS-TBMC procedures were successfully completed, achieving an overall diagnostic yield of 88.4%. Conclusive TBMC procedures were associated with larger specimen sizes (7.0 vs. 5.0 mm, p

Abstract Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration–time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.

Abstract Although bone dehiscence may occur during orthodontic tooth movement into the narrow alveolar ridge, a non-invasive prevention method is yet to be fully established. We show for the first time prevention of bone dehiscence associated with orthodontic tooth movement by prophylactic injection of bone anabolic agents in mice. In this study, we established a bone dehiscence mouse model by applying force application and used the granular type of scaffold materials encapsulated with bone morphogenetic protein (BMP)-2 and OP3-4, the receptor activator of NF-κB ligand (RANKL)-binding peptide, for the prophylactic injection to the alveolar bone. In vivo micro-computed tomography revealed bone dehiscence with decreased buccal alveolar bone thickness and height after force application, whereas no bone dehiscence was observed with the prophylactic injection after force application, and alveolar bone thickness and height were kept at similar levels as those in the control group. Bone histomorphometry analyses revealed that both bone formation and resorption parameters were significantly higher in the injection with force application group than in the force application without the prophylactic injection group. These findings suggest that the prophylactic local delivery of bone anabolic reagents can prevent bone dehiscence with increased bone remodelling activity.

Abstract Efforts are underway to develop technology for automatically determining the sex of chick embryos, aimed at establishing a stable and efficient poultry farming system while also addressing animal welfare concerns. This study investigated the possibility of chick sexing through blood analysis using Raman spectroscopy. Raman spectra were obtained from whole blood and its constituents, such as red blood cells (RBCs) and blood plasma, collected from chicks aged 1–2 days, using a 785-nm excitation wavelength. Principal component analysis (PCA) revealed statistically significant sex-dependent spectral variations in whole blood and RBCs, whereas blood plasma showed less clear dependency. These spectral differences between male and female chicks were attributed to differences in the proportion of spectral components from oxygenated (oxy-) and deoxygenated (deoxy-) RBCs, with males exhibiting a slightly stronger contribution of oxy-RBCs compared to females. This reflects the higher oxygen affinity of hemoglobin (Hb) in males compared to females. A model for discriminating chick sex was built using the ratios of certain Raman band characteristics of oxy-RBCs and deoxy-RBCs, achieving a sensitivity of 100%. This spectroscopic method holds promise for developing technology to discriminate the sex of early chicken embryos in ovo by detecting differences in oxygen saturation of RBCs based on sex.

Abstract A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time (PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p

Abstract Benralizumab, a monoclonal antibody targeting IL-5 receptors, reduces exacerbations and oral corticosteroid requirements for severe, uncontrolled eosinophilic asthma. In Japan, geographic disparities in asthma outcomes suggest differential prescribing and access. This study aimed to quantify regional prescribing variations for benralizumab nationwide. Using Japan’s National Database (NDB) of insurance claims (2009–2019), benralizumab standardized claim ratios (SCRs) were calculated for 47 prefectures. Correlations between SCRs and other biologics’ SCRs, economic variables like average income, and physician densities were evaluated through univariate analysis and multivariate regressions. Income-related barriers to optimal prescribing were examined. Wide variation emerged in benralizumab SCRs, from 40.1 to 184.2 across prefectures. SCRs strongly correlated with omalizumab (r = 0.61, p

Abstract Deamination of bases is a form of DNA damage that occurs spontaneously via the hydrolysis and nitrosation of living cells, generating hypoxanthine from adenine. E. coli endonuclease V (eEndoV) cleaves hypoxanthine-containing double-stranded DNA, whereas human endonuclease V (hEndoV) cleaves hypoxanthine-containing RNA; however, hEndoV in vivo function remains unclear. To date, hEndoV has only been examined using hypoxanthine, because it binds closely to the base located at the cleavage site. Here, we examined whether hEndoV cleaves other lesions (e.g., AP site, 6-methyladenine, xanthine) to reveal its function and whether 2′-nucleoside modification affects its cleavage activity. We observed that hEndoV is hypoxanthine-specific; its activity was the highest with 2′-OH modification in ribose. The cleavage activity of hEndoV was compared based on its base sequence. We observed that it has specificity for adenine located on the 3′-end of hypoxanthine at the cleavage site, both before and after cleavage. These data suggest that hEndoV recognizes and cleaves the inosine generated on the poly A tail to maintain RNA quality. Our results provide mechanistic insight into the role of hEndoV in vivo.

Abstract Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.

Abstract This study aimed to investigate the rate of sedentary behaviour and differences in physical outcomes and activities of daily living (ADL) based on sedentary behaviour time of hospitalized older cardiovascular disease patients undergoing phase I cardiac rehabilitation. Older cardiovascular disease patients were enrolled from October 2020 to September 2023 and were divided into the high sedentary behaviour group (≥ 480 min/day) and low sedentary behaviour group (

Abstract Despite high vaccination rates globally, countries are still grappling with new COVID infections, and patients diagnosed as mild dying at home during outpatient treatment. Hence, this study aim to identify, then validate, biomarkers that could predict if newly infected COVID-19 patients would subsequently require hospitalization or could recover safely with medication as outpatients. Serum cytokine/chemokine data from 129 COVID-19 patients within 7 days after the onset of symptoms in Bangladesh were used as training data. The majority of patients were infected with the Omicron variant and over 88% were vaccinated. Patients were divided into those with mild symptoms who recovered, and those who deteriorated to moderate or severe illness. Using the Lasso method, 15 predictive markers were identified and used to classify patients into these two groups. The biomarkers were then validated in a cohort of 194 Covid patients in Japan with a predictive accuracy that exceeded 80% for patients infected with Delta and Omicron variants, and 70% for Wuhan and Alpha variants. In an environment of widespread vaccination, these biomarkers could help medical practitioners determine if newly infected COVID-19 patients will improve and can be managed on an out-patient basis, or if they will deteriorate and require hospitalization.

Abstract Distal femoral osteotomy (DFO) is performed alone or with high tibial osteotomy (HTO) for patients with osteoarthritis and distal femur deformities. DFO is technically demanding, particularly when creating an anterior flange. Herein, we examined the morphological characteristics of the distal femur based on the cortical shape as a surgical reference for biplanar DFO. Computed tomography images of 50 valgus and 50 varus knees of patients who underwent biplanar DFO or total knee arthroplasty were analyzed. Axial slices at the initial level of the transverse osteotomy in the DFO and slices 10 mm proximal and 10 mm distal to that level were selected. The medial and lateral cortical angles and heights (MCLA, LCLA, MCH, and LCH) were measured on axial slices. Statistical comparisons were performed between the medial and lateral cortices and valgus and varus knees. MCLA and MCH were significantly smaller and lower, respectively, than LCLA and LCH (P

Abstract The advent of Artificial Intelligence (AI)-based object detection technology has made identification of position coordinates of surgical instruments from videos possible. This study aimed to find kinematic differences by surgical skill level. An AI algorithm was developed to identify X and Y coordinates of surgical instrument tips accurately from video. Kinematic analysis including fluctuation analysis was performed on 18 laparoscopic distal gastrectomy videos from three expert and three novice surgeons (3 videos/surgeon, 11.6 h, 1,254,010 frames). Analysis showed the expert surgeon cohort moved more efficiently and regularly, with significantly less operation time and total travel distance. Instrument tip movement did not differ in velocity, acceleration, or jerk between skill levels. The evaluation index of fluctuation β was significantly higher in experts. ROC curve cutoff value at 1.4 determined sensitivity and specificity of 77.8% for experts and novices. Despite the small sample, this study suggests AI-based object detection with fluctuation analysis is promising because skill evaluation can be calculated in real time with potential for peri-operational evaluation.

Abstract Adolescent idiopathic scoliosis (AIS) affects approximately 3% of the global population. Recent studies have drawn attention to abnormalities in the dynamics of the CSF as potential contributors. This research aims to employ the Time-Spatial Labeling Inversion Pulse (Time-SLIP) MRI to assess and analyze cerebrospinal fluid (CSF) dynamics in AIS patients. 101 AIS patients underwent Time-SLIP MRI. Images were taken at the mid-cervical and craniocervical junction regions. The sum of the maximum movement distances of CSF on the ventral and dorsal sides of the spinal canal within a single timeframe was defined and measured as Travel Distance (TD). Correlations between TD, age, Cobb angle, and Risser grade were analyzed. TD comparisons were made across Lenke classifications. TD for all patients was a weak correlation with the Cobb angle (r = − 0.16). Comparing TD between Lenke type 1 and 5, type 5 patients display significantly shorter TD (p

Abstract Oral bacteria are known to be associated with perioperative complications during hospitalization. However, no presented reports have clarified the relationship of oral bacterial number with medical costs for inpatients. The Diagnosis Procedure Combination (DPC) database system used in Japan provides clinical information regarding acute hospital patients. The present study was conducted to determine the association of oral bacterial numbers in individual patients treated at a single institution with length of hospital stay and medical costs using DPC data. A total of 2369 patients referred by the medical department to the dental department at Hiroshima University Hospital were divided into the low (n = 2060) and high (n = 309) oral bacterial number groups. Length of hospital stay and medical costs were compared between the groups, as well as the associations of number of oral bacteria with Charlson comorbidity index (CCI)-related diseases in regard to mortality and disease severity. There was no significant difference in hospital stay length between the low (24.3 ± 24.2 days) and high (22.8 ± 20.1 days) oral bacterial number groups. On the other hand, the daily hospital medical cost in the high group was significantly greater (US$1456.2 ± 1505.7 vs. US$1185.7 ± 1128.6, P

Abstract Here, we focused on the role of Nucleobindin 2 (NUCB2), a multifunctional protein, in gastric carcinoma (GC) progression. NUCB2 expression was investigated in 150 GC cases (20 non-invasive (pT1) and 130 invasive (pT2/pT3/pT4) tumors) by immunohistochemistry (IHC), and in situ hybridization for detection of the mRNA in 21 cases. Using GC cell lines, we determined whether NUCB2 expression was associated with specific cellular phenotypes. In GC clinical samples, NUCB2 was transcriptionally upregulated when compared to normal tissues. High NUCB2 expression was associated with clinicopathological factors including deep tumor invasion, lymphovascular invasion, lymph node metastasis, and advanced clinical stages, and was a significant independent predictor of unfavorable progression-free survival in 150 non-invasive and invasive GC patients. Similar findings were also evident in 72 invasive GC cases in which patients received post-operative chemotherapy, but not in 58 invasive tumors from patients who did not receive the chemotherapy. In cell lines, NUCB2 knockout inhibited proliferation, susceptibility to apoptosis, and migration capability by inducting cellular senescence; this was consistent with higher proliferation and apoptotic indices in the NUCB2 IHC-high compared to NUCB2 IHC-low GC cases. NUCB2-dependent inhibition of senescence in GC engenders aggressive tumor behavior by modulating proliferation, apoptosis, and migration.

Abstract New technologies such as laparoscopic and robotic surgery are spreading, and there is a demand for physicians to keep up with novel methods. In contrast to the recent focus on healthcare professional burnout, the mental and physical costs during surgery are not well-understood. We aimed to quantify surgeons’ workloads in daily urological surgical practice and clarify potential background factors associated with such workloads. Urologists in Hokkaido, Japan, were invited to this study. Between December 2020 and December 2021, participants repeatedly reported workloads, which were assessed using the National Aeronautics and Space Administration-Task Load Index (NASA-TLX), after each surgery in conjunction with participants’ names, patients’ backgrounds, their roles (independent operator, operator under supervision, instructor, and 1st or 2nd assistant), and surgical outcomes, via SurveyMonkey®. Because of the heterogeneity among individuals, a linear mixed-effects model was utilized to analyze factors associated with NASA-TLX, calculating the parameter estimates (PE) of regression coefficients for each factor and their 95% confidence interval (CI). Sixty-five urologists (5 women) joined the study, and 2169 data were collected within 7 days after surgeries. A linear mixed-effects model revealed that female surgeons (PE + 15.56, 95% CI 2.36–28.77), urgent/emergency surgery (PE + 6.65, 95% CI 4.59–8.70), intraoperative complications (PE + 9.26, 95% CI 6.76–11.76), and near-miss incidents (PE + 3.81, 95% CI 2.27–5.36) were associated with higher workloads. Regarding the surgeons’ role, operator under supervision (PE + 12.46, 95% CI 9.86–15.06) showed the highest workloads. Surgeons’ workloads decreased as the number of previous cases of the same procedure increased. Surgeons’ workloads were associated with various factors. Given that the highest workloads were for operators under supervision, instructors should be aware of trainees’ high workloads and devise appropriate instructional interventions.

Abstract The present study tested the combination of mandibular and dental dimensions for sex determination using machine learning. Lateral cephalograms and dental casts were used to obtain mandibular and mesio-distal permanent teeth dimensions, respectively. Univariate statistics was used for variables selection for the supervised machine learning model (alpha = 0.05). The following algorithms were trained: logistic regression, gradient boosting classifier, k-nearest neighbors, support vector machine, multilayer perceptron classifier, decision tree, and random forest classifier. A threefold cross-validation approach was adopted to validate each model. The areas under the curve (AUC) were computed, and ROC curves were constructed. Three mandibular-related measurements and eight dental size-related dimensions were used to train the machine learning models using data from 108 individuals. The mandibular ramus height and the lower first molar mesio-distal size exhibited the greatest predictive capability in most of the evaluated models. The accuracy of the models varied from 0.64 to 0.74 in the cross-validation stage, and from 0.58 to 0.79 when testing the data. The logistic regression model exhibited the highest performance (AUC = 0.84). Despite the limitations of this study, the results seem to show that the integration of mandibular and dental dimensions for sex prediction would be a promising approach, emphasizing the potential of machine learning techniques as valuable tools for this purpose.

Abstract We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan–Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27–0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB.

Abstract Tuberculosis remains a large health threat, despite the availability of the tuberculosis vaccine, BCG. As BCG efficacy gradually decreases from adolescence, BCG-Prime and antigen-booster may be an efficient strategy to confer vaccine efficacy. Mycobacterial DNA-binding protein 1 (MDP1, namely Rv2986c, hupB or HU) is a major Mycobacterium tuberculosis protein that induces vaccine-efficacy by co-administration with CpG DNA. To produce MDP1 for booster-vaccine use, we have created recombinant MDP1 produced in both Escherichia coli (eMDP1) and Mycolicibacterium smegmatis (mMDP1), an avirulent rapid-growing mycobacteria. We tested their immunogenicity by checking interferon (IFN)-gamma production by stimulated peripheral blood cells derived from BCG-vaccinated individuals. Similar to native M. tuberculosis MDP1, we observed that most lysin resides in the C-terminal half of mMDP1 are highly methylated. In contrast, eMDP1 had less post-translational modifications and IFN-gamma stimulation. mMDP1 stimulated the highest amount of IFN-gamma production among the examined native M. tuberculosis proteins including immunodominant MPT32 and Antigen 85 complex. MDP1-mediated IFN-gamma production was more strongly enhanced when combined with a new type of CpG DNA G9.1 than any other tested CpG DNAs. Taken together, these results suggest that the combination of mMDP1 and G9.1 possess high potential use for human booster vaccine against tuberculosis.

Abstract Allergic rhinitis (AR) is caused by type I hypersensitivity reaction in the nasal tissues. The interaction between CD300f and its ligand ceramide suppresses immunoglobulin E (IgE)-mediated mast cell activation. However, whether CD300f inhibits the development of allergic rhinitis (AR) remains elusive. We aimed to investigate the roles of CD300f in the development of AR and the effectiveness of intranasal administration of ceramide liposomes on AR in murine models. We used ragweed pollen-induced AR models in mice. Notably, CD300f deficiency did not significantly influence the ragweed-specific IgE production, but increased the frequency of mast cell-dependent sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in our models. Similar results were also obtained for MCPT5-exprssing mast cell-specific loss of CD300f. Importantly, intranasal administration of ceramide liposomes reduced the frequency of sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in AR models. Thus, CD300f–ceramide interaction, predominantly in mast cells, alleviates the symptoms and progression of AR. Therefore, intranasal administration of ceramide liposomes may be a promising therapeutic approach against AR by targeting CD300f.

Abstract Laboratory animals are typically maintained under 12-h light and 12-h dark (12:12 LD) conditions with a daytime light intensity of ~ 200 lx. In this study, we designed an apparatus that allowed mice to self-select the room light intensity by nose poking. We measured the behavioral rhythms of the mice under this self-controlled light regimen. The mice quickly learned the relationship between their nose pokes and the resulting changes in the light intensity. Under these conditions, the mice exhibited free-running circadian behavior with a period of 24.5 ± 0.4 h. This circadian period was ~ 1 h longer than that of the same strain of mice when they were kept in constant darkness (DD) after 12:12 LD entrainment, and the lengthened period lasted for at least 30 days. The rhythm of the light intensity controlled by the mice also exhibited a similar period, but the phase of the illuminance rhythm preceded the phase of the locomotor activity rhythm. Mice that did not have access to the light controller were also entrained to the illuminance cycle produced by the mice that did have access to the light controller, but with a slightly delayed phase. The rhythm was likely controlled by the canonical circadian clock because mice with tau mutations in the circadian clock gene CSNK1E exhibited short periods of circadian rhythm under the same conditions. These results indicate that the free-running period of mice in the wild may differ from what they exhibit if they are attuned by forced light cycles in laboratories because mice in their natural habitats can self-control their exposure to ambient light, similar to our experimental conditions.

Abstract It is often assumed that future coastal cliff retreat rates will accelerate as global sea level rises, but few studies have investigated how SLR (sea level rise) might change cliff-front wave dynamics. Using a new simple numerical model, this study simulates the number and type (breaking, broken, or unbroken) of cliff-front waves under future SLR scenarios. Previous research shows breaking waves deliver more energy to cliffs than broken waves, and unbroken waves generate minimal impact. Here, we investigated six cliff-platform profiles from three regions (USA, New Zealand, and UK) with varied tidal ranges and wave climates. Model inputs included 2013–2100 hindcast/forecast incident wave height and tidal water level, and three future SLR scenarios. Results show the number of both cliff-front breaking and broken waves generally increase for a high-elevation (relative to tide) cliff-platform junction. In contrast, breaking/broken wave occurrence decrease by 38–92% for a near-horizontal shore platform with a low-elevation cliff-platform junction under a high SRL scenario, leading to high (96–97%) unbroken wave occurrence. Overall, results suggest the response of cliff-front waves to future SLR is complex and depends on shore platform geometries and SLR scenarios, indicating that future cliff retreat rates may not homogeneously accelerate under SLR.

Abstract All attempts to identify male-specific growth genes in humans have failed. This study aimed to clarify why men are taller than women. Microarray-based transcriptome analysis of the cartilage tissues of four adults and chondrocytes of 12 children showed that the median expression levels of SHOX, a growth gene in the pseudoautosomal region (PAR), were higher in male samples than in female samples. Male-dominant SHOX expression was confirmed by quantitative RT-PCR for 36 cartilage samples. Reduced representation bisulfite sequencing of four cartilage samples revealed sex-biased DNA methylation in the SHOX-flanking regions, and pyrosequencing of 22 cartilage samples confirmed male-dominant DNA methylation at the CpG sites in the SHOX upstream region and exon 6a. DNA methylation indexes of these regions were positively correlated with SHOX expression levels. These results, together with prior findings that PAR genes often exhibit male-dominant expression, imply that the relatively low SHOX expression in female cartilage tissues reflects the partial spread of X chromosome inactivation into PAR. Altogether, this study provides the first indication that sex differences in height are ascribed, at least in part, to the sex-dependent epigenetic regulation of SHOX. Our findings deserve further validation.