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This study attempted to develop a mobile-based health management application targeting middle-aged men experiencing andropause, with the aim of allowing them to prevent and continuously manage health issues that may arise during the experience of andropause. The mobile web-based andropause health management program focused on providing a wide range of information and enhancing self-management by integrating various sources of information. Additionally, the app was developed based on the Android OS (used in domestic smartphones), enabling comprehensive information access anytime and anywhere in daily life, and offering various self-measurement features to facilitate effective self-management for individuals experiencing andropause. Currently, existing andropause management apps are designed for women, making this study’s program unique as it is developed for middle-aged men. Furthermore, by connecting various psychological counseling programs, this application can be utilized as a resource for mental health management, allowing for shortened intervention times and flexible, accessible interventions when necessary. While this andropause app for men was developed through user satisfaction surveys, it is necessary to conduct a larger study to test the effectiveness of the andropause health management program for middle-aged men.

Abstract Background DNA methylation is a critical regulatory mechanism of gene expression, influencing various human diseases and traits. While traditional expression quantitative trait loci (eQTL) studies have helped elucidate the genetic regulation of gene expression, there is a growing need to explore environmental influences on gene expression. Existing methods such as PrediXcan and FUSION focus on genotype-based associations but overlook the impact of environmental factors. To address this gap, we present MOSES (methylation-based gene association), a novel approach that utilizes DNA methylation to identify environmentally regulated genes associated with traits or diseases without relying on measured gene expression. Results MOSES involves training, imputation, and association testing. It employs elastic-net penalized regression models to estimate the influence of CpGs and SNPs (if available) on gene expression. We developed and compared four MOSES versions incorporating different methylation and genetic data: (1) cis-DNA methylation within 1 Mb of promoter regions, (2) both cis-SNPs and cis-CpGs, 3) both cis- and a part of trans- CpGs (±5Mb away) from promoter regions), and 4) long-range DNA methylation (±10 Mb away) from promoter regions. Our analysis using nasal epithelium and white blood cell data from the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study demonstrated that MOSES, particularly the version incorporating long-range CpGs (MOSES-DNAm 10 M), significantly outperformed existing methods like PrediXcan, MethylXcan, and Biomethyl in predicting gene expression. MOSES-DNAm 10 M identified more differentially expressed genes (DEGs) associated with atopic asthma, particularly those involved in immune pathways, highlighting its superior performance in uncovering environmentally regulated genes. Further application of MOSES to lung tissue data from idiopathic pulmonary fibrosis (IPF) patients confirmed its robustness and versatility across different diseases and tissues. Conclusion MOSES represents an innovative advancement in gene association studies, leveraging DNA methylation to capture the influence of environmental factors on gene expression. By incorporating long-range CpGs, MOSES-DNAm 10 M provides superior predictive accuracy and gene association capabilities compared to traditional genotype-based methods. This novel approach offers valuable insights into the complex interplay between genetics and the environment, enhancing our understanding of disease mechanisms and potentially guiding therapeutic strategies. The user-friendly MOSES R package is publicly available to advance studies in various diseases, including immune-related conditions like asthma.

This study focused on enhancing the electrical conductivity of metal oxide nanosheet films by increasing the size of the nanosheets to promote the electron flow in the desired in-plane direction. We developed a method for increasing the size of RuO2 metal oxide nanosheets, a 2D material, by controlling the heat-treatment process. The size of the RuO2 nanosheets increased from 0.7 to 3.5 μm by modifying the heat-treatment conditions of KxRuO2, which was used as the precursor material. As a consequence, the electrical conductivity of the large-sized-RuO2 nanosheet-coated films was eight times higher than that of their small-sized counterparts. This lower resistance was attributed to the minimal number of contacts required for electron flow; the contact resistance between the nanosheets being higher than the intrinsic resistance. The proposed approach for enhancing the conductivity of metal oxide 2D materials is very promising and is expected to significantly contribute to the development of advanced flexible electronic devices.

Purpose Short stature is the main characteristic of Turner syndrome (TS) patients and growth hormone (GH) therapy has been essential for achieving the final adult height (Ht). In the present study, the response of TS patients with different types of karyotype abnormalities to GH therapy was analyzed. Methods The clinical parameters of 194 TS patients registered in the LG Growth Study were retrospectively reviewed. Data for 4 groups of subjects were obtained as follows: monosomy X (n=56); X structural abnormality (n=26); X mosaicism without structural abnormality (n=41); X mosaicism with structural abnormality (n=71). Clinical characteristics and growth response parameters were compared over 3 years of GH treatment. Results The baseline Ht standard deviation score (SDS) of all patients was -2.85±0.86. The baseline Ht SDS, body mass index SDS, and chronological age (years)-bone age (years) were significantly different based on chromosomal abnormalities. The growth velocity (GV; cm/yr) in the first year was the highest and significantly different among the groups. The GV in the second year also showed an increase in the X mosaicism without structural abnormality group compared with the monosomy X group. The change in Ht SDS (ΔHt SDS) over 3 years was not statistically different between karyotypes. Conclusions The response to 3 years of GH therapy did not differ based on the karyotype of TS patients although the initial Ht SDS was the lowest in the monosomy X group.

Abstract Few studies evaluated patient-reported outcomes (PROs) for patients with hematologic malignancies receiving with Chimeric Antigen Receptor T (CAR-T) cell therapy. We performed a systematic review and meta-analysis to evaluate the benefits of CAR-T cell therapies focused on PROs. A systematic literature searched from PubMed, Cochrane, and the Web of Science from inception to September 2023. Study selection and data extraction were conducted independently by two reviewers based on pre-specified criteria. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias checklist was used to evaluate the methodological quality of the included studies. The random-effects model was employed to calculate the combined effect and 95% Confidence intervals. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the protocol was registered with PROSPERO (CRD42024586706). We identified 20,110 studies. Of those, 15 studies with 16 different PRO measures (PROMs) were included in the meta-analysis. CAR-T cell therapy improved PROs in the six domains of general health status, pain, fatigue, depression, social function, and cognitive function: from the general health status (SMD: 0.57, 95% CI: 0.34 to 0.81) to cognitive function (SMD: 0.25, 95% CI: 0.14 to 0.37). The current meta-analysis shows that CAR-T cell therapy produces clinically meaningful differences in PROs. These results suggest that the professional perspective and patient values and preferences should be weighed equally when considering CAR-T cell therapy for hematologic malignancies.

Abstract Excess exogenous supplementation of d-galactose (d-gal), a monosaccharide and reducing sugar, generates reactive oxygen species (ROS), leading to cell damage and death. ROS accumulation is critical in aging. Therefore, d-gal-induced aging mouse models are used in aging studies. Herein, we evaluated d-gal’s effect on neonatal testis development using an in vitro organ culture method. Mouse testicular fragments (MTFs) derived from neonatal testes (postnatal day 5) were cultured with 500 mM d-gal for 5 days. d-gal-treated MTFs showed a significantly increased and decreased expression of undifferentiated and differentiated germ cell markers, respectively, with a substantial reduction in meiotic cells. In d-gal-exposed MTFs, expression levels of Sertoli cell markers (Sox9 and Wt1) increased, while those of StAR and 17β-HSD3, whose expressions are abundant in d-Gal treated adult Leydig cells, decreased. Additionally, the enzyme 3 β-HSD1, essential for steroidogenesis in Leydig cells, was significantly reduced in d-gal-exposed MTFs compared to that in controls.d-gal significantly increased the expression of Bad, Bax, and cleaved caspase-3 and -8. Via oxidative stress in MTF. Overall, d-gal negatively regulates germ cell and Leydig cell development in neonatal testes through pro-apoptotic mechanisms and ROS.

Abstract Electrical cardioversion (ECV) a widely utilized intervention for persistent atrial fibrillation (AF) aimed at restoring sinus rhythm. However, ECV can be ineffective, raising questions about subsequent treatment options. This study aimed to compare the outcomes of non-ablation therapy versus ablation therapy following unsuccessful ECV. A total of 125 consecutive patients with persistent AF who underwent unsuccessful ECV between November 2017 and August 2023 was included in this retrospective analysis. Of these, 51.2% received only medical therapy (non-ablation therapy group, n = 64), while 48.8% underwent AF ablation (ablation therapy group, n = 61). Various ablation methods were employed, including catheter and thoracoscopic ablation. Ablation therapy was associated with significantly better AF-free survival compared to non-ablation therapy [hazard ratio (HR), 0.37; 95% confidence interval (CI) 0.22–0.61; p 5 year (HR 1.51; 95% CI 0.930–2.437; p = 0.10), BMI ≤ 25 kg/m2 (HR 1.61; 95% CI 1.004–2.581; p = 0.05) and diabetes (HR 2.38; 95% CI 0.902–6.266; p = 0.08) were considerable as predictor of AF recurrence. Ablation therapy following unsuccessful ECV was associated with maintaining sinus rhythm, regardless of the specific ablation method utilized.

Despite the accumulating evidence showing the essential role of pentatricopeptide repeat (PPR) proteins in organellar biogenesis and plant development in Arabidopsis thaliana and maize (Zea mays), the functions of most PPR proteins in rice (Oryza sativa) are still unknown. A former study demonstrated that the mitochondria-localized Arabidopsis PPR19 is crucial for mitochondrial function and normal plant growth and development. In this study, we characterized the functional role of a rice ortholog (LOC_Os12g04110) of Arabidopsis PPR19 protein. The loss-of-function osppr19 mutant displayed delayed seed germination and stunted root and seedling growth compared with wild-type. The height of the osppr19 mutant was significantly shorter, and the grain mass of the mutant was lower than that of the wild-type. The osppr19 mutant carried few filled grains and a higher number of aborted seeds than the wild-type. The structures of mitochondria in the osppr19 mutant were abnormal, and more reactive oxygen species were accumulated in the mutant, suggesting defective mitochondrial biogenesis and function in the osppr19 mutant. Importantly, the amount of mature mitochondrial transcripts was significantly decreased in the mutant. Taken together, these results suggest that the mitochondrial OsPPR19 is essential for mitochondrial biogenesis and function, which is crucial for plant growth and development of rice grain.

Abstract Effective antihypertensive therapy is essential for achieving optimal blood pressure (BP) control and reducing cardiovascular events. This double-blind, multicenter, randomized trial aimed to compare the antihypertensive efficacy and safety of a combination of amlodipine (AML) and candesartan cilexetil (CC) versus AML monotherapy in patients with essential hypertension (HTN). After a 4-week run-in period with AML 5 mg, patients whose HTN remained uncontrolled (diastolic BP [DBP]) ≥ 90 mmHg and

Purpose: The leaves of Perilla frutescens var. acuta (PFA) are generally reported to have antioxidant, anti-allergic, anti-inflammatory, and antitumor effects and commonly used as a traditional medicine in East Asia. This study aimed to investigate the protective effect and antioxidant activity of PFA on busulfan-induced testicular dysfunction, histological damage, oxidative stress (OS), sperm quality, and hormone levels using a mouse model. Materials and Methods: C57BL/6 male mice were divided into four groups: control, busulfan-only treated, and varying concentrations of PFA (100 and 200 mg/kg) with busulfan. In the busulfan group, 40 mg/kg of busulfan was intraperitoneally injected to induce azoospermia. Mice were orally administered PFA for 35 consecutive days after busulfan administration. Samples were collected and assessed for testis/body weight, testicular histopathology, sperm quality, serum hormone levels, and OS to evaluate the effects of PFA treatment on spermatogenesis dysfunction induced by busulfan. Results: The busulfan-induced testicular dysfunction model showed reduced testis weight, adverse histological changes, significantly decreased sex hormones and sperm quality, and attenuated OS. These results indicate that PFA treatment significantly increased testis weight, testis/body weight, epididymal sperm count, motility, and testosterone level compared with busulfan alone. PFA treatment also attenuated the busulfan-induced histological changes. Furthermore, compared with mice treated with busulfan alone, PFA supplementation upregulated the testicular mRNA expression of the antioxidant enzymes superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (Gpx1), with a decrease in malondialdehyde (MDA) production and an increase in SOD and GPx activities. Conclusions: This study shows that PFA exerts a protective effect against testicular damage by attenuating OS induced by busulfan. Our results suggest that PFA is a potentially relevant drug used to decrease the side effects induced by busulfan on testicular function and sperm during cancer chemotherapy.

We present findings across three randomized trials of "Descubriendo la Lectura" (DLL), an intervention designed to improve literacy skills of Spanish-speaking first graders struggling with reading. DLL is a one-to-one Spanish-language literacy program lasting 12-20 weeks offered to a school's lowest performing emerging bilingual first graders. Directly replicating procedures across three cohorts, we examined Spanish and English literacy outcomes for approximately 400 students across 30 schools, 10 districts, and five states. Analyses revealed statistically significant effects of student-level assignment to DLL on all 11 Spanish-language outcomes, with an average impact of d = 0.57. Impacts across the four English-language outcomes were positive but not statistically significant. Descriptive results suggest that the Spanish-language impacts are reliably replicated, most likely due to the intervention's strong implementation supports.

Drawing on state reading achievement data provided by a California school district, we analyze the achievement impacts of Achieve3000, an intervention designed to offer K-12 students expanded opportunities to acquire literacy skills. Achieve3000 is a personalized, technology-adaptive program to supplement regular instruction in English language arts, science, and social studies. We apply propensity score matching methods to match 1,761 participating Achieve3000 students to 945 similar students to estimate the effects of the Achieve3000 intervention. Applying a doubly-robust regression model, our results suggest that Achieve3000 students outperformed comparison students by a mean effect size of 0.06. Further, two-stage least squares regression models reveal that treatment students' scores increased statistically significantly by 0.001 standard deviations for both each activity completed and for each additional hour of Achieve3000 participation. Despite some problems of implementation, our quasi-experimental evidence of the positive impacts of Achieve3000 suggests a possibly promising way to overcome COVID-19 learning losses through computer-based, one-on-one tutoring at scale.

Purpose: This study analyzes the advantages and disadvantages of the electoral mechanism of local education superintendents in South Korea, draws conclusions and makes suggestions for future reforms. Design/methodology/approach: The research method of this study included document analysis and interviews. Document analysis was used to collect and analyze the relevant official documents of education superintendents across countries. Semi-structured interviews were conducted with four professors and two superintendents. Findings: The results of the interviews indicate the following: 1) Korean stakeholders are getting more familiar with the direct election of superintendents, as the interviews indicate a more mature direct election system due to previous experience and public officials taking direct election into account; 2) The direct election of superintendents has advantages and disadvantages. The advantages include increasing the participation of the general public in education, and the disadvantages include conflict between the central government and local superintendents belonging to different political parties. However, the current system is likely to be retained; 3) The superintendent systems in various countries differ due to their respective traditions and social contexts. However, the authors can always learn lessons and implications from foreign countries if the authors compare their education systems with their foreign counterparts. Research limitations/implications: As far research limitations, although this was a small study, it shows the importance of collecting multiple stakeholders' views on the direct election of education superintendents as a basis for future reform of education management. Practical implications: The Korean system for electing superintendents provides a good model for other countries reflecting on the educational autonomy and accountabilities of their own systems. Social implications: The direct election of superintendents provides an example of professionalism, independence and political neutrality in education that other countries can learn from. The separation of general and educational administration in Korea through direct elections protects educational activities from political influence. Originality/value: In terms of originality/value, this study adds a new perspective to the debate about whether the general public should directly elect education superintendents, as well as to the literature on local education management.

Background: The climate of Korean peninsula is characterized by four distinct seasons. In recent years, global warming has accelerated, and summers in Korea are typically hot and humid. However, the precise extent of climatic damage caused in Hanwoo farming has not yet been reported, by long raise periods. This study was conducted to investigate the effects of birth and slaughter season on economical carcass characteristics in Hanwoo cattle. Methods: Hanwoo steer carcass data was collected from the Korean Institute for Animal Products Quality Evaluation database for 2021-2022. Hanwoo birth and slaughter season was classified as spring (March-May), summer (June-August), fall (September-November), and winter (December-February). Results: The carcass mass and loin area were significantly higher in winter- and spring-born Hanwoo than in summer- and fall-born cattle. However, back fat thickness was significantly higher in winter- and spring-slaughtered steers than in summer-slaughtered cattle. In addition, the marbling score was highest in summer-slaughtered steers, but meat yield grade differed between Hanwoo steers of different ages. Conclusions: Out results indicate that carcass mass and loin area were correlated with birth season, whereas back fat thickness and marbling score were related with slaughter season. These results will contribute to improving meat production quality in the Hanwoo industry.

Abstract This study investigates the impact of the anatomical separation point of the dorsal ulnar cutaneous nerve (DUCN) on nerve conduction studies (NCS). Involving 25 subjects with DUCN NCS findings, it utilizes ultrasound to mark the DUCN's divergence from the ulnar nerve. NCS was performed at four points relative to the separation point. The findings indicate the maximal amplitudes occurred 2 cm distal to the separation point. The study suggests it is ideal when the stimulation is performed between the seperation point and 2 cm distal to it.

Abstract T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) exhibits unique, cell type- and context-dependent characteristics and functions. Here, we report that TIM-3 on myeloid cells plays essential roles in modulating lung inflammation. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have lower body weight and shorter lifespan than WT mice. Intriguingly, the lungs of FSF-TIM3/LysM-Cre+ mice display excessive inflammation and features of disease-associated pathology. We further revealed that galectin-3 levels are notably elevated in TIM-3-overexpressing lung-derived myeloid cells. Furthermore, both TIM-3 blockade and GB1107, a galectin-3 inhibitor, ameliorated lung inflammation in FSF-TIM3/LysM-Cre+/− mice. Using an LPS-induced lung inflammation model with myeloid cell-specific TIM-3 knock-out mice, we demonstrated the association of TIM-3 with both lung inflammation and galectin-3. Collectively, our findings suggest that myeloid TIM-3 is an important regulator in the lungs and that modulation of TIM-3 and galectin-3 could offer therapeutic benefits for inflammation-associated lung diseases.

Background/Aims The association between inflammatory bowel disease (IBD) and gallstone and renal stone formation has been established. However, few studies have investigated this association in patients with intestinal Behçet’s disease (BD). We aimed to examine the prevalence of gallstones and renal stones in patients with intestinal BD and identify potential risk factors. Methods We analyzed gallstone and renal stone occurrences in 553 patients diagnosed with intestinal BD who had undergone cross-sectional imaging examinations between March 2005 and April 2021 at the IBD Center, Severance Hospital, Seoul, South Korea. Logistic regression models were used to identify risk factors for gallstone and renal stone formation. Results Of 553 patients over a mean 12.1-year duration, 141 (25.4%) patients had gallstones and 35 (6.3%) had renal stones. In multivariate logistic regression analysis, disease duration > 19 years (OR 2.91, 95% CI 1.56–5.44, p < 0.001), prior intestinal BD-related surgery (OR 2.29, 95% CI 1.42–3.68, p < 0.001), and disease activity index for intestinal BD scores ≥ 75 (OR 2.23, 95% CI 1.12–4.45, p = 0.022) were associated with increased gallstone occurrence. A positive correlation was observed between renal stones, disease duration > 19 years (OR 5.61, 95% CI 1.98–15.90, p = 0.001) and frequent hospitalization (> 3 times) (OR 3.29, 95% CI 1.52–7.13, p = 0.002). No significant correlation was observed between gallstone and renal stone occurrence. Conclusions These findings contribute to greater understanding concerning gallstone and renal stone prevalence and associated risk factors in patients with intestinal BD.

Background/Aims Limited knowledge exists regarding the optimal timing and relative advantages of primary surgery compared to medical treatment in ileocecal Crohn’s disease (CD). This study aimed to compare long-term outcomes between medication-based treatment versus surgery in newly diagnosed ileocecal CD patients in an Asian population. Methods Among the 885 patients diagnosed with CD and enrolled in the study site hospital cohort between 1980 and 2013, 93 (10.5%) had ileocecal CD. Patients were categorized into either the surgical or medical remission group based on their initial management strategy that led to remission. The rates of relapse, hospitalization, and surgery after achieving remission were compared using Kaplan-Meier curves. Results The numbers of patients assigned to surgical and medical remission groups were 15 (17.0%) and 73 (83.0%), respectively. The surgical remission group exhibited a lower relapse rate and longer maintenance of remission (10.7 vs. 3.7 yr; p = 0.017) during a median follow-up of 6.6 years. Hospitalization after the first remission tended to be lower in the surgical remission group (p = 0.054). No cases required repeated intestinal resection after the initial surgical remission, whereas a 23% surgery rate was reported at 5 years after initial medical treatment (p = 0.037). In the multivariable analysis, the initial medication-based treatment was significantly associated with relapse (hazard ratio = 3.23, p = 0.039). Conclusions In selected cases of localized ileocecal CD, ileocolic resection might be a favorable alternative to medication-based treatment, as it demonstrates a lower relapse rate and longer maintenance of remission.

Herein, we determined and analyzed the chloroplast (cp) genome sequence of Lonicera harae for the first time. The chloroplast genome was 154,959 bp and contained a large single copy (LSC) of approximately 88,849 bp as well as a small single copy (SSC) of 18,832 bp separated by a pair of 23,639 bp inverted repeats (IRs). The overall G+C content in the L. harae chloroplast genome was 38.4%. A total of 114 unique genes were annotated, comprising 80 protein-coding genes (PCGs), 30 transfer RNAs (tRNAs), and four ribosomal RNAs (rRNAs). Of these, 17 contained one or two introns. Phylogenetic analysis of 54 accessions revealed that L. harae forms a clade with L. fragrantissima. This newly sequenced chloroplast genome provides valuable molecular phylogenomic information for future studies to determine the taxonomic position of L. harae and the phylogenetic relationships within the genus Lonicera.

This study aims to clarify the concept and promote understanding by conducting a concept analysis of the parenting behaviors of fathers during early childhood, a critical period where parenting behaviors and direction have a significant impact. This study is a concept analysis of the parenting behaviors of fathers with conducted using Walker and Avant’s method. The analysis utilized data collected from 1960 to February 2023. The attributes of paternal caregiving behavior in early childhood identified in this study include general and universal attitudes or behaviors, father-child interactions, caregiving and discipline based on love, and instinctive and explicit caregiving behaviors. The antecedents of paternal caregiving behavior in early childhood were the perception of caregiving and the actual caregiving behaviors. The findings of this study underscore the need for a comprehensive measurement tool to assess the parenting behaviors of fathers with early childhood. Such a tool should integrate all key attributes identified in this study to accurately evaluate and support effective parenting practices during this formative period.

The purpose of this study was to confirm subjective perceptions of cardiovascular disease risk among professional male drivers. Using the Q-methodology, we systematically analyzed and classified subjective perceptions of cardiovascular disease risk among professional drivers, thus identifying characteristics of each type. Q methodology, which is a research method to study people’s subjective points of views, was used. 34 Q-statements (Q-sample) were derived from the Q population (Concourse) and were arranged in rank order by each of 35 participants into a normal distribution grid (from −4 to +4). A QUANL program was used to analyze the collected data. The subjective perceptions of cardiovascular disease risk among professional male drivers were classified into four types: first, the risk detection type; second, the prevention effort type; third, the symptom recognition type; and finally, the risk neglect type. Efforts should be made to maintain the physical and mental health promotion of the subjects, including education on symptoms related to cardiovascular disease, awareness and prevention of high-risk factors and severity, and various efforts. Furthermore, it is necessary to develop and implement tailored health promotion programs for preventing cardiovascular disease, considering the diverse characteristics of professional drivers.

Abstract Background While significant research exists on gut microbiota changes after anti-tumor necrosis factor-alpha (anti TNF-α) therapy for ulcerative colitis, little is known about the longitudinal changes related to the effects of anti TNF-α. This study aimed to investigate the dynamics of gut microbiome changes during anti TNF-α (adalimumab) therapy in patients with ulcerative colitis (UC). Results The microbiota composition was affected by the disease severity and extent in patients with UC. Regardless of clinical remission status at each time point, patients with UC exhibited microbial community distinctions from healthy controls. Distinct amplicon sequence variants (ASVs) differences were identified throughout the course of Adalimumab (ADA) treatment at each time point. A notable reduction in gut microbiome dissimilarity was observed only in remitters. Remitters demonstrated a decrease in the relative abundances of Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus as the treatment progressed. Additionally, there was an observed increase in the relative abundances of Bifidobacterium and Dorea. Given the distribution of the 48 ASVs with high or low relative abundances in the pre-treatment samples according to clinical remission at week 8, a clinical remission at week 8 with a sensitivity and specificity of 72.4% and 84.3%, respectively, was predicted on the receiver operating characteristic curve (area under the curve, 0.851). Conclusions The gut microbiota undergoes diverse changes according to the treatment response during ADA treatment. These changes provide insights into predicting treatment responses to ADA and offer new therapeutic targets for UC.

Abstract Background There is limited research on the intra‐individual efficacy of ventricular pacing minimization algorithms developed by Biotronik—the Ventricular Pace Suppression algorithm (VpS) and the Intrinsic Rhythm Support plus algorithm (IRSplus) (BIOTRONIK SE & Co. KG, Berlin, Germany). We performed a randomized pilot trial that evaluated the efficacy of two algorithms in patients with symptomatic sinus node dysfunction (SND) who received a dual‐chamber pacemaker. Methods The trial was conducted in 11 tertiary hospitals in South Korea. The patients were randomized to either the VpS or IRSplus algorithm group after a 3‐month period of fixed atrioventricular (AV) delay. The primary outcome was the ventricular pacing percentage (Vp%) at each follow‐up visit. The secondary outcomes were the occurrence of heart failure (HF) and atrial fibrillation (AF) during the study period. Results Data from 131 patients were analyzed. Initially, their average Vp% over 3 months with a fixed AV interval was 14.1 ± 19.4%. Patients were randomly assigned to VpS and IRSplus groups, with 66 and 65 in each. Algorithms reduced average Vp% to 4.0 ± 11.3% at 9 months and 6.7 ± 14.9% at 15 months. These algorithms were more effective for patients with paced AV delay (PAVD) ≤300 ms compared to those with PAVD >300 ms. Both algorithms were equally effective in reducing Vp%. Clinical AF or HF hospitalization was not observed during the study period. Conclusion The VpS and IRSplus algorithms are effective and safe in minimizing unnecessary ventricular pacing in patients with SND.

The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety.

Background/Aims The impact of vaccination on inflammatory bowel disease (IBD) patients is still unknown, and no studies have assessed the changes in patient-reported outcomes (PROs) after vaccination in patients with IBD. Therefore, in this study, we investigated the impact of vaccines on the PROs of patients with IBD. Methods We conducted a questionnaire survey of patients with IBD who visited outpatient clinics at 4 specialized IBD clinics of referral university hospitals from April 2022 to June 2022. A total of 309 IBD patients were included in the study. Patient information was collected from a questionnaire and their medical records, including laboratory findings, were reviewed retrospectively. Risk factors associated with an increase in PROs after COVID-19 vaccination were analyzed using logistic regression analyses. In addition, we assessed whether there were differences in variables by vaccine order using the linear mixed model. Results In multivariate analysis, young age ( < 40 years) and ulcerative colitis (UC) were found to be independent risk factors for aggravation of PROs in patients with IBD. In all patients, platelet count significantly increased with continued vaccination in multiple pairwise comparisons. In UC patients, PROs such as the short health scale, UC-abdominal signs and symptoms, and UC-bowel signs and symptoms were aggravated significantly with continued vaccination. There was no significant increase in the variables of patients with Crohn’s disease. Conclusions Therefore, there may be a need to counsel patients with IBD younger than 40 years of age, and patients with UC before they receive COVID-19 vaccinations.

Acanthoic acid, a diterpene isolated from the root bark of Acanthopanax koreanum Nakai, possesses diverse pharmacological activities, including anti-inflammatory, anti-diabetic, gastrointestinal protection, and cardiovascular protection. This study is the first to investigate the egg-hatching rates of Drosophila melanogaster affected by acanthoic acid. Notably, male flies supplemented with 10 μM acanthoic acid exhibited a strong increase in hatching rates compared with controls under adverse temperature conditions, suggesting a potential protective effect against environmental stressors. Molecular docking simulations revealed the binding affinities and specific interactions between acanthoic acid and proteins related to male infertility, including SHBG, ADAM17, and DNase I, with binding affinity values of −10.2, −6.8, and −5.8 kcal/mol, respectively. Following the docking studies, molecular dynamic simulations were conducted for a duration of 100 ns to examine the stability of these interactions. Additionally, a total binding energy analysis and decomposition analysis offered insights into the underlying energetic components and identified key contributing residues.

Abstract In recent years, human anatomy education has faced challenges with traditional donor dissection, leading to the emergence of virtual dissection as an alternative. This study aims to investigate the academic performance and satisfaction of medical students by comparing the virtual and donor dissections. An open-labeled crossover randomized controlled trial was conducted with 154 first-year medical students in Human Anatomy and Neuroanatomy laboratories, which were divided into three classes. Students were randomly assigned to either the virtual (virtual dissection followed by donor dissection) or donor (donor dissection followed by virtual dissection) groups in each class. A curriculum, incorporating head-mounted displays (HMDs), a life-sized touchscreen, and tablets, was developed. Data was evaluated through quizzes and surveys. In the Human Anatomy laboratory, each class of the donor group conducted heart extraction, dissection and observation. In observation class, the virtual group had a significantly higher mean quiz score than the donor group (p

Abstract Bioelectronic implants in the deep brain provide the opportunity to monitor deep brain activity with potential applications in disease diagnostics and treatment. However, mechanical mismatch between a probe and brain tissue can cause surgical trauma in the brain and limit chronic probe-based monitoring, leading to performance degradation. Here, we report a transient shuttle-based probe consisting of a PVA and a mesh-type probe. A rigid shuttle based on PVA implants an ultrathin mesh probe in the target deep brain without a tangle, while creating both a sharp edge for facile penetration into the brain and an anti-friction layer between the probe and brain tissue through dissolving its surface. The capability to shuttle dissolved materials can exclude the retracted process of the shuttle in the brain. Complete dissolution of the shuttle provides a dramatic decrease (~1078-fold) in the stiffness of the probe, which can therefore chronically monitor a wide area of the brain. These results indicate the ability to use a simplistic design for implantation of wide and deep brain probes while preventing unnecessary damage to the brain and probe degradation during long-term use.

BackgroundMicrobial profiles in patients with chronic obstructive pulmonary disease (COPD) provide insights for predicting, preventing, and treating exacerbations. This study aimed to analyze the impact of microbial diversity and spectrum on COPD exacerbation.MethodsFrom November 1, 2018, to May 31, 2023, we prospectively enrolled patients with stable disease (SD) and exacerbation of COPD (ECOPD). Sputum samples were collected for microbiome DNA sequencing, and amplicon sequence variants were analyzed.ResultsWe collected sputum samples from 38 patients: 17 samples from patients with SD and samples from patients with ECOPD at two time points—during exacerbation (AE-1: 21 samples) and again during stabilization after 2 weeks of treatment (AE-2: 17 samples). Alpha diversity indices, specifically observed feature count and Fisher’s alpha index, were significantly higher in SD (133.0 [98.0–145.0]; 17.1 [12.7–19.6]) compared to AE-1 (88.0 [72.0–125.0], p = 0.025; 10.9 [8.5–16.1], p = 0.031). The SD showed significantly higher abundances of Neisseria (linear discriminant analysis [LDA] 4.996, adj.p = 0.021), Fusobacterium (LDA 3.688, adj.p = 0.047), and Peptostreptococcus (LDA 3.379, adj.p = 0.039) at the genus level compared to AE-1. At the species level, N. perflava (LDA 5.074, adj.p = 0.010) and H. parainfluenzae (LDA 4.467, adj. p = 0.011) were more abundant in SD. Hub genera in the microbial network included Haemophilus, Granulicatella, Neisseria, Lactobacillus, and Butyrivibrio in SD and Streptococcus, Gemella, Actinomyces, Klebsiella, and Staphylococcus in AE-1.ConclusionCOPD exacerbations are linked to changes in specific strains of normal flora. Maintaining microbial diversity and balance within the microbial network is critical for preventing and managing COPD exacerbations.

Clonal hematopoiesis of indeterminate potential (CHIP) allows estimation of clonal dynamics and documentation of somatic mutations in the hematopoietic system. Recent studies utilizing large cohorts of the general population and patients have revealed significant associations of CHIP burden with age and disease status, including in cancer and chronic diseases. An increasing number of cancer patients are treated with immune checkpoint inhibitors (ICIs), but the association of ICI response in non-small cell lung cancer (NSCLC) patients with CHIP burden remains to be determined. We collected blood samples from 100 metastatic NSCLC patients before and after ICI for high-depth sequencing of the CHIP panel and 63 samples for blood single-cell RNA sequencing. Whole exome sequencing was performed in an independent replication cohort of 180 patients. The impact of CHIP status on the immunotherapy response was not significant. However, metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs. 5/42 for controls; p = 0.01). In addition, lung squamous cell carcinoma (LUSC) patients showed increased burden of larger clones compared to lung adenocarcinoma (LUAD) patients (8/43 for LUSC vs. 2/50 for LUAD; p = 0.04). Furthermore, single-cell RNA-seq analysis of the matched patients showed significant enrichment of inflammatory pathways mediated by NF-κB in myeloid clusters of the severe CHIP group. Our findings suggest minimal involvement of CHIP mutation and clonal dynamics during immunotherapy but a possible role of CHIP as an indicator of immunologic response in NSCLC patients.

Objectives: Metabolic syndrome is associated with an increased risk of diabetes, cardiovascular disease, and all-cause mortality. Some evidence suggests that the cardiometabolic health benefits of protein intake may vary by the source (animal or plant); however, the evidence is inconsistent. This study aimed to assess the risk of developing metabolic syndrome according to the protein source. Participants: Among a total of 3,310 participants aged 40 years or older in the Ansan and Ansung population based prospective cohort, 1,543 incident cases of metabolic syndrome were identified between 2007 and 2018. Measurements: Dietary intake was assessed using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) by quintile (Q), adjusting for demographics and health-related lifestyle factors. Results: Higher intake of animal protein (HRquintile5 (Q5) vs quintile1 (Q1) [95% CIs]: 0.76 [0.59−0.96], P-trend ≤ 0.0307) and a higher relative intake of animal protein (HRQ5 vs.Q1: 0.78 [0.64−0.95], P-trend ≤ 0.0017) were associated with a significantly decreased risk of developing metabolic syndrome. In subgroup analyses, associations between the risk of metabolic syndrome and the relative intake of animal and plant protein differed according to whether the total protein intake was within the recommended nutrient intake (RNI). Specifically, significant associations were observed only among those with a total protein consumption below the RNI (HRQ5vs Q1 [95% CIs]: 0.72 [0.56−0.93] for the relative intake of animal protein), but not among those consuming above the RNI. This association was more significant in women than in men. Conclusion: A higher absolute and relative intake of animal protein were associated with a significantly decreased risk of metabolic syndrome, particularly among those who consumed less than the RNI of protein.

Nicotinamide Adenine Dinucleotide (NAD) is an endogenous substance in redox reactions and regulates various functions in metabolism. NAD and its precursors are known for their anti-ageing and anti-obesity properties and are mainly active in the liver and muscle. Boosting NAD+ through supplementation with the precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), enhances insulin sensitivity and circadian rhythm in the liver, and improves mitochondrial function in the muscle. Recent evidence has revealed that the adipose tissue could be another direct target of NAD supplementation by attenuating inflammation and fat accumulation. Moreover, murine studies with genetically modified models demonstrated that nicotinamide phosphoribosyltransferase (NAMPT), a NAD regulatory enzyme that synthesizes NMN, played a critical role in lipogenesis and lipolysis in an adipocyte-specific manner. The tissue-specific effects of NAD+ metabolic pathways indicate a potential of the NAD precursors to control metabolic stress particularly via focusing on adipose tissue. Therefore, this narrative review raises an importance of NAD metabolism in white adipose tissue (WAT) through a variety of studies using different mouse models.

BackgroundGrowth hormone deficiency (GHD) and idiopathic short stature (ISS) are the major etiologies of short stature in children. For the diagnosis of GHD and ISS, meticulous evaluations are required, including growth hormone provocation tests, which are invasive and burdensome for children. Additionally, sella magnetic resonance imaging (MRI) is necessary for assessing etiologies of GHD, which cannot evaluate hormonal secretion. Recently, radiomics has emerged as a revolutionary technique that uses mathematical algorithms to extract various features for the quantitative analysis of medical images. ObjectiveThis study aimed to develop a machine learning–based model using sella MRI–based radiomics and clinical parameters to diagnose GHD and ISS. MethodsA total of 293 children with short stature who underwent sella MRI and growth hormone provocation tests were included in the training set, and 47 children who met the same inclusion criteria were enrolled in the test set from different hospitals for this study. A total of 186 radiomic features were extracted from the pituitary glands using a semiautomatic segmentation process for both the T2-weighted and contrast-enhanced T1-weighted image. The clinical parameters included auxological data, insulin-like growth factor-I, and bone age. The extreme gradient boosting algorithm was used to train the prediction models. Internal validation was conducted using 5-fold cross-validation on the training set, and external validation was conducted on the test set. Model performance was assessed by plotting the area under the receiver operating characteristic curve. The mean absolute Shapley values were computed to quantify the impact of each parameter. ResultsThe area under the receiver operating characteristic curves (95% CIs) of the clinical, radiomics, and combined models were 0.684 (0.590-0.778), 0.691 (0.620-0.762), and 0.830 (0.741-0.919), respectively, in the external validation. Among the clinical parameters, the major contributing factors to prediction were BMI SD score (SDS), chronological age–bone age, weight SDS, growth velocity, and insulin-like growth factor-I SDS in the clinical model. In the combined model, radiomic features including maximum probability from a T2-weighted image and run length nonuniformity normalized from a T2-weighted image added incremental value to the prediction (combined model vs clinical model, P=.03; combined model vs radiomics model, P=.02). The code for our model is available in a public repository on GitHub. ConclusionsOur model combining both radiomics and clinical parameters can accurately predict GHD from ISS, which was also proven in the external validation. These findings highlight the potential of machine learning–based models using radiomics and clinical parameters for diagnosing GHD and ISS.

Background This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments. Methods and Results Postprocedural, 4‐dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT‐TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23‐mm SAPIEN3, Edwards Lifesciences; and 29‐mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self‐expanding valves (39.1% versus 14.9%, P=0.004). In per‐cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1–1.3]; P

This study assessed the seasonal distribution and factors associated with PM2.5 in nationwide subway stations in Korea. A total of 229,644 data points collected over one year were used to determine one-day PM2.5 concentrations from 642 subway stations. The geometric mean of indoor PM2.5 concentrations was 26.6 µg/m3. PM2.5 concentrations were higher in the Seoul metropolitan area (SMA) compared to non-Seoul metropolitan areas (NSMA), with the highest level occurring in winter, followed by spring, fall, and summer, similar to the trend observed for outdoor PM2.5 concentrations. In SMA, PM2.5 concentrations were significantly associated with the operation year, number of air cleaners on platforms, and number of passengers. These findings may help in the development of national strategies for managing indoor PM2.5 concentrations in subway stations, taking into account spatial and temporal factors.

Background We hypothesized that analysis of serial ECGs could predict new‐onset atrial fibrillation (AF) more accurately than analysis of a single ECG by detecting the subtle cardiac remodeling that occurs immediately before AF occurrence. Our aim in this study was to compare the performance of 2 types of machine learning (ML) algorithms. Methods and Results Standard 12‐lead ECGs of patients selected by cardiologists between January 2010 and May 2021 were used for ML model development. Two ML models (single ECG and serial ECG) were developed using a light gradient boosting machine‐learning algorithm. Model performance was evaluated based on the area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, and F1 score. We trained the ML models on 415 964 ECGs from 176 090 patients. When testing the 2 ML models using external validation data sets, the performance of the serial‐ML model was significantly better than that of the single‐ML model for predicting new‐onset AF (single‐ versus serial‐ML model: sensitivity 0.744 versus 0.810; specificity 0.742 versus 0.822; accuracy 0.743 versus 0.816; F1 score 0.743 versus 0.815; area under the receiver operating characteristic curve 0.812 versus 0.880; P

Abstract Background The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear. Results This study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models. Conclusions These findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism.

Abstract Background This study aimed to investigate the trends of aggressive care at the end-of-life (EoL) for patients with advanced cancer in Korea and to identify factors affecting such care analyzing nationwide data between 2012 to 2018. Methods This was a population-based, retrospective nationwide study. We used administrative data from the National Health Insurance Service and the Korea Central Cancer Registry to analyze 125,350 patients aged 20 years and above who died within one year of a stage IV cancer diagnosis between 2012 and 2018. Results The overall aggressiveness of EoL care decreased between 2012 and 2018. In patients’ last month of life, chemotherapy use (37.1% to 32.3%; p

Background: Despite its anticancer activity, cisplatin exhibits severe testicular toxicity when used in chemotherapy. Owing to its wide application in cancer therapy, the reduction of damage to normal tissue is of imminent clinical need. In this study, we evaluated the effects of catechin hydrate, a natural flavon-3-ol phytochemical, on cisplatin-induced testicular injury. Methods: Type 2 mouse spermatogonia (GC-1 spg cells) were treated with 0-100 μM catechin and cisplatin. Cell survival was estimated using a cell proliferation assay and Ki-67 immunostaining. Apoptosis was assessed via flow cytometry with the Dead Cell Apoptosis assay. To determine the antioxidant effects of catechin hydrate, Nrf2 expression was measured using qPCR and CellROX staining. The anti-inflammatory effects were evaluated by analyzing the gene and protein expression levels of iNOS and COX2 using qPCR and immunoblotting. Results: The 100 μM catechin hydrate treatment did not affect healthy GC-1 spg cells but, prevented cisplatin-induced GC-1 spg cell death via the regulation of anti-oxidants and inflammation-related molecules. In addition, the number of apoptotic cells, cleaved-caspase 3 level, and BAX gene expression levels were significantly reduced by catechin hydrate treatment in a cisplatin-induced GC-1 spg cell death model. In addition, antioxidant and anti-inflammatory marker genes, including Nrf2, iNOS, and COX2 were significantly downregulated by catechin hydrate treatment in cisplatin-treated GC-1 cells. Conclusions: Our study contributes to the opportunity to reintroduce cisplatin into systemic anticancer treatment, with reduced testicular toxicity and restored fertility.

Abstract Background Risk factors for cardiovascular disease, including elevated blood pressure, are known to increase risk of Alzheimer’s disease. There has been increasing awareness of the relationship between long-term blood pressure (BP) patterns and their effects on the brain. We aimed to investigate the association of repeated BP measurements with Alzheimer’s and vascular disease markers. Methods We recruited 1,952 participants without dementia between August 2015 and February 2022. During serial clinic visits, we assessed both systolic BP (SBP) and diastolic BP (DBP), and visit-to-visit BP variability (BPV) was quantified from repeated measurements. In order to investigate the relationship of mean SBP (or DBP) with Alzheimer’s and vascular markers and cognition, we performed multiple linear and logistic regression analyses after controlling for potential confounders (Model 1). Next, we investigated the relationship of with variation of SBP (or DBP) with the aforementioned variables by adding it into Model 1 (Model 2). In addition, mediation analyses were conducted to determine mediation effects of Alzheimer’s and vascular makers on the relationship between BP parameters and cognitive impairment. Results High Aβ uptake was associated with greater mean SBP (β = 1.049, 95% confidence interval 1.016–1.083). High vascular burden was positively associated with mean SBP (odds ratio = 1.293, 95% CI 1.015–1.647) and mean DBP (1.390, 1.098–1.757). High tau uptake was related to greater systolic BPV (0.094, 0.001–0.187) and diastolic BPV (0.096, 0.007–0.184). High Aβ uptake partially mediated the relationship between mean SBP and the Mini-Mental State Examination (MMSE) scores. Hippocampal atrophy mediated the relationship between diastolic BPV and MMSE scores. Conclusions Each BP parameter affects Alzheimer’s and vascular disease markers differently, which in turn leads to cognitive impairment. Therefore, it is necessary to appropriately control specific BP parameters to prevent the development of dementia. Furthermore, a better understanding of pathways from specific BP parameters to cognitive impairments might enable us to select the managements targeting the specific BP parameters to prevent dementia effectively.

Abstract The bioartificial liver (BAL) system can potentially rescue acute liver failure (ALF) patients by providing partial liver function until a suitable donor liver can be found or the native liver has self-regenerated. In this study, we established a suitable cryopreservation process for the development of an off-the-shelf BAL system. The viability of hepatocyte spheroids cryopreserved in liquid nitrogen was comparable to that of fresh primary hepatocyte spheroids. When hepatocyte spheroids were subjected to cryopreservation in a deep freezer, no statistically significant differences were observed in ammonia removal rate or urea secretion rate based on the cryopreservation period. However, the functional activity of the liver post-cryopreservation in a deep freezer was significantly lower than that observed following liquid nitrogen cryopreservation. Moreover, cryopreserving spheroid hydrogel beads in a deep freezer resulted in a significant decrease (approximately 30%) in both ammonia removal and urea secretion rates compared to the group cryopreserved in liquid nitrogen. The viabilities of spheroid hydrogel beads filled into the bioreactor of a BAL system were similar across all four groups. However, upon operating the BAL system for 24 h, the liver function activity was significantly higher in the group comprising hydrogel beads generated after thawing hepatocyte spheroids cryopreserved in liquid nitrogen. Consequently, the manufacturing of beads after the cryopreservation of hepatocyte spheroids is deemed the most suitable method, considering efficiency, economic feasibility, and liver function activity, for producing a BAL system.

This study analyzes the impact of the information environment (IE) and credit default swap (CDS) transaction costs on information transmission between the stock and CDS markets. Using the daily regression analysis on the Korean firm’s stock and CDS data from 2004 to 2023, the results show that companies with superior IE in the stock market exhibit a larger and more sensitive total information flow from the stock market to the CDS market. Companies with lower transaction costs in the CDS market demonstrate faster information flow. In the case of companies with superior IE, fundamental information is reflected in stock prices with high weight and thus the CDS spreads change reflecting information about stock prices. According to this study’s findings, the primary factor influencing the information flow from the stock market to the CDS market is the information environment of the company in the stock market, rather than transaction costs in the CDS market.

Abstract We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

Abstract Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.

Abstract Background The prevalence of multidrug-resistant tuberculosis (MDR-TB) among Korean tuberculosis patients is about 4.1%, which is higher than the OECD average of 2.6%. Inadequate drug use and poor patient compliance increase MDR-TB prevalence through selective pressure. Therefore, prompt detection of drug resistance in tuberculosis patients at the time of diagnosis and quantitative monitoring of these resistant strains during treatment are crucial. Methods A multiplex droplet digital PCR (ddPCR) assay was developed and assessed using DNA material of nine Mycobacterium tuberculosis strains with known mutation status that were purchased from the Korean National Tuberculosis Association. We collected a total of 18 MDR-TB residual samples referred for PCR analysis. Total DNA was extracted from the samples and subjected to the quadruplex ddPCR assay. Their results were compared to those of known resistance phenotypes. Results The analytical sensitivity and specificity of the multiplex ddPCR assay for detecting INH, RIF, EMB, FQ, and SM resistance-causing mutations ranged from 71.43 to 100% and 94.12–100%, respectively. Follow-up sample results showed that the quadruplex ddPCR assay was sensitive enough to detect IS6110 and other mutations even after onset of treatment. Conclusions We developed a sensitive and accurate multiplex ddPCR assay that can detect the presence of tuberculosis quantitatively and resistance-conveying mutations concurrently. This tool could aid clinicians in the diagnosis and treatment monitoring of tuberculosis.

Background Hyperglycemia has shown a negative association with cognitive dysfunction. We analyzed patients with high preoperative blood glucose level and hemoglobin A1c (HbA1c) level to determine the prevalence of postoperative delirium. Methods We reviewed a database of 23,532 patients with diabetes who underwent non-cardiac surgery. Acute hyperglycemia was defined as fasting blood glucose > 140 mg/dl or random glucose > 180 mg/dl within 24 h before surgery. Chronic hyperglycemia was defined as HbA1c level above 6.5% within three months before surgery. The incidence of delirium was compared according to the presence of acute and chronic hyperglycemia. Results Of the 23,532 diabetic patients, 21,585 had available preoperative blood glucose level within 24 h before surgery, and 18,452 patients reported levels indicating acute hyperglycemia. Of the 8,927 patients with available HbA1c level within three months before surgery, 5,522 had levels indicating chronic hyperglycemia. After adjustment with inverse probability weighting, acute hyperglycemia was related to higher incidence of delirium (hazard ratio: 1.33, 95% CI [1.10,1.62], P = 0.004 for delirium) compared with controls without acute hyperglycemia. On the other hand, chronic hyperglycemia did not correlate with postoperative delirium. Conclusions Preoperative acute hyperglycemia was associated with postoperative delirium, whereas chronic hyperglycemia was not significantly associated with postoperative delirium. Irrespective of chronic hyperglycemia, acute glycemic control in surgical patients could be crucial for preventing postoperative delirium.

Introductionα-galactosylceramide (α-GalCer), a prototypical agonist of invariant natural killer T (iNKT) cells, stimulates iNKT cells to produce various cytokines such as IFNγ and IL4. Moreover, repeated α-GalCer treatment can cause protective or pathogenic outcomes in various immune-mediated diseases. However, the precise role of α-GalCer-activated iNKT cells in sepsis development remains unclear. To address this issue, we employed a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced murine sepsis model and two alternative models.MethodsSepsis was induced in wild-type (WT) C57BL/6 (B6) mice by three methods (LPS/D-GalN, α-GalCer/D-GalN, and cecal slurry), and these mice were monitored for survival rates. WT B6 mice were intraperitoneally injected with α-GalCer or OCH (an IL4-biased α-GalCer analog) one week prior to the induction of sepsis. To investigate the effects of α-GalCer-mediated iNKT cell activation on sepsis development, immune responses were analyzed by flow cytometry using splenocytes and liver-infiltrating leukocytes. In addition, a STAT6 inhibitor (AS1517499) and an IL10 inhibitor (AS101) were employed to evaluate the involvement of IL4 or IL10 signaling. Furthermore, we performed B cell adoptive transfers to examine the contribution of α-GalCer-induced regulatory B (Breg) cell populations in sepsis protection.ResultsIn vivo α-GalCer pretreatment polarized iNKT cells towards IL4- and IL10-producing phenotypes, significantly attenuating LPS/D-GalN-induced septic lethality in WT B6 mice. Furthermore, α-GalCer pretreatment reduced the infiltration of immune cells to the liver and attenuated pro-inflammatory cytokine production. Treatment with a STAT6 inhibitor was unable to modulate disease progression, indicating that IL4 signaling did not significantly affect iNKT cell-mediated protection against sepsis. This finding was confirmed by pretreatment with OCH, which did not alter sepsis outcomes. However, interestingly, prophylactic effects of α-GalCer on sepsis were significantly suppressed by treatment with an IL10 antagonist, suggesting induction of IL10-dependent anti-inflammatory responses. In addition to IL10-producing iNKT cells, IL10-producing B cell populations were significantly increased after α-GalCer pretreatment.ConclusionOverall, our results identify α-GalCer-mediated induction of IL10 by iNKT and B cells as a promising option for controlling the pathogenesis of postoperative sepsis.

Background: Several biologics have been developed and used to treat severe asthma. However, commercialized biologics have limitations in treating T2-low asthma because their main target is the T2 inflammation marker. Therefore, there is an unmet need for treating T2-low severe asthma. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is an auxiliary protein in the mammalian multi-aminoacyl-tRNA synthetase complex. AIMP1 also acts as a cytokine and induces the secretion of proinflammatory cytokines. Since anti-AIMP1 has been shown to reduce interleukin (IL)-6, tumor necrosis factor-α, and IL-17A levels in a mouse model, it could be effective in the treatment of T2-low severe asthma. Methods: Wild-type BALB/c mice were sensitized and challenged with intranasal inoculation of a crude HDM extract. Atliximab, a chimeric AIMP1 antibody, was administered once (20 μg, 40 μg, 100 μg) on Day 14. We evaluated airway hyperresponsiveness (AHR), performed cellular analyses of the bronchoalveolar lavage fluid (BALF), measured inflammatory cytokine levels, and examined peribronchial histological features. Results: Atliximab reduced AIMP1 levels in asthmatic mice in a dose-dependent manner. AHR and Inflammatory cells such as neutrophils and eosinophils in the BALF decreased in asthmatic mice treated with atliximab. The levels of IL-6, IL-13, and transforming growth factor-β (TGF-β) in the lung tissue decreased in asthmatic mice treated with a high dose of atliximab (100 μg). Atliximab also reduced goblet cell hyperplasia and peribronchial fibrosis. Conclusions: Atliximab improved asthmatic airway inflammation including neutrophilic inflammation in HDM-induced asthma mice. These data suggest that anti-AIMP1 plays an important role in the treatment of severe T2-low asthma.

BackgroundDetermining brain atrophy is crucial for the diagnosis of neurodegenerative diseases. Despite detailed brain atrophy assessments using three-dimensional (3D) T1-weighted magnetic resonance imaging, their practical utility is limited by cost and time. This study introduces deep learning algorithms for quantifying brain atrophy using a more accessible two-dimensional (2D) T1, aiming to achieve cost-effective differentiation of dementia of the Alzheimer’s type (DAT) from cognitively unimpaired (CU), while maintaining or exceeding the performance obtained with T1-3D individuals and to accurately predict AD-specific atrophy similarity and atrophic changes [W-scores and Brain Age Index (BAI)].MethodsInvolving 924 participants (478 CU and 446 DAT), our deep learning models were trained on cerebrospinal fluid (CSF) volumes from 2D T1 images and compared with 3D T1 images. The performance of the models in differentiating DAT from CU was assessed using receiver operating characteristic analysis. Pearson’s correlation analyses were used to evaluate the relations between 3D T1 and 2D T1 measurements of cortical thickness and CSF volumes, AD-specific atrophy similarity, W-scores, and BAIs.ResultsOur deep learning models demonstrated strong correlations between 2D and 3D T1-derived CSF volumes, with correlation coefficients r ranging from 0.805 to 0.971. The algorithms based on 2D T1 accurately distinguished DAT from CU with high accuracy (area under the curve values of 0.873), which were comparable to those of algorithms based on 3D T1. Algorithms based on 2D T1 image-derived CSF volumes showed high correlations in AD-specific atrophy similarity (r = 0.915), W-scores for brain atrophy (0.732 ≤ r ≤ 0.976), and BAIs (r = 0.821) compared with those based on 3D T1 images.ConclusionDeep learning-based analysis of 2D T1 images is a feasible and accurate alternative for assessing brain atrophy, offering diagnostic precision comparable to that of 3D T1 imaging. This approach offers the advantage of the availability of T1-2D imaging, as well as reduced time and cost, while maintaining diagnostic precision comparable to T1-3D.