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Abstract Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer’s disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.

Abstract Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to and from the resorbing bone surface. However, the regulatory mechanisms and pathophysiological relevance of these processes remain largely unexplored. Bone histomorphometric analyses in Ccr5-deficient mice showed abnormalities in the morphology and functional phenotype of their osteoclasts, compared to wild type mice. We observed disorganized clustering of nuclei, as well as centrosomes that organize the microtubule network, which was concomitant with impaired cathepsin K secretion in cultured Ccr5-deficient osteoclasts. Intriguingly, forced expression of constitutively active Rho or Rac restored these cytoskeletal phenotypes with recovery of cathepsin K secretion. Furthermore, a gene-disease enrichment analysis identified that PLEKHM1, a responsible gene for osteopetrosis, which regulates lysosomal trafficking in osteoclasts, was regulated by CCR5. These experimental results highlighted that CCR5-mediated signaling served as an intracellular organizer for centrosome clustering in osteoclasts, which was involved in the pathophysiology of bone metabolism.

Summary: Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. Methods: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. Findings: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P

Abstract Background The human exposome is composed of diverse metabolites and small chemical compounds originated from endogenous and exogenous sources, respectively. Genetic and environmental factors influence metabolite levels, while the extent of genetic contributions across metabolic pathways is not yet known. Untargeted profiling of human metabolome using high-resolution mass spectrometry (HRMS) combined with genome-wide genotyping allows comprehensive identification of genetically influenced metabolites. As such previous studies of adults discovered and replicated genotype–metabotype associations. However, these associations have not been characterized in children. Results We conducted the largest genome by metabolome-wide association study to date of children (N = 441) using 619,688 common genetic variants and 14,342 features measured by HRMS. Narrow-sense heritability (h 2) estimates of plasma metabolite concentrations using genomic relatedness matrix restricted maximum likelihood (GREML) method showed a bimodal distribution with high h 2 (> 0.8) for 15.9% of features and low h 2 (

Abstract Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p

Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.

Abstract Background Whole exome sequencing (WES) is widely adopted in clinical and research settings; however, one of the practical concerns is the potential false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known disease-associated genes. We developed a web-based tool to quickly gauge whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should be considered instead to minimize false negatives in candidate genes. Results WEScover is a novel web application that provides an intuitive user interface for discovering breadth and depth of coverage across population-scale WES datasets, searching either by phenotype, by targeted gene panel(s) or by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage. Conclusions WEScover allows users to efficiently query genes and phenotypes for the coverage of associated exons by WES and recommends use of panel tests for the genes with potential incomplete coverage by WES.

Abstract Tissue-resident macrophages are highly specialized to their tissue-specific microenvironments, activated by various inflammatory signals and modulated by genetic and environmental factors. Osteoclasts and microglia are distinct tissue-resident cells of the macrophage lineage in bone and brain that are responsible for pathological changes in osteoporosis and Alzheimer’s disease (AD), respectively. Osteoporosis is more frequently observed in individuals with AD compared to the prevalence in general population. Diagnosis of AD is often delayed until underlying pathophysiological changes progress and cause irreversible damages in structure and function of brain. As such earlier diagnosis and intervention of individuals at higher risk would be indispensable to modify clinical courses. Pleiotropy is the phenomenon that a genetic variant affects multiple traits and the genetic correlation between two traits could suggest a shared molecular mechanism. In this review, we discuss that the Pyk2-mediated actin polymerization pathway in osteoclasts and microglia in bone and brain, respectively, is the horizontal pleiotropic mediator of shared risk factors for osteoporosis and AD.

The high levels of energy consumption commonly seen today have severe consequences. For example, energy consumption in buildings traditionally takes the form of electricity generated from fossil fuels, which causes serious air pollution. Hence, the efficient application of clean energy systems in buildings is crucial. An increasing number of small-scale apartment buildings, such as single-room apartments and dormitories, have emerged as modern culture, and societal trends have led to a greater number of people living on their own. In this study, two strategies were proposed to improve the efficiency of solid oxide fuel cell co-generation systems (SOFC–CGSs) in small-scale apartments. A small-scale apartment building in Busan, Korea, was selected as the research object to verify the effect of the proposed strategies. One strategy was sharing a single SOFC–CGS among multiple households, and the other was integrating an SOFC–CGS with a photovoltaic (PV) system. The efficiency of the SOFC–CGS is expected to improve under these two operational strategies. In addition, the two proposed operational strategies were combined to improve the efficiency of the SOFC–CGS. To verify the proposed strategies, various simulations were conducted in this study. The simulation results indicate that each of the proposed strategies can improve the efficiency of the SOFC–CGS and save energy to varying degrees.

Abstract Glioblastoma (GBM) is the most malignant primary brain tumor in adults with substantial genomic alterations. The median survival is approximately 14.6 months, despite aggressive therapeutic intervention, which comprised of surgical resection, radiotherapy, and chemotherapy. Recent studies on cancer genomic have revealed crucial insights into dynamic molecular subgroups within GBM, which govern distinct clinical response and sensitivity of each individual to therapy. In the present study, we analyzed genomic composition of primary GBMs between two ethnic groups [IRCR (Institute of Refractory Cancer Research), and TCGA (The Cancer Genome Atlats)] to explore genomic and molecular features that constitute malignant behavior of glioblastoma based on distinct ethnicity. We identified enrichments of MAPK and p53 pathways in IRCR patients, while aberrant activation of Receptor Tyrosine Kinases (RTKs) were predominant in TCGA cohort. We also discovered differential clinical prognosis between two groups and explored essential features that present such diversity.

In recent years, urban regeneration strategic plans have been implemented across South Korea to curb the negative impacts of depopulation, physical deterioration and economic decline. By adopting a people-centered regeneration process, context-sensitive plans are formulated by integrating local people’s perceptions and expectations. This paper examines urban regeneration plans implemented in Ami-dong Tombstone Cultural Village, a declining hillside village in Busan, using “people–place–process framework of place attachment” to analyze the process of articulating “sense of place” through community-driven approaches. Based on archival research, site investigations, secondary data and semi-structured interviews, the paper explores the revival of social capital, integration of place-sensitivity and improvement of everyday landscapes through affective, behavioral and cognitive responses of urban professionals and community members involved in the project. Findings of the study show that place attachment, sense of community and community participation in regeneration can help in re-creating meaningful places. Lessons from Ami-dong offer insights on ways to strengthen people–people and people–place relationships through design and planning processes in a declining context with an aging population.

Students with reading disabilities generally know fewer words (breadth) with less in-depth knowledge of those words (depth) than typical students. The present study examined the effects of a "moderately rich vocabulary instruction" in which both breadth and depth of vocabulary are addressed. Nineteen U.S. 4th- and 5th-grade students with reading disabilities learned 12 words in the moderate-encounter condition, where students practiced the target words six times in the context of rich vocabulary instructional activities. The results showed that students with reading disabilities remembered more taught word definitions and understood more sentences that contained taught words than those from the control condition. The findings suggest that providing moderately rich vocabulary instruction with a moderate number of rich vocabulary practices can yield good word learning and sentence comprehension containing target words for students with reading difficulties.

Background Recently, Cervi Parvum Cornu pharmacopuncture has been widely used. But no studies on the indicator materials for Cervi Parvum Cornu pharmacopuncture have been conducted. The aim of this study was to select indicator materials that would aid in the uniform preparation of standardized Cervi Parvum Cornu pharmacopuncture. Methods Three lots of Cervi Parvum Cornu pharmacopuncture were analysed. Each lot was prepared using the same methods and materials. Chondroitin sulfate, alanine, and leucine were selected as the indicator materials for Cervi Parvum Cornu. For standardization, chondroitin sulfate analysis was performed using the colorimetric method, while alanine and leucine were analyzed using liquid chromatography-mass spectrometry (LC-MS). Results Analysis of the three lots of Cervi Parvum Cornu pharmacopuncture found chondroitin sulfate levels of 108.9 ± 17.3 ug/ml, 118.8 ± 5.0 ug/ml and 112.3 ± 11.9 ug/ml. Alanine levels were 44.9 ± 2.8 ug/ml, 44.6 ± 0.3 ug/ml, and 43.9 ± 0.2 ug/ml. Leucine levels were 29.6 ± 0.7 ug/ml, 29.0 ± 0.1 ug/ml, and 29.4 ± 0.1 ug/ml. Conclusions These results suggest that chondroitin sulfate, alanine, and leucine may be useful for the standardization of Cervi Parvum Cornu pharmacopuncture.

Skin aging is driven by a combination of internal and external mechanisms, with ultraviolet (UV) radiation being a prominent external factor contributing to photoaging. Photoaging manifests through several signs, including decreased skin hydration, diminished elasticity, coarse wrinkles, and dyspigmentation. Cacao beans, known for their flavonoids and polyphenols, offer potential anti-aging benefits. To explore this, we conducted a study using both in vitro experiments and clinical trials. Our results demonstrated that cacao powder significantly improved skin hydration and moisture retention in both experimental settings. Specifically, in UVB-damaged human dermal fibroblasts (HDFs) and H2O2-treated keratinocytes (KCs), cacao powder displayed notable antioxidant properties. Furthermore, cacao powder enhanced the activity of antioxidant enzymes and promoted the production of hyaluronic acid in KCs, contributing to better skin hydration. It also effectively inhibited the expression of matrix metalloproteinase-1, an enzyme associated with wrinkle formation, and stimulated collagen synthesis in HDFs. Clinical trials conducted on participants with aged skin revealed a significant improvement in skin hydration and a reduction in skin wrinkles after 12 weeks of cacao powder consumption, supporting the in vitro findings. These results suggest that cacao powder holds promise as a natural ingredient for improving skin hydration and reducing wrinkles, underscoring its potential in anti-aging skincare.

Abstract Non-small cell lung cancer (NSCLC) is histologically classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC). However, some tumors are histologically ambiguous and other pathophysiological features or microenvironmental factors may be more prominent. Here we report integrative multiomics analyses using data for 229 patients from a Korean NSCLC cohort and 462 patients from previous multiomics studies. Histological examination reveals five molecular subtypes, one of which is a NSCLC subtype with PI3K-Akt pathway upregulation, showing a high proportion of metastasis and poor survival outcomes regardless of any specific NSCLC histology. Proliferative subtypes are present in LUAD and LSCC, which show strong associations with whole genome doubling (WGD) events. Comprehensive characterization of the immune microenvironment reveals various immune cell compositions and neoantigen loads across molecular subtypes, which predicting different prognoses. Immunological subtypes exhibit a hot tumor-enriched state and a higher efficacy of adjuvant therapy.

The purpose of the study was to describe and analyze the self-efficacy of South Korean adapted physical education (APE) majors in teaching persons with disabilities. The research design was a qualitative descriptive case study. The participants were five APE majors (four men and one woman, age ranged from 20 to 25) attending a university in South Korea. The data sources were interviews, program curriculum reviews, and a researcher's journal entries; and analyzed using thematic analysis. Four themes emerged, which were: (a) determinants of self-efficacy, (b) relationships with APE faculty, (c) increased awareness, and (d) I am not confident. Findings exposed APE majors as more likely to gain confidence after volunteering to work with persons with disabilities and developing relationships with them. The results showed the importance of integrating hands-on practicum teaching experiences in APE courses for the majors to develop their positive self-efficacy in teaching persons with disabilities.

The problem of air pollution in Korea has become progressively more serious in recent years. Since electricity is advertised as clean energy, some newly developed buildings in Korea are using only electricity for all energy needs. In this research, the annual amount of air pollution attributable to energy under the traditional method in a dormitory building, which is supplying both natural gas and electricity to the building, was compared with the annual amount of air pollution attributable to supplying only electricity. The results showed that the building using only electricity emits much more air pollution than the building using electricity and natural gas together. Under the traditional method of energy supply, a residential solid oxide fuel cell cogeneration system (SOFC−CGS) for minimizing environmental pollution of the building was simulated. Furthermore, as a high load factor could lead to high efficiency of the SOFC−CGS, sharing of the SOFC−CGS by multi-households could increase its efficiency. Finally, the environmental pollution from using one system in one household was compared with that from sharing one system by multi-households. The results showed that the environmental pollution from sharing the system was relatively higher but still similar to that when using one system in one household.

BackgroundData on the clinical impact of beta-blockers (BBs) in patients with myocardial infarction (MI) who had non-reduced left ventricular ejection fraction (LVEF) after percutaneous coronary intervention are limited.MethodsFrom 2016 to 2020, we evaluated a cohort of 12,101 myocardial infarction patients with a non-reduced LVEF (≥40%) from the Korean Acute Myocardial Infarction Registry V. Patients were divided into two groups based on their BB (carvedilol, bisoprolol, or nebivolol) treatment at discharge: with beta-blocker treatment (BB, n = 9,468) and without beta-blocker treatment (non-BB, n = 2,633). The primary endpoint after discharge was the occurrence of patient-oriented composite endpoints (POCEs), including all-cause mortality, any MI, or any revascularization at 1-year follow-up.ResultsThe median follow-up period was 353 days (interquartile range, 198–378 days). At 1-year follow-up, no significant differences were observed in the primary endpoint between the BB group and the non-BB group. Before propensity score (PS) matching, the POCE incidence was 3.1% in the BB group vs. 3.4% in the non-BB group [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.68–1.09, p = 0.225]. After PS matching, the POCE incidence remained similar between the two groups (3.7% vs. 3.4%, HR 1.01, 95% CI 0.76–1.35, p = 0.931). Individual outcomes, including all-cause mortality, myocardial infarction, and revascularization, also showed no significant differences between the two groups. Independent predictors of 1-year POCEs after discharge were age, chronic kidney disease, reduced LVEF, and multivessel disease.ConclusionBB treatment in patients with acute MI and non-reduced LVEF was not associated with a significant reduction in cardiovascular outcomes at 1-year follow-up.

BackgroundAdherence to oral anticoagulant therapy is essential to prevent ischemic stroke in patients with atrial fibrillation (AF). ObjectiveThis study aimed to evaluate whether smartphone app–based interventions improve medication adherence in patients with AF. MethodsThis open-label, multicenter randomized controlled trial (ADHERE-App [Self-Awareness of Drug Adherence to Edoxaban Using an Automatic App Feedback System] study) enrolled patients with AF treated with edoxaban for stroke prevention. They were randomly assigned to app-conditioned feedback (intervention; n=248) and conventional treatment (control; n=250) groups. The intervention group received daily alerts via a smartphone app to take edoxaban and measure blood pressure and heart rate at specific times. The control group received only standard, guideline-recommended care. The primary end point was edoxaban adherence, measured by pill count at 3 or 6 months. Medication adherence and the proportion of adequate medication adherence, which was defined as ≥95% of continuous medication adherence, were evaluated. ResultsMedication adherence at 3 or 6 months was not significantly different between the intervention and control groups (median 98%, IQR 95%-100% vs median 98%, IQR 91%-100% at 3 months, P=.06; median 98%, IQR 94.5%-100% vs median 97.5%, IQR 92.8%-100% at 6 months, P=.15). However, the proportion of adequate medication adherence (≥95%) was significantly higher in the intervention group at both time points (76.8% vs 64.7% at 3 months, P=.01; 73.9% vs 61% at 6 months, P=.007). Among patients aged >65 years, the intervention group showed a higher medication adherence value and a higher proportion of adequate medication adherence (≥95%) at 6 months. ConclusionsThere was no difference in edoxaban adherence between the groups. However, the proportion of adequate medication adherence was higher in the intervention group, and the benefit of the smartphone app–based intervention on medication adherence was more pronounced among older patients than among younger patients. Given the low adherence to oral anticoagulants, especially among older adults, using a smartphone app may potentially improve medication adherence. Trial RegistrationInternational Clinical Trials Registry Platform KCT0004754; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=28496&search_page=L International Registered Report Identifier (IRRID)RR2-10.1136/bmjopen-2021-048777

Bee venom (BV), a type of toxin extracted from honeybees (Apis mellifera), has been empirically and widely used to treat inflammatory diseases throughout Asia. Essential BV (eBV) was developed by removing phospholipase A2 (PLA2) and histamine to lower occurrence of allergic reaction. This study investigated the anti-allergic and anti-inflammatory activities of eBV in vitro and in vivo and its underlying mechanism of action.The anti-inflammatory potential of eBV was assessed in vivo using a carrageenan-induced paw edema model. To further investigate the mechanism by which eBV exerts anti-allergic and anti-inflammatory effects, compound 48/80-stimulated RBL-2H3 cells and lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells were studied in vitro.Release of β-hexosaminidase and histamine was increased by eBV in a dose-dependent manner, but these levels were lower in eBV compared to original BV at the same concentration. In addition, eBV suppressed compound 48/80-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in RBL-2H3 cells. eBV was also shown to suppress nitric oxide (NO) production by down-regulating mRNA expression and subsequent protein expression of inflammatory mediators in LPS-induced RAW 264.7 cells. Phosphorylation of activators and signal transducers of transcription 1/interferon regulatory factor 3 (STAT1/IRF3) was attenuated by eBV treatment. eBV significantly inhibited carrageenan-induced acute edema in vivo. Serum levels of prostaglandin E2 (PGE2), TNF-α, and IL-1β were also down-regulated by eBV.These results demonstrate that eBV inhibits allergic and inflammatory response by reducing inflammatory mediator production via regulation of the STAT1/IRF3 signaling pathway, suggesting that eBV is a feasible candidate for regulation of allergic-inflammatory response in complementary and alternative medicine.

ObjectivesCongenital muscular torticollis, a common disorder that refers to the shortening of the sternocleidomastoid in infants, is sensitive to correction through physical therapy when treated early. If physical therapy is unsuccessful, surgery is required. In this study, we developed a support vector regression model for congenital muscular torticollis to investigate the prognosis of the physical therapy treatent in infants.MethodsFifty-nine infants with congenital muscular torticollis received physical therapy until the degree of neck tilt was less than 5°. After treatment, the mass diameter was reevaluated. Based on the data, a support vector regression model was applied to predict the prognoses.Results10-, 20-, and 50-fold cross-tabulation analyses for the proposed model were conducted based on support vector regression and conventional multi-regression method based on least squares. The proposed methodbased on support vector regression was robust and enabled the effective analysis of even a small amount of data containing outliers.ConclusionsThe developed support vector regression model is an effective prognostic tool for infants with congenital muscular torticollis who receive physical therapy.

Background: The objective of this study was to determine the incidence of tuberculosis (TB) among workers at medical institutions based on interferon-gamma release assay (IGRA) and compare it with that of workers at educational institutions and the general population. Methods: From March 2017 to December 2020, we used a cohort of workers from medical and educational institutions in Korea, who underwent IGRA as part of a national screening program for latent tuberculosis infection (LTBI). After connecting to the National Health Insurance Service (NHIS) database to detect for any actual cases of active TB, we estimated standardized incidence ratio (SIR) and the expected number of cases to compare the incidence of TB with that of the general population. Results: Significant disparities in TB incidence were revealed among workers in medical and educational institutions, based on IGRA results, age, and occupation. Individuals positive for IGRA in medical institutions displayed substantially higher SIR for TB, 7.19 (6.15–8.41), compared to counterparts in educational institutions, 3.69 (3.02–4.51). Comparing by age group, we see that the SIRs are higher in younger age groups compared to older ones, with 37.30 (28.11–49.50) and 11.89 (7.28–19.41) for IGRA-positive medical and education workers under 30 years of age, respectively. In the results by occupation within the medical institutions, nurses had the highest SIR at 14.17 (11.14–18.04). Conclusions: Healthcare workers in medical institutions are more likely to develop actual TB after a positive result of LTBI screening in Korea. Intensive management and surveillance programs should be reinforced.

The extensive use of β-lactam antibiotics has led to significant resistance, primarily due to hydrolysis by β-lactamases. OXA class D β-lactamases can hydrolyze a wide range of β-lactam antibiotics, rendering many treatments ineffective. We investigated the effects of single amino acid substitutions in OXA-10 on its substrate spectrum. Broad-spectrum variants with point mutations were searched and biochemically verified. Three key residues, G157D, A124T, and N73S, were confirmed in the variants, and their crystal structures were determined. Based on an enzyme kinetics study, the hydrolytic activity against broad-spectrum cephalosporins, particularly ceftazidime, was significantly enhanced by the G157D mutation in loop 2. The A124T or N73S mutation close to loop 2 also resulted in higher ceftazidime activity. All structures of variants with point mutations in loop 2 or nearby exhibited increased loop 2 flexibility, which facilitated the binding of ceftazidime. These results highlight the effect of a single amino acid substitution in OXA-10 on broad-spectrum drug resistance. Structure–activity relationship studies will help us understand the drug resistance spectrum of β-lactamases, enhance the effectiveness of existing β-lactam antibiotics, and develop new drugs.