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Abstract The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39+CD9+ IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39+CD9+ IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39+CD9+ IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma.

Abstract Chemical accidents significantly impact environmental and human health. However, studies investigating the impacts of such accidents have primarily focused on single-route exposures, potentially underestimating the extent of damage. This study aimed to conduct an aggregate risk assessment for multi-route exposure to hazardous chemicals to ensure systematic and rational management of the health impacts on residents exposed to chemical accidents, considering the behavior of a hazardous chemical from a chemical accident within environmental media. Drawing upon a real chemical accident that occurred in Siheung, Gyeonggi-do, in 2019, leakage of 500 L of toluene over an hour was assumed. Employing a multimedia environmental dynamics model, the time-dependent concentrations across various environmental media were calculated, and the average daily dose (ADD), hazard quotient (HQ), and hazard index (HI) for each exposure route included in the multi-route exposure assessment were derived. Health risks were deemed present if the calculated HQ and HI values exceeded the threshold of 1. The results indicated the highest ADD values among the 0–9 age group, with inhalation exposure registering the highest ADD across all exposure routes. However, no significant health risks were observed, with both HQ and HI values not exceeding 1. This aggregate risk assessment approach is proposed as an effective preliminary evaluation method for health impact assessments in areas affected by chemical accidents. Graphical Abstract

Abstract Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.

BackgroundThis study aimed to investigate the association between continuous polypharmacy and hospitalization, emergency department (ED) visits, and death.MethodsThis retrospective study utilized 6,443,896 patients aged between 65 and 84 years of National Health Insurance claims data from 2016 to 2018. Polypharmacy and excessive polypharmacy were defined as the concurrent use of 5 or more and 10 or more medications, respectively, for durations of both 90 days or more and 180 days or more within a 1-year observation period. The primary outcome measures included all-cause hospitalization, ED visits, and mortality. Multiple logistic regression models were used adjusting for patients’ general characteristics, comorbidities, and history of hospitalization or ED visits.ResultsAmong 2,693,897 patients aged 65–84 years who had used medicines for 180 days or more (2,955,755 patients taking medicines for 90 days or more), the adverse outcomes were as follows: 20.5% (20.3%) experienced hospitalization, 10.9% (10.8%) visited the ED, and 1% (1%) died, respectively. In patients who exhibited polypharmacy for more than 180 days, the adjusted odds ratio of adverse outcomes was 1.32 (95% confidence interval [CI], 1.31–1.33) for hospitalization, 1.32 (95% CI, 1.31–1.33) for ED visits, 1.63 (95% CI, 1.59–1.67) for death, and that in excessive polypharmacy patients for more than 180 days was 1.85 for hospitalization, 1.92 for ED visits, and 2.57 for death, compared to non-polypharmacy patients.ConclusionOur results suggest that polypharmacy in older adults might lead to negative health consequences. Thus, interventions to optimize polypharmacy may need to be implemented.

Abstract Interpreting the relationship between different taste function tests of different stimuli, such as chemical and electrical stimulation, is still poorly understood. This study aims to analyze visually as well as quantitatively how to interpret the relationship of results between taste function tests using different stimuli. Patients who underwent the whole mouth test and Electrogustometry (EGM) at a tertiary medical center between August 2018 and December 2018 were reviewed retrospectively with electronic medical records. Of the 110 patients, a total of 86 adults who self-reported that their taste function was normal through a questionnaire were enrolled. EGM measured the thresholds of the chorda tympani (CT) and glossopharyngeal nerve (GL) area of the tongue. The whole mouth test measured detection and recognition thresholds for sweet, salty, bitter, sour, and umami taste. Statistical analyses of Pearson’s, Spearman’s rank and polyserial correlation and multidimensional scaling (MDS) was performed. The EGM threshold for the average value of both CT regions and the recognition threshold of the whole mouth test were significantly correlated in sweet, salty, bitter, and sour taste (r = 0.244–0.398, P

Abstract Polypharmacy may cause adverse health outcomes in the elderly. This study examined the prevalence of continuous polypharmacy and hyper‐polypharmacy, factors associated with polypharmacy, and the most frequently prescribed medications among older adults in South Korea. This was a retrospective observational study using National Health Insurance claims data. In total, 7,358,953 Korean elderly patients aged 65 years and older were included. Continuous polypharmacy and hyper‐polypharmacy were defined as the use of ≥5 and ≥10 medications, respectively, for both ≥90 days and ≥180 days within 1 year. A multivariate logistic regression analysis was conducted with adjustment for general characteristics (sex, age, insurance type), comorbidities (12 diseases, number of comorbidities, and Elixhauser Comorbidity Index [ECI] classification), and healthcare service utilization. Among 7.36 million elderly patients, 47.8% and 36.9% had polypharmacy for ≥90 and ≥180 days, and 11.9% and 7.1% of patients exhibited hyper‐polypharmacy for ≥90 and ≥180 days, respectively. Male sex, older age, insurance, comorbidities (cardio‐cerebrovascular disease, diabetes mellitus, depressive disorder, dementia, an ECI score of ≥3), and healthcare service utilization were associated with an increased probability of polypharmacy. The therapeutic class with the most prescriptions was drugs for acid‐related disorders (ATC A02). The number of outpatient visit days more strongly influenced polypharmacy than hospitalizations and ED visits. This study provides health policymakers with important evidence about the critical need to reduce polypharmacy among older adults.

Introduction: Serum level of high-mobility group box 1 protein is reportedly correlated with the severity of obstructive sleep apnea. Objective: We tried to evaluate the possibility of using the serum high-mobility group box 1 protein level as a biologic marker in obstructive sleep apnea patients. Methods: We generated a chronic intermittent hypoxia murine model that reflected human obstructive sleep apnea. Obstructive sleep apnea patients who underwent polysomnography were prospectively enrolled. Serum samples were obtained from mice and obstructive sleep apnea patients, and the serum high-mobility group box1 protein level was measured by enzyme-linked immunosorbent assay. Results: Serum high-mobility group box 1 protein level was 56.16 ± 30.33 ng/mL in chronic intermittent hypoxia and 18.63 ± 6.20 ng/mL in control mice (p 0.05). Instead, this protein level was significantly correlated with lowest arterial oxygen concentration (SaO2) (p

Abstract Objective The aim of this systematic review and meta‐analysis was to investigate the association between obstructive sleep apnea (OSA) and erythrocytosis. Methods The PubMed, Web of Science, and Cochrane Library databases were searched for articles examining hematocrit values in patients with OSA and control individuals published till September 1, 2021. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated, and subgroup analyses were performed. Results Eleven eligible studies with a total of 4608 patients with OSA were included in this meta‐analysis. Pooled outcomes revealed that hematocrit values were significantly higher in patients with OSA than in controls (SMD, 0.19; 95% CI, 0.08–0.29; p

IntroductionThe olfactory epithelium (OE) and olfactory bulb (OB) are the major components of the olfactory system and play critical roles in olfactory perception. However, the embryonic development of OE and OB by using the olfactory specific genes has not been comprehensively investigated yet. Most previous studies were limited to a specific embryonic stage, and very little is known, till date, about the development of OE.MethodsThe current study aimed to explore the development of mouse olfactory system by spatiotemporal analysis of the histological features by using the olfactory specific genes of olfactory system from the prenatal to postnatal period.ResultsWe found that OE is divided into endo-turbinate, ecto-turbinate, and vomeronasal organs, and that putative OB with putative main and accessory OB is formed in the early developmental stage. The OE and OB became multilayered in the later developmental stages, accompanied by the differentiation of olfactory neurons. Remarkably, we found the development of layers of olfactory cilia and differentiation of OE to progress dramatically after birth, suggesting that the exposure to air may facilitate the final development of OE.DiscussionOverall, the present study laid the groundwork for a better understanding of the spatial and temporal developmental events of the olfactory system.

Accumulating evidence suggests that two chronic respiratory diseases, nontuberculous mycobacterium (NTM)-pulmonary disease (PD) and allergic asthma, are frequently present together and that they likely influence the disease development and progression of each other. However, their precise interactions regarding the pathogenesis of comorbid diseases versus that of individual diseases are not well understood. In this study, comorbid diseases (i.e., Mycobacteria avium (Mav) pulmonary infection (PI) (Mav-PI) and ovalbumin-induced allergic asthma) were established in mice in different orders and at different time periods. Individual disease-specific characteristics, including alterations in immune cell populations and antigen-specific immune responses, were analyzed and compared. To assess Mav-PI pathogenesis, lung inflammation and bacterial burden levels were also determined. Allergic asthma induction in the presence of Mav-PI markedly aggravated Mav-PI pathogenesis by increasing the bacterial burden and the severity of lung inflammation. Interestingly, the general outcome of allergic asthma with goblet cell hyperplasia was alleviated at a chronic stage in the comorbid mouse model. Overall, the increase in the number of Mav CFUs was inversely correlated with the Mav-specific Th17 response, as confirmed by comparing BALB/c and C57BL/6J mice. Overall, the pathogenesis of existing Mav-PI is more severely affected by allergen exposure than vice versa. This Mav-PI exacerbation is associated with disruption of Mav-specific Th17 responses. This study provides the first evidence that the Mav-specific Th17 response plays an important role in the control of Mav pathogenesis in the presence of allergic asthma, indicating that targeting the Th17 response has therapeutic potential for NTM-PD accompanied by allergic asthma.

Background: Polypharmacy has become a global health problem and is associated with adverse health outcomes in the elderly. This study evaluated the prevalence of polypharmacy and hyper-polypharmacy in elderly patients in South Korea during 2010–2019.Methods: We analyzed the outpatient care of persons aged ≥65 years covered by National Health Insurance (NHI) using NHI claims data from 2010 to 2019. Polypharmacy was defined as the use of ≥5 medications, and hyper-polypharmacy was defined as the use of ≥10 medications, and we examined them over periods of ≥90 days and ≥180 days. The average annual percent change (AAPC) was calculated using Joinpoint statistical software.Results: The prevalence of polypharmacy among ≥90 days of medication use elderly decreased from 42.5% in 2010 to 41.8% in 2019, and the prevalence of hyper-polypharmacy for ≥90 days increased from 10.4% to 14.4%. The prevalence of polypharmacy for ≥180 days increased from 37.8% in 2010 to 38.1% in 2019, and the prevalence of hyper-polypharmacy for ≥180 days increased from 6.4% to 9.4%. The prevalence of polypharmacy for ≥90 days and ≥180 days steadily increased among elderly patients, with AAPCs of 3.7 and 4.5, respectively.Conclusion: The prevalence of polypharmacy for ≥90 days and ≥180 days remained stably high, with rates of about 42 and 38%, respectively, and hyper-polypharmacy increased over the past 10 years in South Korea. Therefore, strategies to address polypharmacy need to be implemented. Further research is also required to identify the clinical outcomes (including mortality risks) associated with polypharmacy.

Objectives Cultural familiarity and safety must be considered when assessing olfactory ability. The YSK olfactory function (YOF) test is a new olfactory function test using culturally familiar odorants to Koreans. Methods The YOF test comprises three subtests for threshold (T), discrimination (D), and identification (I). The identification test included eight universal and four Korean culture-friendly odorants, which were selected considering eight major functional groups. Data were obtained from 1,127 subjects over 19 years old. Subjects were classified as having normosmia (n=542), hyposmia (n=472), and anosmia (n=113) by self-reported olfactory function. The YOF test and the Korean version of the Sniffin’ stick test (KVSS-II) were performed on the same day in random order. Diagnostic cutoffs for anosmia and hyposmia were calculated using the Youden index (J). Results The mean values for each T/D/I subtest and the total TDI score were as follows: normosmia (T, 4.6±2.3; D, 8.6±2.1; I, 11.1±1.7; TDI score, 24.2±4.5); hyposmia (T, 3.3±2.2; D, 7.1±2.5; I, 9.2±3.1; TDI score, 19.5±6.4); and anosmia (T, 1.7±1.2; D, 5.1±2.5; I, 5.0±3.2; TDI score, 11.8±5.6). The correlation coefficients between the YOF test and KVSS-II were 0.57, 0.65, 0.80, and 0.86 for T, D, I, and the TDI score, respectively (P

Abstract Background The purpose of this study was to determine the therapeutic value of drug-induced sleep endoscopy (DISE) by comparing the outcomes of tongue base surgery based on Muller’s maneuver (MM) and those based on DISE in obstructive sleep apnea (OSA) patients. Methods Ninety-five patients who underwent the tongue base surgery in combination with palatal surgery for OSA at a tertiary referral hospital between March 2012 and March 2019 were enrolled in this retrospective comparative study. Forty-seven patients underwent MM for surgical decision and 48 patients underwent DISE in addition to MM for surgical decision. Surgical success was defined according to the Sher criteria (postoperative apnea-hypopnea index [AHI]

Objectives We performed a cross-sectional analysis of data from the nationwide Korea National Health and Nutrition Examination Survey to evaluate the association between obesity and chronic rhinosinusitis with nasal polyps (CRSwNP) or without nasal polyp (CRSsNP).Design Retrospective cross-sectional analysis of health survey data.Setting Voluntary survey of representative South Korean populations.Participants In total, 32 384 individuals aged 19 years or older with available data on CRS and obesity were included.Primary and secondary outcome measures Diagnosis of CRSwNP or CRSsNP was performed by trained otolaryngologists through sinus endoscopy and surveys of medical history. General and central obesity was diagnosed using body mass index (BMI) and waist circumference (WC), respectively.Methods A multivariate logistic regression analysis was used to clarify the association between CRSwNP or CRSsNP and obesity according to BMI and WC. Non-obese individuals were recruited as controls.Results The prevalence of CRSwNP was higher in the general (OR, 1.438; 95% CI, 1.170 to 1.768; p

Background: To diagnose and treat respiratory allergic diseases, it is important to identify the specific allergens involved. Many differences exist between common inhalant allergens depending on the residential environment and demographic factors. This study aimed to compare common inhalant allergens between Koreans and non-Koreans according to their residential region, age, and sex. Methods: This study evaluated 15,334 individuals who underwent serum tests for multiple allergen-specific immunoglobulin E at a tertiary academic medical center between January 2010 and December 2016. The individuals included 14,786 Koreans and 548 non-Koreans. The AdvanSure™ Allostation assay (LG Life Science, Korea) was used to test for 33 inhalant allergens. Results: The house dust mite (HDM) was the most common allergen in both Koreans and non-Koreans, although the proportion of individuals with HDM sensitization was greater among Koreans. High sensitization rates for various pollen types were detected among Koreans in Gangwon region, whereas Japanese cedar pollen was unique among Koreans in Jeju region. Grass pollen and animal dander were relatively common among individuals from the Americas, whereas weed and grass pollen accounted for the 10 most common allergens for individuals from Central Asia. The total sensitization rate, sensitization to HDM, and sensitization to animal dander peaked among adolescents and young adults, then subsequently decreased with age. Conclusions: This large-scale study demonstrates that various regional and age-related differences exist in the allergen sensitization rates of Koreans and non-Koreans. These data could be useful for development of avoidance measures, immunotherapy for causative allergens, and policymaking regarding allergic diseases. Key words: Allergen, Epidemiology, House dust mite, Pollen, Sensitization

Mycobacterium avium subspecies hominissuis (MAH) is the most common agent causing nontuberculous mycobacterial disease in humans. It mainly causes chronic and slowly progressive pulmonary disease (PD), which requires a long-term treatment and allows opportunistic co-infection by common pulmonary pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, and Aspergillus spp., thereby resulting in alteration of host immune response. In the present study, we investigated the phenotypical and functional alterations of dendritic cells (DCs), a bridge antigen-presenting cell between innate and adaptive immunity, following MAH infection in response to various toll-like receptor (TLR) agonists mimicking co-infection conditions, along with subsequent T cell response. Interestingly, MAH-infected DCs produced interleukin (IL)-10 significantly and decreased the level of IL-12p70 in response to Poly I:C and LPS, although not so in response to Pam3CSK4, imiquimod, or CpG oligodeoxynucleotide, thereby indicating that the TLR3 and TLR4 agonists functionally altered MAH-infected DCs toward a tolerogenic phenotype. Moreover, IL-10-producing tolerogenic DCs were remarkably induced by MAH and P. aeruginosa co-infection. To precisely elucidate how these TLR agonists induce tolerogenic DCs upon MAH infection, we sought to clarify the major mechanisms involved, using LPS, which caused the greatest increase in IL-10 production by the TLR agonists. Increased IL-10 stimulated the creation of tolerogenic DCs by significantly reducing MHC class II expression and MHC class II-antigen presentation, eventually inhibiting CD4+ T cell proliferation, along with decreased IFN-γ and IL-2. The tolerogenic phenotypes of MAH/LPS-treated DCs were restored by anti-IL-10 neutralization, validating the induction of tolerogenicity by IL-10. Interestingly, IL-10-producing-tolerogenic DCs were observed after infection with live MAH, rather than with inactivated or dead MAH. In addition, TLR2−/− and TLR4−/− DCs confirmed the association of IL-10 production with TLR2 and TLR4 signaling; IL-10 production synergistically increased when both TLR4 and TLR2 were involved. Expression of Cox2 and PGE2 increased along with IL-10 while that of IL-10 was inhibited by their selective inhibitors celecoxib and anti-EP2 antibody, respectively. Thus, the tolerogenic phenotypes of MAH/LPS-treated DCs were proven to be induced by Cox-2/PGE2-dependent EP2 signaling as the main mechanism. These findings may provide important clues that the tolerogenic cascade in MAH-infected DCs induced by TLR 4 signaling can alter host immune response.

Recent brain connectome studies have evidenced distinct and overlapping brain regions involved in processing olfactory perception. However, neural correlates of hypo- or anosmia in olfactory disorder patients are poorly known. Furthermore, the bottom-up and top-down processing of olfactory perception have not been well-documented, resulting in difficulty in locating the disease foci of olfactory disorder patients. The primary aim of this study is to characterize the bottom-up process of the neural dynamics across peripheral and central brain regions in anesthetized mice. We particularly focused on the neural oscillations of local field potential (LFP) in olfactory epithelium (OE), olfactory blub (OB), prefrontal cortex (PFC), and hippocampus (HC) during an olfactory oddball paradigm in urethane anesthetized mice. Odorant presentations evoked neural oscillations across slow and fast frequency bands including delta (1–4 Hz), theta (6–10 Hz), beta (15–30 Hz), low gamma (30–50 Hz), and high gamma (70–100 Hz) in both peripheral and central nervous systems, and the increases were more prominent in the infrequently presented odorant. During 5 s odorant exposures, the oscillatory responses in power were persistent in OE, OB, and PFC, whereas neural oscillations of HC increased only for short time at stimulus onset. These oscillatory responses in power were insignificant in both peripheral and central regions of the ZnSO4-treated anosmia model. These results suggest that olfactory stimulation induce LFP oscillations both in the peripheral and central nervous systems and suggest the possibility of linkage of LFP oscillations in the brain to the oscillations in the peripheral olfactory system.

Purpose. We hypothesized that CIH may affect the upper airway immune system and aimed to verify whether CIH can induce airway inflammation in a murine obstructive sleep apnea (OSA) model. Methods. C57BL6 male mice were exposed to intermittent hypoxia (CIH group; 5 ~ 21% FiO2, 120 sec cycles, 12 h/d, n=6) or room air (Sham group, n=6) for up to 4 weeks in identical chambers. Nasal and lung tissues and lavage fluid were collected and analyzed by multiplex assay. Lung lavage fluid was also utilized for FACS analysis to determine eosinophil count. Results. We determined the protein level of 24 different cytokines, chemokines, and inflammatory mediators. Among various cytokines, levels of IL-1α, IL-1β, IL-4, IL-6, and IL-13 were significantly elevated in nose or lung tissue from the CIH group. In addition, MCP-1 and periostin were elevated in nose and lung tissue and lavage fluid from the CIH group. Conclusions. CIH for 4 weeks altered the levels of inflammatory mediators in both the nose and lungs of mouse model. We suggest that the airway immune system may be deteriorated by CIH and allergic inflammation in the upper or lower airway could be worsened by sleep apnea.