Real-World Effectiveness of Biologics in Patients With Severe Asthma: Analysis of the KoSAR.

PURPOSE: Severe asthma is associated with high morbidity and healthcare utilization; however, treatment options for these patients are limited. This study aimed to determine the therapeutic effects of biologics in clinical practice. METHODS: This multicenter, retrospective cohort study included 136 patients who received biologics for at least 4 months between September 2017 and July 2022 at 25 medical centers affiliated with the Korean Severe Asthma Registry (KoSAR). The study evaluated the treatment effects, including acute exacerbation rates, maintenance of oral corticosteroid dosages, lung function, quality of life, blood eosinophil count, and fractional exhaled nitric oxide (FeNO) levels, by comparing measurements before and after 4 months of biologic treatment. Responses for each medication was evaluated based on the Global Evaluation of Treatment Effectiveness score, and any adverse reactions were summarized. RESULTS: With the administration of biologics over the course of 4 months, there was a reduction in asthma acute exacerbations, a significant improvement in lung function, and a significant decrease in daily maintenance dose of oral steroid. Blood eosinophil counts decreased in the mepolizumab and reslizumab groups, while FeNO levels decreased only in the dupilumab group. The Asthma Control Test, Quality of Life Questionnaire for Adult Korean Asthmatics, and the EuroQol-visual analogue scale scores showed a significant improvement. Most patients (80.15%) responded to the biologic treatment. Meanwhile, non-responders often had chronic rhinosinusitis as a comorbidity, exhibited lower lung function, and required higher doses of oral steroids. No severe adverse events were reported. CONCLUSIONS: Biologics are highly effective in Korean patients with Type 2 severe asthma, significantly reducing acute exacerbation rates and doses of oral corticosteroids, while also improving lung function. Therefore, it seems beneficial to administer biologics without any restrictions to patients exhibiting Type 2 severe asthma.

Characteristics of Severe Asthma in the Elderly: Observations From the Korean Severe Asthma Registry (KoSAR).

PURPOSE: Few studies have compared the clinical characteristics of severe asthma (SA) in elderly patients compared to that in nonelderly patients. METHODS: We analyzed data from the Korean SA Registry, a nationwide, real-world observational study of SA in Korea. The baseline clinical characteristics, disease control status, and medication use of the patients were compared between elderly (≥ 65 years) and nonelderly groups. RESULTS: Of the 864 patients with SA, 260 (30.1%) were in the elderly group. The elderly group had lower atopy rate, but had higher prevalence of chronic obstructive pulmonary disease (COPD), hypertension, and osteoporosis than did the nonelderly group. The elderly group had a lower rate of type 2 inflammation and lower levels of forced expiratory volume in 1 second (FEV1) (% predicted) and FEV1/forced vital capacity ratio than did the nonelderly group (P < 0.05 for all). However, asthma symptom scores and the frequency of asthma exacerbation were not significantly different between the 2 groups. Of controller medications, biologics were less frequently used in the elderly group (P < 0.05 for all). CONCLUSIONS: SA in the elderly is characterized by lower lung function, less type 2-low airway inflammation, and comorbidity with COPD. These findings are being taken into consideration in the management of elderly patients with SA in real-world clinical practice.

Association of Gout with Head and Neck Cancer: Longitudinal Follow-Up Studies Using a National Health Insurance Database in South Korea.

Objective: Previous studies have reported controversial results on the association between gout and the risk of cancer. This study aimed to investigate the relationship between gout and the incidence of head and neck cancer (HNC). Methods: The data of participants who underwent health checkups in 2009 were analyzed using the National Health Insurance Database in South Korea. A total of 14,348 HNC patients and 57,392 control participants were analyzed for a prior history of gout. Overlap weighting was applied, and odds ratios (ORs) of gout for HNC patients were analyzed. The overlap-weighted model adjusted for demographic, socioeconomic, and lifestyle factors and comorbidities. HNC sites were classified as oral cavity cancer, oropharyngeal cancer, nasopharyngeal cancer, hypopharyngeal cancer, nasal cavity/sinus cancer, larynx cancer, or salivary gland cancer, and the ORs of gout were estimated for each site. Results: Overall, patients with HNC had 1.12-fold greater odds of having gout (95% confidence intervals [CIs] = 1.04-1.20). According to the site of HNC, oral cavity cancer, oropharynx cancer, and larynx cancer demonstrated high odds of having gout (OR = 1.25, 95% CI = 1.16-1.34 for oral cavity cancer; OR = 1.08, 95% CI = 1.01-1.15 for oropharynx cancer; and OR = 1.12, 95% CI = 1.06-1.20 for larynx cancer). On the other hand, nasal cavity/sinus cancer, nasopharynx cancer, and salivary gland cancer presented low odds of having gout (OR = 0.78, 95% CI = 0.72-0.84 for nasal cavity/sinus cancer; OR = 0.89, 95% CI = 0.83-0.96 for nasopharynx cancer; and OR = 0.88, 95% CI = 0.81-0.96 for salivary gland cancer). Conclusions: A prior history of gout was associated with a high overall incidence of HNC. Oral cavity cancer, oropharynx cancer, and larynx cancer have a high incidence in gout patients. However, nasal cavity/sinus cancer, nasopharyngeal cancer, and salivary gland cancer have low incidences in gout patients. The impact of gout on HNC risk should be specifically considered according to the site of the HNC.

Association of Cough Severity with Asthma Control and Quality of Life in Patients with Severe Asthma.

PURPOSE: Symptoms are important components in determining asthma control and in the adjustment of treatment levels. However, clinical relevance of cough in severe asthma is not well-understood. This study aimed to evaluate the severity and association of cough with patient-reported outcomes (PROs) in patients with severe asthma. METHODS: This study analyzed cross-sectional data from the Korean Severe Asthma Registry. The severity of coughing and wheezing symptoms was assessed using a Visual Analog Scale (VAS) ranging from 0 to 100 for each symptom. Additionally, PROs included the Asthma Control Test (ACT), the Severe Asthma Questionnaire (SAQ), and the EuroQoL 5-Dimension (EQ-5D) index. Multivariate linear regression analysis was employed to explore the relationship between cough severity and other PRO scores. RESULTS: A total of 498 patients with severe asthma (age: 57.9 ± 13.1 years, females: 60.2%) were analyzed. The cough VAS score was higher than the wheeze score (median 30, [interquartile range 10-50] vs. 20 [0-50]; P < 0.001). Additionally, 22.5% of patients ranked in a higher tertile for cough severity compared to wheezing, while 18.5% ranked higher for wheezing severity than cough. Significant correlations were observed between cough and wheeze VAS scores (r = 0.61, P < 0.05) and between each symptom's VAS score and the SAQ (cough: r = -0.41, P < 0.001; wheeze: r = -0.52, P < 0.001), ACT scores (cough: r = -0.50, P < 0.001; wheeze: r = -0.63, P < 0.001) and EQ-5D index (cough: r = -0.40, P < 0.001; wheeze: r = -0.45, P < 0.001). In univariate regression analysis, the cough VAS score had weaker descriptive power (R2) values than the wheeze VAS score in relation to the PRO measures. Nevertheless, cough severity remained significantly associated with ACT, SAQ scores and EQ-5D index in multivariate analyses adjusted for wheeze severity and other confounders. CONCLUSION: Cough frequently presents as a severe symptom in patients with severe asthma and could have distinct impact on asthma control and quality of life.

Association Between COPD and Hearing Loss.

OBJECTIVE: The goal of the present study was to estimate the risk of hearing impairment in patients with COPD using huge nationwide population. METHODS: A retrospective case-control study was performed using the National Health Insurance Database in South Korea from 2002 through 2019. Totally 614,370 COPD patients and matched 2,170,504 control participants were selected at a 1:4 ratio. Hearing impairment was defined based on the registered data in the Ministry of Health and Welfare of Korea with six levels of severity of hearing impairment. The propensity score was calculated, and overlap-weighted multinomial logistic regression was used to calculate the odds ratios of COPD for hearing impairment. RESULTS: A total of 2.67% of COPD patients and 1.9% of control participants had hearing impairment. The COPD patients indicated 1.10-1.21 times higher odds for hearing impairment according to the severity of hearing impairment than the control group. In accordance with age and sex, the younger age group (<65 years old) and female group demonstrated higher odds for hearing impairment related to the presence of COPD. The high odds for hearing impairment in patients with COPD was consistent in all other subgroups, except for the underweight group. CONCLUSIONS: COPD was associated with an increased risk of hearing impairment in the general population in Korea. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Association between asthma and cardiovascular diseases: A longitudinal follow-up study using a national health screening cohort.

Background: Asthma has been suggested to be a risk factor for cardiovascular diseases (CVDs), although the evidence supporting this relationship is inconclusive. This study aimed to explore the long-term associations between asthma and asthma exacerbations with the occurrence of cardiovascular diseases (CVDs) such as ischemic heart disease (IHD), heart failure (HF), and cerebral stroke, utilizing data from a nationwide cohort. Materials and methods: This study utilized data from the Korean National Health Insurance Service-Health Screening Cohort database (2002-2015), including information on 111,316 asthma patients and an equal number of 1:1 matched control participants. A propensity score overlap-weighted Cox proportional hazards regression model was used to analyze the overlap-weighted hazard ratios (HRs) of asthma and exacerbated asthma for cardiovascular diseases (CVDs) within this cohort. Results: During the follow-up period, the incidence rate (IR) of IHD per 1000 person-years (PYs) was 7.82 in patients with asthma and 5.79 in controls. The IR of HF was 2.53 in asthmatic patients and 1.36 in controls. After adjustment for covariates, asthmatic patients exhibited 1.27-fold and 1.56-fold higher HRs for IHD (95% confidence interval (CI) = 1.23-1.37, P < 0.001) and HF (95% CI = 1.36-1.63, P < 0.001) than the controls, respectively. In addition, there was an increased HR for IHD and HF in the asthma exacerbation group compared with the nonexacerbated asthma group (adjusted HR, 1.29, 95% CI = 1.24-1.34, P < 0.001 for IHD and aHR 1.68, 95% CI = 1.58-1.79, P < 0.001 for HF). However, the occurrence of stroke was decreased in asthmatic patients compared with controls (aHR = 0.96, 95% CI = 0.93-0.99, P = 0.008). Conclusions: Adults with asthma are more likely to develop CVDs. Additionally, severe asthma exacerbations are significantly associated with an increased occurrence of CVDs.

The Association of Chronic Periodontitis as a Potential Risk Factor with Rheumatoid Arthritis: A Nested Case-Control Study Using a Korean National Health Screening Cohort.

Growing research has proposed that rheumatoid arthritis (RA) and chronic periodontitis (CP) share similar pathophysiological mechanisms involving inflammation and tissue destruction. However, the potential correlation of CP as a contributing factor for the occurrence of RA warrants validation in the Korean population, where both diseases are prevalent, especially considering the increasingly aging demographic in Korea. This study examined 5139 RA cases and 509,727 matched controls from a Korean national cohort dataset (2002-2019) by carefully employing propensity score matching to ensure comparability between groups. Baseline characteristics were compared using standardized differences, and logistic regression was employed to estimate the impact of CP history on RA likelihood while controlling for covariates. We fully examined medical records documenting CP occurrences within the two-year period leading up to the index date, conducting comprehensive subgroup analyses. While a 1-year history of CP did not show a significant association with likelihood of RA, a 2-year history of CP increased RA likelihood by 12%, particularly among older adults, females, rural residents, and those with certain comorbidities such as hypercholesterolemia. Interestingly, this association persisted even among individuals with non-smoking habits, normal weight, and infrequent alcohol consumption. These findings suggest that chronic CP exposure for at least 2 years may independently elevate RA risk in Korean adults. The association in certain subgroups appears to suggest a predisposition toward genetic susceptibilities over lifestyle and environmental factors. Predicting RA in CP patients may be challenging, emphasizing the importance of regular RA screening, especially in high-risk subgroups.

Work-related asthma in adults with severe asthma from the Korean Severe Asthma Registry (KoSAR).

Background: Exposure to allergens or irritants in the workplace may affect asthma control and the quality of life (QoL) of patients with asthma. Objective: To examine the prevalence and characteristics of work-related asthma (WRA) in adult patients with severe asthma. Methods: We analyzed data from the Korean Severe Asthma Registry (KoSAR), which is a nationwide multicenter observational study on severe asthma in Korea. Severe asthma was defined according to the American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines. WRA was identified on the basis of asthma symptom aggravation at the workplace, as indicated by responses to a structured questionnaire. We compared the demographic and clinical characteristics and QoL between adult patients with severe asthma and WRA and those without WRA. Results: Among 364 patients with severe asthma who were employed at the time of enrollment, 65 (17.9%) had WRA. There were no significant differences in age, sex, obesity, or smoking history between the WRA and non-WRA groups. However, individuals with WRA exhibited a higher prevalence of anxiety (7.7% vs 2.4%, P = 0.046) and depression (12.3% vs 3.7%, P = 0.010) than those without. The levels of asthma control, lung function, and frequency of asthma exacerbations were similar between the two groups, but patients with WRA reported lower QoL, as determined by the Quality of Life Questionnaire for Adult Korean Asthmatics (56.6 ± 14.6 vs. 63.5 ± 13.9, P < 0.001). Conclusion: Patients with severe asthma and WRA are more likely to experience anxiety and depression and have lower QoL than those without WRA.

Remote optogenetic control of the enteric nervous system and brain-gut axis in freely-behaving mice enabled by a wireless, battery-free optoelectronic device.

Wireless activation of the enteric nervous system (ENS) in freely moving animals with implantable optogenetic devices offers a unique and exciting opportunity to selectively control gastrointestinal (GI) transit in vivo, including the gut-brain axis. Programmed delivery of light to targeted locations in the GI-tract, however, poses many challenges not encountered within the central nervous system (CNS). We report here the development of a fully implantable, battery-free wireless device specifically designed for optogenetic control of the GI-tract, capable of generating sufficient light over large areas to robustly activate the ENS, potently inducing colonic motility ex vivo and increased propulsion in vivo. Use in in vivo studies reveals unique stimulation patterns that increase expulsion of colonic content, likely mediated in part by activation of an extrinsic brain-gut motor pathway, via pelvic nerves. This technology overcomes major limitations of conventional wireless optogenetic hardware designed for the CNS, providing targeted control of specific neurochemical classes of neurons in the ENS and brain-gut axis, for direct modulation of GI-transit and associated behaviours in freely moving animals.

Investigating the Connection between Chronic Periodontitis and Parkinson's Disease: Findings from a Korean National Cohort Study.

Recent research suggests a potential relevance between chronic periodontitis (CP) and Parkinson's disease (PD), raising concerns about comorbid PD among elderly CP patients. However, the epidemiologic basis for this association remains unclear. Employing a nested case-control design, this study explored the association between CP and subsequent PD occurrences in Korean adults, leveraging a validated national population-based dataset covering the period from 2002 to 2019. It included 8794 PD patients and 35,176 matched control individuals, established through propensity score matching for age, sex, residential area, and income. Baseline characteristics were compared using standardized differences, and logistic regression was employed to assess the impact of CP histories on PD likelihood while controlling for covariates. We performed a thorough examination of CP events within both 1-year and 2-year intervals preceding the index date, incorporating subgroup analyses. Our analysis revealed no statistically significant association between CP history and PD development overall. However, subgroup analysis revealed a slightly increased likelihood of PD development among CP individuals with a high disease burden (Charlson Comorbidity Index score ≥ 2). In conclusion, although our study did not find a significant overall association between CP history and PD development, the elevated likelihood of PD in subgroups with high disease burden may suggest that comorbidities influence PD probability among certain CP patients. Considering comorbid conditions in PD screening for some individuals with CP may be also important.

Associations between Peritonsillar Abscess and Deep Neck Infection in Chronic Periodontitis Patients: Two Nested Case-Control Studies Using a National Health Screening Cohort.

Background/Introduction: Odontogenic infection is one of the main etiologies of deep neck infection (DNI). However, the relationship between chronic periodontitis (CP) and the incidence of DNI has not been examined. This study aimed to evaluate the incidence of DNI and peritonsillar abscess (PTA) after CP. Methods: The Korean National Health Insurance Service-National Sample Cohort 2002-2019 was used. In Study I, 4585 PTA patients were matched with 19,340 control I participants. A previous history of CP for 1 year was collected, and the odds ratios (ORs) of CP for PTA were analyzed using conditional logistic regression. In Study II, 46,293 DNI patients and 185,172 control II participants were matched. A previous history of CP for 1 year was collected, and conditional logistic regression was conducted for the ORs of CP for DNI. Secondary analyses were conducted in demographic, socioeconomic, and comorbidity subgroups. Results: In Study I, a history of CP was not related to the incidence of PTA (adjusted OR = 1.28, 95% confidence interval [CI] = 0.91-1.81). In Study II, the incidence of DNI was greater in participants with a history of CP (adjusted OR = 1.55, 95% CI = 1.41-1.71). The relationship between CP history and DNI was greater in groups with young, male, low-income, and rural residents. Conclusions: A prior history of CP was associated with a high incidence of DNI in the general population of Korea. Patients with CP need to be managed for the potential risk of DNI.

In-depth correlation analysis between tear glucose and blood glucose using a wireless smart contact lens.

Tears have emerged as a promising alternative to blood for diagnosing diabetes. Despite increasing attempts to measure tear glucose using smart contact lenses, the controversy surrounding the correlation between tear glucose and blood glucose still limits the clinical usage of tears. Herein, we present an in-depth investigation of the correlation between tear glucose and blood glucose using a wireless and soft smart contact lens for continuous monitoring of tear glucose. This smart contact lens is capable of quantitatively monitoring the tear glucose levels in basal tears excluding the effect of reflex tears which might weaken the relationship with blood glucose. Furthermore, this smart contact lens can provide an unprecedented level of continuous tear glucose data acquisition at sub-minute intervals. These advantages allow the precise estimation of lag time, enabling the establishment of the concept called 'personalized lag time'. This demonstration considers individual differences and is successfully applied to both non-diabetic and diabetic humans, as well as in animal models, resulting in a high correlation.

A skin-interfaced, miniaturized platform for triggered induction, capture and colorimetric multicomponent analysis of microliter volumes of sweat.

Eccrine sweat can serve as a source of biomarkers for assessing physiological health and nutritional balance, for tracking loss of essential species from the body and for evaluating exposure to hazardous substances. The growing interest in this relatively underexplored class of biofluid arises in part from its non-invasive ability for capture and analysis. The simplest devices, and the only ones that are commercially available, exploit soft microfluidic constructs and colorimetric assays with purely passive modes of operation. The most sophisticated platforms exploit batteries, electronic components and radio hardware for inducing sweat, for electrochemical evaluation of its content and for wireless transmission of this information. The work reported here introduces a technology that combines the advantages of these two different approaches, in the form of a cost-effective, easy-to-use device that supports on-demand evaluation of multiple biomarkers in sweat. This flexible, skin-interfaced, miniaturized system incorporates a hydrogel that contains an approved drug to activate eccrine sweat glands, electrodes and a simple circuit and battery to delivery this drug by iontophoresis through the surface of the skin, microfluidic channels and microreservoirs to capture the induced sweat, and multiple colorimetric assays to evaluate the concentrations of chloride, zinc, and iron. As demonstrated in healthy human participants monitored before and after a meal, such devices yield results that match those of traditional laboratory analysis techniques. Clinical studies that involve cystic fibrosis pediatric patients illustrate the use of this technology as a simple, painless, and reliable alternative to traditional hospital systems for measurements of sweat chloride.

Enhancing Query Formulation for Universal Image Segmentation.

Recent advancements in image segmentation have been notably driven by Vision Transformers. These transformer-based models offer one versatile network structure capable of handling a variety of segmentation tasks. Despite their effectiveness, the pursuit of enhanced capabilities often leads to more intricate architectures and greater computational demands. OneFormer has responded to these challenges by introducing a query-text contrastive learning strategy active during training only. However, this approach has not completely addressed the inefficiency issues in text generation and the contrastive loss computation. To solve these problems, we introduce Efficient Query Optimizer (EQO), an approach that efficiently utilizes multi-modal data to refine query optimization in image segmentation. Our strategy significantly reduces the complexity of parameters and computations by distilling inter-class and inter-task information from an image into a single template sentence. Furthermore, we propose a novel attention-based contrastive loss. It is designed to facilitate a one-to-many matching mechanism in the loss computation, which helps object queries learn more robust representations. Beyond merely reducing complexity, our model demonstrates superior performance compared to OneFormer across all three segmentation tasks using the Swin-T backbone. Our evaluations on the ADE20K dataset reveal that our model outperforms OneFormer in multiple metrics: by 0.2% in mean Intersection over Union (mIoU), 0.6% in Average Precision (AP), and 0.8% in Panoptic Quality (PQ). These results highlight the efficacy of our model in advancing the field of image segmentation.

Association between Gout and Gastric Cancer: A Nested Case-Control Study Using a National Health Sample Cohort.

Given the global significance of gout and gastric cancer (GC) as major health problems with interrelated impacts, we examined the development of GC in Korean patients with gout. We conducted a nested case-control study using data from 10,174 GC patients and 40,696 control patients from the Korean National Health Insurance Service-National Sample Cohort database. Propensity score matching (1:4) with propensity score overlap-weighted adjustment was used to reduce selection bias and estimate the odds ratio (OR) and 95% confidence intervals (CIs) for the association between gout and GC. An adjusted OR for GC was not significantly higher in patients with gout than in control patients (1.02; 95% CI, 0.93-1.12; p = 0.652). Additionally, no association between gout and GC was observed in subgroup analyses such as sex, age, level of income, region of residence, or Charlson Comorbidity Index score. In conclusion, these results suggest that gout is not a significant independent risk factor for GC among the Korean population. Additional investigation is required to establish a causal association between gout and GC, and to generalize these results to general populations.

Association between the Use of Proton Pump Inhibitors and Cardiovascular Diseases: A Nested Case-Control Study Using a National Health Screening Cohort.

We investigated the association of proton pump inhibitor (PPI) use with the risk of stroke and ischemic heart disease (IHD). The Korean National Health Insurance Service-Health Screening cohort from 2002 to 2003, the participants of which were followed up until 2019, was used. In study I, 45,905 participants who were diagnosed with stroke were matched with 91,810 control I participants. The history of PPI medication was examined. In study II, 40,928 participants who were diagnosed with IHD were matched with 81,856 control II participants. In both study I and study II, the previous history of PPI medication was examined. A propensity score overlap-weighted multivariable logistic regression analysis was conducted to estimate the overlap-weighted odds ratios (ORs) of PPI use for stroke (study I) and IHD (study II). Current PPI use was linked with higher odds for stroke in study I. The odds for stroke were higher in groups with a longer duration of PPI use (OR = 0.96 [95% CI = 0.92-1.00] < 1.55 [1.50-1.61] < 1.62 [1.57-1.68] for < 30 days, 30 to 180 days, and ≥180 days of PPI use). Previous PPI use was linked with higher odds for IHD in study II. The odds for stroke were higher in groups with a longer duration of PPI use (OR = 1.13 [95% CI = 1.08-1.18] < 2.12 [2.04-2.21] < 2.60 [2.51-2.69] for <30 days, 30 to 180 days, and ≥180 days of PPI use). Current PPI medication is associated with a high risk of stroke and IHD. A longer duration of PPI medication was related to a higher risk of stroke and IHD. However, a prior history of PPI medication was not linked with a high risk of stroke or IHD.

Unlocking the Protective Potential of Upper Respiratory Infection Treatment Histories against Alzheimer's Disease: A Korean Adult Population Study.

With increasing interest in the inflammation-pathogen infection hypothesis and its potential links to Alzheimer's disease (AD) development, there is growing consideration of using upper respiratory infection (URI) treatments as interventions for AD. This nested case-control study explored the potential association between prior URI histories and AD development in a Korean adult population using the national health screening cohort data (2002-2019). The study included 26,920 AD patients and 107,680 matched control individuals, focusing on those seeking respiratory treatment. Logistic regression analyses assessed the impact of URI histories and treatment on AD risk while adjusting for covariates. Our results revealed that over a 1-year period, individuals with URI histories (≥1, ≥2, or ≥3 instances) exhibited decreasing probabilities of developing AD, with risk reductions of 19%, 15%, and 12%, respectively. Expanding our investigation to a 2-year period consistently showed a 17% reduction in AD risk. This effect remained robust across diverse demographic groups and after adjusting for covariates, encompassing comorbidities, hypertension, hyperlipidemia, blood glucose levels, and lifestyle factors. Subgroup analyses further substantiated this association. In conclusion, our findings cautiously suggest a potential protective role of prior URI treatment histories in mitigating the risk of AD development.

Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBß in Human Osteosarcoma Cell Cultures.

REV-ERBα and its paralog, REV-ERBß, encoded by NR1D1 and NR1D2 genes, are key nuclear receptors that link the circadian timing system and metabolic homeostasis. Since heme is an endogenous ligand, REV-ERBs have been considered key components of the circadian molecular clock and can be pharmacologically targeted to treat various circadian rhythm-related diseases, such as cardiometabolic, inflammatory, and neuropsychiatric diseases, as well as cancer. REV-ERBs are believed to be functionally redundant and compensatory, although they often affect the expression of gene subsets in an isoform-specific manner. Therefore, this study aimed to identify the redundant and distinct roles of each isoform in controlling its target genes by comparing the transcriptome profiles of a panel of mutant U2OS human osteosarcoma cells in which either NR1D1 or NR1D2 was ablated. Indeed, our transcriptomic analyses revealed that most REV-ERB-regulated genes are controlled by redundant or even additive actions. However, the RNA expression profiles of each single mutant cell line also provide strong evidence for isoform-dependent actions. For example, REV-ERBα is more responsible for regulating the NF-κΒ signaling pathway, whereas a group of extracellular matrix components requires REV-ERBß to maintain their expression. We found that REV-ERBs have isoform-selective functions in the regulation of certain circadian output pathways despite their overlapping roles in the circadian molecular clock. Thus, the development of isoform-selective REV-ERB modulators can help treat metabolic disturbances and certain types of cancer.

Predictors of Early and Late Lung Function Improvement in Severe Eosinophilic Asthma on Type2-Biologics in the PRISM Study.

BACKGROUND: The determinants linked to the short- and long-term improvement in lung function in patients with severe eosinophilic asthma (SEA) on biological treatment (BioT) remain elusive. OBJECTIVE: We sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT. METHODS: 140 adult patients with SEA who received mepolizumab, dupilumab, or reslizumab were followed up for 6 months to evaluate improvement in forced expiratory volume in one second (FEV1). Logistic regression was used to determine the association between potential prognostic factors and improved lung function at 1 and 6 months of treatment. RESULTS: More than a third of patients with SEA using BioT showed early and sustained improvements in FEV1 after 1 month. A significant association was found between low baseline FEV1 and high blood eosinophil count and sustained FEV1 improvement after 1 month (0.54 [0.37-0.79] and 1.88 [1.28-2.97] odds ratios and 95% confidence interval, respectively). Meanwhile, among patients who did not experience FEV1 improvement after 1 month, 39% exhibited improvement at 6 months follow-up. A high ACT score measured at this visit was the most reliable predictor of late response after 6 months of treatment (OR and 95% CI 1.75 [1.09-2.98]). CONCLUSION: Factors predicting the efficacy of biological agents that improve lung function in SEA vary according to the stage of response.

Prospective direct comparison of biologic treatments for severe eosinophilic asthma: Findings from the PRISM study.

BACKGROUND: Although various monoclonal antibodies have been used as add-on therapy for severe eosinophilic asthma (SEA), to the best of our knowledge, no direct head-to-head comparative study has evaluated their efficacy. OBJECTIVE: To compare the efficacy of reslizumab, mepolizumab, and dupilumab in patients with SEA. METHODS: This was a multicenter, prospective observational study in patients with SEA who had received 1 of these biologic agents for at least 6 months. Cox proportional hazard models were used to compare the risk of the first exacerbation event, adjusting for sputum or blood eosinophils and common asthma-related covariates. The annual exacerbation rate was analyzed using a negative binomial model, and a mixed-effect model was used to analyze changes in forced expiratory volume in 1 second and asthma control test score over time. RESULTS: A total of 141 patients with SEA were included in the analysis; 71 (50%) received dupilumab; 40 (28%) received reslizumab, and 30 (21%) received mepolizumab. During the 12-month follow-up, 27.5%, 43.3%, and 38.0% of patients in the reslizumab, mepolizumab, and dupilumab groups, respectively, experienced at least 1 exacerbation. However, after adjusting for confounding factors, the dupilumab and mepolizumab groups showed similar outcomes in time-to-first exacerbation, exacerbation rate, forced expiratory volume in 1 second, and asthma control test score to those of the reslizumab group. CONCLUSION: In patients with SEA, treatment with reslizumab, mepolizumab, and dupilumab resulted in comparable clinical outcomes within a 12-month period. TRIAL REGISTRATION: The cohort protocol was sanctioned by the Institutional Review Board of each study center (clinicaltrial.gov identifier NCT05164939).