Discovery of novel FGFR4 inhibitors through a build-up fragment strategy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments.

Comparative Analysis of Clinical Outcomes Using Propensity Score Matching: Coronavirus Disease 2019 vs. Seasonal Influenza in Korea.

BACKGROUND: The advent of the omicron variant and the formulation of diverse therapeutic strategies marked a new epoch in the realm of coronavirus disease 2019 (COVID-19). Studies have compared the clinical outcomes between COVID-19 and seasonal influenza, but such studies were conducted during the early stages of the pandemic when effective treatment strategies had not yet been developed, which limits the generalizability of the findings. Therefore, an updated evaluation of the comparative analysis of clinical outcomes between COVID-19 and seasonal influenza is requisite. METHODS: This study used data from the severe acute respiratory infection surveillance system of South Korea. We extracted data for influenza patients who were infected between 2018 and 2019 and COVID-19 patients who were infected in 2021 (pre-omicron period) and 2022 (omicron period). Comparisons of outcomes were conducted among the pre-omicron, omicron, and influenza cohorts utilizing propensity score matching. The adjusted covariates in the propensity score matching included age, sex, smoking, and comorbidities. RESULTS: The study incorporated 1,227 patients in the pre-omicron cohort, 1,948 patients in the omicron cohort, and 920 patients in the influenza cohort. Following propensity score matching, 491 patients were included in each respective group. Clinical presentations exhibited similarities between the pre-omicron and omicron cohorts; however, COVID-19 patients demonstrated a higher prevalence of dyspnea and pulmonary infiltrates compared to their influenza counterparts. Both COVID-19 groups exhibited higher in-hospital mortality and longer hospital length of stay than the influenza group. The omicron group showed no significant improvement in clinical outcomes compared to the pre-omicron group. CONCLUSION: The omicron group did not demonstrate better clinical outcomes than the pre-omicron group, and exhibited significant disease severity compared to the influenza group. Considering the likely persistence of COVID-19 infections, it is imperative to sustain comprehensive studies and ongoing policy support for the virus to enhance the prognosis for individuals affected by COVID-19.

Proposed Etiotypes for Chronic Obstructive Pulmonary Disease: Controversial Issues.

The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) revised the definition of chronic obstructive pulmonary disease (COPD) to broadly include a variety of etiologies. A new taxonomy, composed of etiotypes, aims to highlight the heterogeneity in causes and pathogenesis of COPD, allowing more personalized management strategies and emphasizing the need for targeted research to understand and manage COPD better. However, controversy arises with including some diseases under the umbrella term of COPD, as their clinical presentations and treatments differ from classical COPD, which is smoking-related. COPD due to infection (COPD-I) and COPD due to environmental exposure (COPD-P) are classifications within the new taxonomy. Some disease entities in these categories show distinct clinical features and may not benefit from conventional COPD treatments, raising questions about their classification as COPD subtypes. There is also controversy regarding whether bronchiectasis with airflow limitations should be classified as an etiotype of COPD. This article discusses controversial issues associated with the proposed etiotypes for COPD in terms of COPD-I, COPD-P, and bronchiectasis. While the updated COPD definition by GOLD 2023 is a major step towards recognizing the disease's complexity, it also raises questions about the classification of related respiratory conditions. This highlights the need for further research to improve our understanding and approach to COPD management.

Secondary immunodeficiency and non-cystic fibrosis bronchiectasis.

Bronchiectasis is a chronic respiratory disease characterized by the abnormal dilation of the bronchi that causes cough, sputum, and recurrent infections. Identifying the underlying cause is a critical aspect of managing bronchiectasis because it may be associated with various respiratory or systemic diseases. Immunodeficiency is a rare but important cause of bronchiectasis, and its treatability is a significant trait for bronchiectasis management. Primary immunodeficiencies in bronchiectasis are well recognized, but secondary immunodeficiencies remain under-reported and under-researched. Secondary immunodeficiencies may result from various diseases and conditions, such as hematologic malignancies, human immunodeficiency virus infection, renal transplantation, and the use of immunosuppressive drugs, and may contribute to the occurrence of bronchiectasis. Recurrent pulmonary and/or extra-pulmonary infections in bronchiectasis may indicate the presence of secondary immunodeficiency in patients with these underlying conditions. Regarding treatment, examining the underlying condition, managing bronchiectasis adequately, and prophylactic antibiotics (e.g., macrolide) and/or supplementing immunoglobulin G therapy may provide potential benefits. Considering the projected increase in the prevalence of secondary immunodeficiencies and bronchiectasis, future guidelines and research on the diagnosis and optimized treatment are needed.

Rapid Progression of Acute Interstitial Pneumonia in a Patient with Low MDA-5 Antibody Titer.

BACKGROUND Melanoma differentiation associated gene-5 antibody (MDA-5 Ab) is one of the diagnostic autoantibodies that appears in idiopathic inflammatory myopathies (IIMs). Unlike when other autoantibodies are positive, when this antibody is positive, there is less characteristic muscle involvement. However, this MDA-5 Ab-positive myopathy presents extremely rapid progression of interstitial lung disease, resulting in a high mortality rate. Previous studies reported that the prognosis of this lung disease will be determined by the titer and suggest that low titers of MDA-5 antibody can indicate a good prognosis in associated interstitial lung disease. CASE REPORT Our case describes a 55-year-old woman who presented with acute respiratory symptoms and dyspnea. After hospitalization, symptoms and chest imaging worsened rapidly, and the radiology image of lung disease featured interstitial changes not seen in typical infections. We treated the patient with a high-flow oxygen nasal cannula, empirical antibiotics, and a systemic steroid. While treatment for a disease of unknown cause was continued, low titer of MDA-5 antibody was identified. CONCLUSIONS This case suggests 2 points to consider about non-infectious interstitial changes with acute respiratory distress syndrome. First, when treating rapidly progressing interstitial pneumonia of an unknown cause, it is recommended to consider lung involvement of MDA-5 Ab dermatomyositis. Second, a low titer of MDA-5 Ab can be associated with better prognosis in this MDA-5 Ab dermatomyositis-related lung disease.

Prevalence of and factors associated with likely obstructive sleep apnea in individuals with airflow limitation.

Introduction: Obstructive sleep apnea (OSA) is frequently associated with airflow limitation (AFL). However, information on the prevalence of and factors associated with likely OSA in individuals with AFL in Korea is limited. Methods: Data from the 2019 Korea National Health and Nutrition Examination Survey (KNHANES) were used, and 3,280 individuals (2,826 individuals without AFL and 454 individuals with AFL) were included. AFL was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7. A score ≥ 5 on the STOP-BANG questionnaire was used to identify individuals with likely OSA. The prevalence of likely OSA was compared between individuals with and without AFL. In addition, factors associated with likely OSA in individuals with AFL were evaluated using multivariable logistic regression analysis. Results: Of 3,280 individuals, 13.8% had an AFL. The prevalence of likely OSA was significantly higher in individuals with AFL than in individuals without AFL (9.2% vs. 5.0%, p = 0.014). Among 454 individuals with AFL, obesity (adjusted odds ratio [aOR] = 14.78, 95% confidence interval [CI] = 4.20-52.02) was most strongly associated with likely OSA, followed by heavy alcohol consumption (aOR = 4.93, 95% CI = 1.91-12.70), hypertension (aOR = 4.92, 95% CI = 1.57-15.46), overweight (aOR = 4.71, 95% CI = 1.76-12.64), college graduate (aOR = 4.47, 95% CI = 1.10-18.22), and history of pulmonary tuberculosis (aOR = 3.40, 95% CI = 1.06-10.96). Conclusion: In Korea, approximately 1 in 10 individuals with AFL had likely OSA. Overweight and obesity, heavy alcohol consumption, high educational level, hypertension, and history of pulmonary tuberculosis were associated with likely OSA in individuals with AFL.

Mechanical ventilation in patients with idiopathic pulmonary fibrosis in Korea: a nationwide cohort study.

BACKGROUND/AIMS: The prognosis of patients with idiopathic pulmonary fibrosis (IPF) and respiratory failure requiring mechanical ventilation is poor. Therefore, mechanical ventilation is not recommended. Recently, outcomes of mechanical ventilation, including those for patients with IPF, have improved. The aim of this study was to investigate changes in the use of mechanical ventilation in patients with IPF and their outcomes over time. METHODS: This retrospective, observational cohort study used data from the National Health Insurance Service database. Patients diagnosed with IPF between January 2011 and December 2019 who were placed on mechanical ventilation were included. We analyzed changes in the use of mechanical ventilation in patients with IPF and their mortality using the Cochran- Armitage trend test. RESULTS: Between 2011 and 2019, 1,227 patients with IPF were placed on mechanical ventilation. The annual number of patients with IPF with and without mechanical ventilation increased over time. However, the ratio was relatively stable at approximately 3.5%. The overall hospital mortality rate was 69.4%. There was no improvement in annual hospital mortality rate. The overall 30-day mortality rate was 68.7%, which did not change significantly. The overall 90-day mortality rate was 85.3%. The annual 90-day mortality rate was decreased from 90.9% in 2011 to 83.1% in 2019 (p = 0.028). CONCLUSION: Despite improvements in intensive care and ventilator management, the prognosis of patients with IPF receiving mechanical ventilation has not improved significantly.

Clinical outcomes of fluoroquinolones combination therapy in patients with hospital-acquired pneumonia: a retrospective cohort study using national health insurance claims data in Korea.

Background: Fluoroquinolones are one of the commonly used antibiotics for the initial empiric combination treatment. However, there is insufficient evidence to support the use of fluoroquinolones combination therapy for the treatment of hospital-acquired pneumonia (HAP). This study aimed to evaluate the effectiveness of fluoroquinolones as part of the empiric combination therapy for HAP using national health insurance claims data in Korea. Methods: We compared the clinical outcomes of patients with HAP who received fluoroquinolones combination and those treated with cefepime or piperacillin/tazobactam monotherapy. The primary outcome was hospital mortality, and the secondary outcome was readmission caused by pneumonia as the primary cause of hospitalization within 7 days after discharge from index hospitalization. The association between the combination with fluoroquinolones and outcomes was evaluated with logistic regression analysis. Results: Among the 9,955 patients with HAP administered with cefepime or piperacillin/tazobactam, 4,918 (49%) received fluoroquinolones combination. During hospitalization, 1,059 (11%) patients with HAP died. Compared with the monotherapy group, the fluoroquinolones combination therapy group was associated with a higher mortality risk [adjusted odds ratio (OR), 1.30; 95% confidence interval (CI): 1.02-1.65]. After adjusting for potential confounding factors, the association remained significant in the non-high-risk HAP group (adjusted OR, 1.30; 95% CI: 1.02-1.66). Meanwhile, the mortality risk was similar between the fluoroquinolones combination therapy group and the monotherapy group of patients with high-risk HAP (adjusted OR, 0.99; 95% CI: 0.35-1.16). Among the patients alive and discharged (n=8,896), 152 (1.7%) were readmitted within 7 days after discharge. The fluoroquinolones combination therapy group was more likely to be readmitted because of pneumonia than the monotherapy group in patients with high-risk HAP (adjusted OR, 1.60; 95% CI: 1.04-2.47). Conclusions: Fluoroquinolones combined with ß-lactams was prescribed in nearly half of patients with low-risk HAP, and it was associated with a higher mortality risk in real-world practice. However, it was not associated with hospital mortality even in patients with high-risk HAP.