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Characteristics of Severe Asthma With Fungal Sensitization in Korea
No full textPURPOSE: Severe asthma with fungal sensitization (SAFS) is associated with life-threatening exacerbation and severe airflow limitation. We aimed to investigate the prevalence of fungal sensitization in asthma and clinical characteristics of SAFS. METHODS: This study analyzed data from the Cohort for Reality and Evolution of Adult Asthma in Korea and the Korean Severe Asthma Registry cohorts. Study subjects were classified based on fungal sensitization and asthma severity. Clinical characteristics of patients with severe asthma were compared according to fungal sensitization status. RESULTS: The rate of skin test positivity to fungi was 14.1% and 7.1% in severe asthma (n = 270) and non-severe asthma (n = 2,605). Patients with SAFS were diagnosed with asthma earlier than those with severe asthma without fungal sensitization (SANFS) (P = 0.019), and had a lower body mass index compared to the SANFS group (P = 0.044). Factional exhaled nitric oxide levels and sputum eosinophilia/neutrophilia showed significant differences between the SAFS and SANFS groups (all P < 0.05). Patients with SAFS were more frequently treated with biologics (36.8% vs. 24.6%, P = 0.116) than those with SANFS. Multivariate analysis revealed that early diagnosed asthma was significantly associated with SAFS. CONCLUSIONS: The prevalence of fungal sensitization in severe asthma is approximately twice as high as in non-severe asthma. Early diagnosed asthma may be a risk factor for SAFS, and patients with SAFS face a greater burden of additional treatment compared to those with SANFS. SAFS has a distinct airway inflammation profile that differentiates it from SANFS
Does robotic circumferential oversewing reduce anastomotic leakage in stapled anastomosis for rectal cancer surgery?
No full textBACKGROUND: Anastomotic leakage (AL) remains a challenging complication of rectal cancer surgery. In patients diagnosed with low risk of AL, low anterior resection (LAR) is often performed without creating a stoma. However, AL can still occur even in patients considered to be at low risk. This study assessed the effects of circumferential oversewing (CO) on AL in patients undergoing robotic LAR without fecal diversion. METHODS: We retrospectively reviewed data from 225 patients with rectal cancer who underwent robotic LAR without fecal diversion. They were divided into CO and non-CO groups. The CO group received oversewing along the circular staple line. The AL rate was assessed after the inverse probability of treatment weighting (IPTW) adjustments. RESULTS: After IPTW adjustment, no significant differences in baseline characteristics were observed between the two groups. Overall complication and AL rates were 12.0% and 4.5%, respectively. Although no difference in overall complications was observed between the two groups, patients in the CO group had a significantly lower AL rate than the non-CO group (1.7% vs. 10.3%, p = 0.010). Logistic regression analysis revealed that the CO procedure was a protective factor against AL (IPTW-adjusted OR 0.153, 95% CI 0.036-0.643, p = 0.010). CONCLUSIONS: The application of the CO procedure in patients with LAR who were not indicated for stoma creation may contribute to reducing the risk of AL
Utility of plasma GFAP as a secondary endpoint for clinical trials in Alzheimer's disease
No full textBACKGROUND: Clinical trials have recently incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint. To include plasma GFAP as a secondary endpoint, it is essential to characterize its longitudinal progression in target populations. OBJECTIVE: To evaluate the potential use of plasma GFAP changes as a secondary endpoint in Alzheimer's disease trials. METHODS: We longitudinally evaluated plasma GFAP in individuals with amyloid-beta (Abeta)-PET scans at baseline in three well-characterized cohorts. Cox proportional hazards regression tested the association between changes in plasma GFAP and cognitive function. Analysis of the 95 % confidence interval of annualized change in plasma GFAP provided statistical inference for a significant longitudinal change. Effect size was calculated as the group mean divided by the standard deviation (SD). We estimated the sample size needed to test a 25% drug effect with 80% power on reducing changes in GFAP. RESULTS: We assessed 487 individuals [176 cognitively unimpaired (CU; 29% Abeta positive) and 311 cognitively impaired (CI; 51% Abeta positive)] with some degree of cerebrovascular disease (Fazekas 1-3), over a mean (SD) follow-up of 1.84 (0.46) years. Changes in plasma GFAP were significantly associated with worsening in Clinical Dementia Rating sum of boxes (CDR-SB) score across the population (p < 0.0001). In CU, only Abeta positive individuals showed significant changes in GFAP (p < 0.001). On the other hand, both CI Abeta positive and negative individuals showed longitudinal progression in GFAP levels (p < 0.0001). The effect size of changes in plasma GFAP was higher in CU Abeta positive (0.44), followed by CI Abeta positive (0.42) and CI Abeta negative (0.38). Clinical trials focusing on CU Abeta positive would require 1320 individuals per study arm, while focusing on CI Abeta positive would require 1440 individuals per study arm. CONCLUSION: Plasma GFAP increased in parallel with cognitive decline, making it a candidate for monitoring disease progression in trials aimed at mitigating cognitive deterioration. Although Abeta positivity significantly accelerated GFAP progression, the fact that GFAP was increased in CI Abeta negative with cerebrovascular disease supports its potential use as a secondary endpoint in this population as well
Exosomal Liquid Biopsy for the Early Detection of Gastric Cancer: The DESTINEX Multicenter Study
No full textIMPORTANCE: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, primarily attributed to delayed detection. The invasive and cost-prohibitive nature of endoscopy for GC screening highlights the urgent need for noninvasive biomarkers. OBJECTIVE: To develop an exosome-based diagnostic signature to facilitate blood-based, early detection of patients with GC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, population-based, retrospective, case-control study that analyzed specimens collected between January 1, 2016, and December 30, 2020. The study encompassed the discovery, training, validation, and evaluation phases of biomarker development. This study was conducted at 4 major referral centers: Nagoya University Hospital in Japan and Ajou University Hospital, Asan Medical Center, and Samsung Medical Center in South Korea, providing a broad representation of advanced clinical care settings. The study included patients with GC, classified according to the TNM (tumor-node-metastasis) classification (8th edition), and controls without disease. Key sociodemographic data, including age and sex, were recorded for all participants. Data were analyzed from October 2022 to July 2024. EXPOSURES: Results were obtained from tissue and serum microRNA (miRNA) profiling and expression analysis. Frozen tissue collection and blood draws were conducted intraoperatively, preoperatively, and 3 months postoperatively. MAIN OUTCOMES AND MEASURES: Diagnostic performance of GC detection using an exosome-based miRNA signature. RESULTS: A total of 809 specimens from 480 patients (mean [SD] age, 61.9 [9.8] years; 336 male [70%]) in the training and validation cohorts were analyzed. A panel of 8 cell-free miRNAs and 10 exosomal miRNAs was initially developed in the discovery phase, which was subsequently reduced using machine learning algorithms to a panel of 8 cell-free and 9 exosomal miRNAs during the training phase. This 17-miRNA signature robustly identified GC with area under the curve (AUC) values of 96.3% (95% CI, 94.3%-98.4%) and 95.3% (95% CI, 92.8%-97.9%) in the training and validation cohorts, respectively. Additionally, 5 overlapping miRNAs were observed between cell-free and exosomal panels and exhibited a comparable efficacy in identifying patients with GC. Finally, we established a 10-miRNA signature (Destinex), which successfully identified early-stage (pT1) GC (AUC = 96.8%; 95% CI, 93.5%-100%). Finally, a significant decrease in miRNA expression levels in postsurgery serum specimens confirmed the robustness of the panel specificity. CONCLUSION AND RELEVANCE: Results of this case-control study suggest that the Destinex assay was robust for early detection of GC, highlighting its potential for clinical application in the noninvasive identification of GC
Dysregulation of FGFR1 signaling in the hippocampus facilitates depressive disorder
No full textMajor depressive disorder (MDD) is a complex psychological disorder with a sophisticated molecular etiology. Although its connection with fibroblast growth factor receptor 1 (FGFR1) in the hippocampus is known, the precise mechanisms underlying its pathophysiology remain unclear. Here we conduct a comprehensive analysis of the molecular profile of the hippocampus in patients with MDD. We identified a distinct overexpression of FGFR1 specifically within the dentate gyrus of patients with MDD. Through the use of optogenetic techniques for the in vivo spatiotemporal dissection of FGFR1 signaling, we uncovered a sequential FGFR1-Notch-brain-derived neurotrophic factor (BDNF) pathway within the dentate gyrus, which can ultimately induce adult hippocampal neurogenesis, significantly contributing to antidepressant effects. We discovered that the dysregulation of this axis by the protein Numb, which demonstrates an age-related increase in individuals with MDD, is closely associated with the development of depressive phenotypes. Remarkably, targeting Numb to restore this axis effectively reversed the depressive phenotype, thus offering new insights into potential therapeutic strategies
MetaboGNN: predicting liver metabolic stability with graph neural networks and cross-species data
No full textThe metabolic stability of a drug is a crucial determinant of its pharmacokinetic properties, including clearance, half-life, and oral bioavailability. Accurate predictions of metabolic stability can significantly streamline the drug discovery process. In this study, we present MetaboGNN, an advanced model for predicting liver metabolic stability based on Graph Neural Networks (GNNs) and Graph Contrastive Learning (GCL). Using a high-quality dataset from the 2023 South Korea Data Challenge for Drug Discovery, which comprises 3,498 training molecules and 483 test molecules, we presented molecular structures as graphs to capture the intricate structural relationships that influence metabolic stability. A GCL-driven pretraining step was employed to enhance model generalizability by learning robust, transferable graph-level representations. Notably, incorporating interspecies differences between human liver microsomes (HLM) and mouse liver microsomes (MLM) further improved predictive accuracy, achieving Root Mean Square Error (RMSE) values of 27.91 (HLM) and 27.86 (MLM), both expressed as the percentage of parent compound remaining after a 30-min incubation. Compared to traditional approaches, MetaboGNN demonstrates superior predictive performance and highlights the importance of considering interspecies enzymatic variations. In addition, attention-based analysis identified key molecular fragments associated with metabolic stability, highlighting chemically meaningful structural determinants. These findings establish MetaboGNN as a powerful tool for metabolic stability prediction, supporting more efficient lead optimization processes in drug discovery
Examining Pediatric Emergency Utilization Trends Before and After the COVID-19 Pandemic: An Eight-Year Cohort Study from a South Korean Tertiary Center
No full textPurpose: This study investigates trends in pediatric emergency department (ED) utilization before and after the COVID-19 pandemic, with a focus on age-specific patterns, triage severity, diagnostic categories, and clinical presentations. Methods: Data were collected for 71,560 individuals (40,428 males and 31,132 females aged 0-18 years) who visited the ED at Samsung Changwon Hospital between 1 January 2016 and 31 December 2023. Patients were categorized into pre-COVID-19 (2016-2019) and post-COVID-19 (2020-2023) periods. Age, Korean Triage and Acuity Scale (KTAS) scores, visit outcomes, diagnostic codes (ICD-10), and vital signs were analyzed. Age-specific analyses were performed in four groups: <12 months, 1-6 years, 7-12 years, and 13-18 years. Results: Since the COVID-19 pandemic, pediatric ED visits have decreased by 55.5%. The proportion of visits by infants (<12 months) and young children (1-6 years) decreased, and adolescent visits increased. Post-pandemic, there was a significant increase in lower-acuity visits (KTAS 4) and discharge rates, alongside a reduction in admissions. Visits for respiratory and infectious diseases (ICD-10 J and A & B codes) decreased markedly, and visits for non-specific symptoms (R codes) and trauma (S & T codes) increased. The mean body weight of young children increased significantly after the COVID-19 period. Conclusions: The COVID-19 pandemic has had a profound and lasting effect on pediatric emergency department utilization, with changes in the number of visits, illness patterns, and severity by age group. These findings highlight the need for age-specific strategies in emergency planning and pediatric public health policy, particularly in managing the indirect effects of pandemic-induced changes in behavior and access to healthcare
Diabetic Wound Repair: From Mechanism to Therapeutic Opportunities
No full textDiabetic wound healing, characterized by persistent inflammation, impaired angiogenesis, and dysfunctional cellular responses, remains a major clinical challenge due to its complex pathophysiology. This challenge is most evident in diabetic foot ulcers (DFUs), which carry high risks of infection, recurrence, and amputation, contributing substantially to patient morbidity, mortality, and healthcare costs. Despite multidisciplinary care, debridement, and advanced dressings, healing outcomes are often suboptimal, highlighting an urgent need for deeper pathophysiological insights and more effective therapeutic strategies. This review synthesizes current understanding of DFU pathogenesis, emphasizing how sustained metabolic dysfunction disrupts fibroblast and immune cell function, thereby perpetuating chronic wounds. We also critically examine commonly used animal models and their limitations in replicating the complexity of human DFUs and discuss emerging therapeutic approaches with translational promise. Advancing our understanding of these mechanisms and validating innovative interventions may ultimately reduce DFU-related amputations and mortality, improve healing outcomes, and enhance patient quality of life. This review aims to catalyze future research and therapeutic innovation in diabetic wound care
Pediatric Firearm Injury: Comparing age-Adjusted Shock Indices for Prediction of Emergency Interventions
No full textOBJECTIVES: To characterize pediatric firearm injury (PFI) and identify predictors of outcomes relevant to emergency care interventions. METHODS: We conducted a retrospective registry review of pediatric patients (below 18 y) presenting to a single level-1 trauma center located in Seattle, Washington, from 2018 through 2023. PFI patients were compared with the otherwise injured patients by anatomic or physiological severity indices, such as injury severity score (ISS) and 3 types of age-adjusted shock index. The shock indices included shock index pediatric age-adjusted, pediatric shock index, and Advanced Trauma Life Support-based shock index (ATLS-SI). Multivariable logistic regression was performed to identify predictors of the need for transfusion or surgical intervention. RESULTS: Of 2610 total trauma patients, 230 (8.8%) were injured by firearms with a median age of 16.0 years (interquartile range: 14.0 to 17.0) and a male proportion of 80.4%. When compared with other injury mechanisms, PFI was associated with more frequent vascular injuries (PFI, 19.1% vs. others, 4.3%), transfusions (31.7% vs. 10.2%), and surgical interventions (23.5% vs. 6.7%). Among the age-adjusted shock indices, an elevated value of ATLS-SI showed the highest specificities for both outcomes [transfusion, 91.7% (95% CI: 86.3-95.5); surgical intervention, 83.5% (77.2-88.7)] and the strongest association with transfusion at an adjusted odds ratio of 4.84 (1.94-12.06). CONCLUSIONS: From this single-center experience, PFI patients are typically male adolescents, more frequently sustain major vascular injuries, and are more likely to require transfusion or surgery. An elevated ATLS-SI at emergency department (ED) arrival is specific for and predictive of the need for emergency care interventions