United States

Background: Asthma is a chronic lung disease characterized by airway hyperresponsiveness leading to reduction in quality of life. Volatile organic compounds (VOCs), easily evaporable chemicals found in fragrances, cleaning chemicals, and personal care products, are known to exacerbate asthma. The home can be a source of asthma triggers, including VOCs, leading to uncontrolled disease. Minimizing triggers in the home is essential for controlling asthma. Given that women are more likely to have greater severity of asthma than men, it is unknown whether there are gender differences in home VOC exposure. The purpose of this project is to examine any differences in VOC levels in the home by gender and education in older adults with asthma.

Methods: In this secondary analysis of a retrospective observational study, older adults ages 60 and above with asthma had VOC levels measured in their homes over a 24-hour period. Participants also completed baseline metrics of lung function and asthma control including forced expiratory volume (FEV-1), asthma control test (ACT), and Fractional Exhaled Nitric Oxide (FeNO). The 19 specific VOCs included in this analysis were detected indoors in 90% of homes or higher.

Results: Participants (N=184) were primarily White (77%), had a mean age at enrollment of 69±6.2 years, and included a female to male ratio of 2.7:1. Almost half (27.8%) were college educated, however 5.4% had less than a high school education. About one-third (33.7%) had an FEV1 percent predicted ≤79%, 36.4% had FeNO ≥25, and 56% had an ACT ≤19. The average of the total VOCs in each home was 68.36±87.37 parts per billion (ppb), the maximum was 603.69 ppb, minimum was 3.41 ppb, and the interquartile range (IQR) was 55.22 ppb. Acetone had the highest mean, median, and IQR of the 19 VOCs across the homes. Males had significantly higher levels of 124-trimethlybenzene in their homes (p= 0.005). Participants with less than a high school education had significantly higher levels of indoor freon113 and of carbon tetrachloride (p=0.019 and p= 0.013, respectively).

Conclusion: Differences in the concentration of specific VOCs in the homes of older adults with asthma by gender and education were identified. These findings may inform education and intervention strategies to reduce residential VOC exposure and improve asthma control in vulnerable populations.

AMA Research Challenge 2025 

Gender and education differences in residential levels of volatile organic compounds in older adults with asthma.

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### Background
Multi-target peptide therapeutics targeting glucagon receptor (GCGR), glucagon-like peptide-1 receptor (GLP1R), and glucose-dependent insulinotropic polypeptide receptor (GIPR) represent a promising approach for treating diabetes and obesity. Triple agonist peptides demonstrate superior efficacy compared to single-target approaches, yet rational design remains computationally challenging due to complex sequence-structure-activity relationships. Existing methods, primarily based on convolutional neural networks, impose limitations including fixed sequence lengths and inadequate representation of molecular topology. Graph Attention Networks(GAT) offer advantages in capturing molecular structures and variable-length peptide sequences while providing interpretable insights into receptor-specific binding determinants.

### Objective
To develop and validate a GAT-based framework for designing novel triple agonist peptides with optimized binding affinity across GCGR, GLP1R, and GIPR, and to compare performance against convolutional neural network approaches.
Methods: A dataset of 234 peptide sequences with experimentally determined binding affinities was compiled from multiple sources. Peptides were represented as molecular graphs with seven-dimensional node features encoding physicochemical properties and positional information. The GAT architecture employed a shared encoder with task-specific prediction heads, implementing transfer learning to address limited GIPR training data. Performance was evaluated using 5-fold cross-validation and independent validation on 24 literature-derived sequences. A genetic algorithm framework was developed for peptide sequence optimization, incorporating multi-objective fitness evaluation based on predicted binding affinity, biological plausibility, and sequence novelty.

### Results
Cross-validation demonstrated robust GAT performance across all receptors, with GCGR achieving high accuracy (AUC-ROC: 0.915 ± 0.050), followed by GLP1R (AUC-ROC: 0.853 ± 0.059), and GIPR showing acceptable performance despite limited data (AUC-ROC: 0.907 ± 0.083). Comparative analysis revealed receptor-specific advantages: GAT significantly outperformed CNN for GCGR prediction (RMSE: 0.942 vs 1.209, p = 0.0013), while CNN maintained superior GLP1R performance (RMSE: 0.552 vs 0.723). Genetic algorithm optimization achieved substantial improvement over baseline, with 4.0% fitness enhancement and generation of 20 candidates exhibiting mean binding probabilities exceeding 0.5 across all targets.

### Conclusions
The GAT-based framework represents a significant advancement in computational peptide design, demonstrating receptor-specific advantages and robust optimization capabilities. Genetic algorithm optimization enables systematic exploration of sequence space while maintaining biological constraints. This approach provides a rational framework for prioritizing experimental validation efforts in triple agonist development.

Machine Learning-Guided Design of Next-Generation Triple Agonist Peptide Therapeutics for Metabolic Disease

### Background
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high recurrence and metastatic rate, leading to a 12% survival rate in patients with metastatic TNBC. Chimeric antigen receptor (CAR) T cell therapy represents a promising therapeutic approach, as it involves genetically modifying T cells by introducing genes encoding a synthetic CAR, which is subsequently expressed on the T cell surface. This modification enables CAR T cells to combine the cytolytic activity of T cells with the antigen-specific recognition ability of a single- chain variable fragment (scFv) domain. This study aims to identify potential gene targets for CAR T cell therapy in brain metastases of TNBC (BM TNBC).

### Methods
Matched primary and brain metastatic TNBC tumor samples from three patients were obtained from the KUMC Biospecimen Repository Core Facility. RNA expression profiling was conducted using the GeoMx Digital Spatial Profiler (NanoString Technologies) in the Andrew Godwin Lab at KUMC. Gene expression was analyzed with the GeoMx Human Cancer Transcriptome Atlas (CTA), which quantifies the expression of approximately 1,800 genes. RNA quantification was performed using nCounter and next-generation sequencing (NGS). Differential gene expression was assessed by comparing metastatic tumor samples to a baseline negative control, with genes exhibiting a ≥2-fold increase in expression identified via volcano plots. Statistical significance was determined using one-way ANOVA with multiple comparisons (Prism software, p < 0.05).

### Results
Secreted phosphoprotein 1 (SPP1) was identified as a highly upregulated gene in metastatic tumor samples compared to normal tissue. SPP1 plays a critical role in tumor proliferation, migration, and chemoresistance, making it a promising candidate for targeted CAR T cell therapy. In vitro CAR T cell experiments are ongoing to assess the efficacy of SPP1-targeted therapies in eliminating TNBC cells.

### Conclusion
This study identifies SPP1 as a highly expressed antigen in BM-TNBC, suggesting its potential as a novel target for CAR T cell therapy. Further investigation through functional assays and animal studies will determine its viability as a therapeutic target in this challenging TNBC subtype.

Assessing Expressed Tumor Antigens for TNBC: A GeoMx Analysis

### Background
Robust, inexpensive biomarkers that capture the combined effects of systemic inflammation, tissue hypoperfusion, and nutritional reserve are needed to refine post–acute myocardial infarction (AMI) risk stratification—especially in the large subset that develops congestive heart failure (CHF). Two emerging candidates are the lactate/albumin ratio (LAR) and the red cell distribution width/albumin ratio (RAR). Separate studies have linked each ratio to short and long term mortality in critical illness, AMI, and heart failure, yet no work has directly compared their performance in a contemporary cardiac cohort, nor examined whether percutaneous coronary intervention (PCI) modulates their prognostic value. We addressed this evidence gap in a large, multi hospital dataset.

### Methods
We performed a retrospective secondary analysis of 8 115 de identified encounters drawn from the HCA corporate database (2016 2024). Adults aged 30–80 years with laboratory confirmed AMI complicated by CHF and documented lactate, RDW, and albumin levels were included; those lacking 90 day follow up or requisite labs were excluded. The primary outcome was all cause mortality at 30, 60, and 90 days. Secondary outcomes were 7 , 15 , and 30 day readmissions. Predictors entered into generalized logistic regression were LAR, RAR, age, sex, race, and PCI status; interaction terms tested whether PCI modified biomarker effects. Model discrimination was assessed with the concordance (C) statistic.

### Results
Elevated LAR and elevated RAR each independently increased the odds of death after adjustment for demographics and PCI. For LAR, the odds of mortality were nearly tripled (OR 2.99, 95 % CI 2.62–3.42; p < 0.001). RAR exerted a significant, but comparatively smaller, (OR 1.68, 95 % CI 1.50–1.89; p < 0.001). Age conferred a 3.8 % rise in mortality odds per year. Female sex, non White race, and receipt of PCI were protective (all p < 0.05). The full model achieved moderate discrimination (C = 0.708). Importantly, elevated LAR, but not RAR, predicted early clinical deterioration, being significantly associated with 7 , 15 , and 30 day readmissions. No significant interaction between PCI and either ratio was observed.

### Conclusion


Both LAR and RAR are powerful, readily obtainable predictors of short term mortality in CHF patients recovering from AMI, with LAR also signaling imminent readmission risk. Routine calculation of these ratios at admission could sharpen bedside prognostication and prompt closer surveillance of high risk individuals. Incorporating LAR and RAR into post AMI care pathways warrants prospective validation and may foster a habit of leveraging routinely collected laboratory data for precision cardiovascular medicine.


Lactate/Albumin and RDW/Albumin Ratios for Mortality and Readmission in Post-MI Heart Failure

Currently, there is no national curricular standard for teaching medical students how to respond to an opioid overdose. At VCOM-Virginia, first-year medical students are trained using the Virginia-state naloxone training program (REVIVE!). This program, however, consists only of a lecture-based training with a pre- and post-training assessment. Prior to this study, there has never been a hands-on component or an assessment of long-term retention. This study was designed as a randomized control trial and took place at the VCOM - Virginia Campus’s Simulation Center. Participants include medical students at VCOM-VA who had never received naloxone training. We enrolled 255 participants, with 96 comprising the control group (w/o simulation) and 114 in the experimental (w/ simulation) after losing participants to follow up. IRB approval was received on 9/26/23 (VCOM IRB Record # 2023-132). The intervention offered to the control group was the unaltered Virginia REVIVE! course curriculum. The experimental group received the classroom-based curriculum, alongside a simulation experience utilizing a high-fidelity manikin synced to the Laerdal Learning Application software. Participants were tasked with assessing the manikin’s vital signs, deciding if their case was severe alcohol intoxication or opioid overdose, and following the rescue protocol as outlined in the didactic portion. All participants received the same 2 post-assessment surveys based on the learning objectives outlined in the REVIVE! course, one immediately following the didactic portion, and one at 6 months following their training date. Additionally, time to recognize a situation as an overdose and self-reported confidence scores were recorded from students following their simulation. At 6-month follow-up, there was a significant difference in average time to recognition between the simulation-trained group and control group. There was also a statistically significant difference in confidence in real world performance with a higher confidence seen in the simulation trained group. Additionally, the simulation-trained group had a smaller difference in post-assessment score change at the 6 month mark; however these results were not statistically significant, thus we can make no conclusions about long-term material retention at this time. Results of this study show that medical students who receive simulation training in opioid overdose rescue feel more confident and respond more quickly than those who receive traditional classroom-based training. In the larger context of medical education, these findings highlight the potential for simulation-based learning to enhance student preparedness and confidence in critical hands-on skills such as naloxone administration. A high-fidelity manikin approach could also be extended to other clinical skills, reinforcing the philosophy of patient-focused care through innovative teaching methods.

Hands-On Naloxone Training: Advancing Curriculum and Assessment Through Simulated Manikins Learning

### Background
Esophageal squamous cell carcinoma (ESCC) disproportionately affects Asian populations and frequently arises in the upper esophagus. Although racial differences in ESCC incidence are recognized, real-world evidence comparing metastatic burden and survival outcomes between Asian and White patients remains scarce. Even less is known about whether these disparities differ by sex. This study evaluates racial disparities in metastasis and 5-year survival among patients with upper esophageal cancer, with novel stratification by sex.

### Methods
We performed a retrospective cohort study using the TriNetX Research Network. Adults (≥18 years) with upper esophageal cancer were identified by ICD-10-CM and ICD-O codes with exclusion of many other cancers. Asian and White patients were propensity score matched 1:1 on age, sex, ethnicity, and nicotine use, then stratified by sex. Metastasis was defined as secondary malignancies to high-yield organs documented after the index upper esophageal cancer diagnosis. Survival was analyzed with Kaplan–Meier methods. Hazard ratios (HR), risk ratios (RR), odds ratios (OR), and 95% confidence intervals (CI) were calculated.

### Results
The matched cohort included 2,268 Asian and 2,268 White patients. Metastasis occurred more frequently in Asian patients (53.0% vs. 29.0%; RR 1.84, OR 2.80, p < 0.0001). Five-year survival was significantly lower in Asian patients (27.6% vs. 41.6%; HR 1.42, p < 0.0001). Among males, metastasis was 54.4% in Asian males vs. 29.9% in White males (p < 0.0001), with 5-year survival of 26.0% in Asian males vs. 38.8% in White males (p < 0.0001). Among females, metastasis remained higher in Asian females (33.9% vs. 18.3%; p < 0.0001), but survival differences were not statistically significant (35.9% vs. 40.5%; p = 0.33).

### Conclusions
Asian patients with upper esophageal cancer, regardless of sex, experience greater metastatic burden compared to their White counterparts. Regarding differences in 5-year survival, Asian patients overall have a decreased survival compared to White patients, mainly attributable to the discrepancies between the male cohorts, with minimal significance in the female cohorts. These disparities may reflect a combination of biological predisposition, decreased health-seeking behaviors, and systemic barriers to care. To address these inequities, culturally tailored screening, early detection, and intervention strategies are urgently needed in high-risk populations, especially in Asian men.

Metastasis and Five-Year Survival Among Asian Patients with Upper Esophageal Carcinoma

### Background
Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of pancreatic β cells, leading to progressive loss of β-cell function and insulin deficiency. Crosstalk between the immune system and β-cell signaling contributes to disease progression, highlighting inflammatory pathways as potential therapeutic targets. While the development of an anti-CD3 monoclonal antibody against autoreactive T cells represents a significant advance in delaying the onset of insulin dependence, new approaches are needed to delay β-cell destruction in patients with diabetes-related autoantibodies. Our lab previously showed that ATI-450, a selective p38α/MK2 inhibitor, and AZD8931, an EGFR/ERBB2/ERBB3 inhibitor, delay the onset and reduce the incidence of T1D in female nonobese diabetic (NOD) mice. To explore the mechanism(s) by which ATI-450 and AZD8931 attenuate T1D, we examined whether these inhibitors could mitigate cytokine-induced β-cell dysfunction by modulating the expression of senescence-related markers and β-cell identity/function genes. 

### Methods
MIN6 cells were co-treated for 24 hours with cytokines (IL-1β, TNF-α, IFN-γ; 2.5 ng/mL each) ± ATI-450 (2µM) or AZD8931 (5 µM). DMSO was used as a control. Total RNA was extracted and reverse-transcribed into cDNA using standard kits. Quantitative real-time PCR was performed using synthesized cDNA and primers obtained from PrimerBank. Samples were run in triplicate, and relative mRNA expression was determined by the ΔΔCt method, normalized to mouse TATA-binding protein levels.

### Results
Cytokine-stress increased the relative expression of the senescence-related marker p21cip1 by 2.5-fold compared to DMSO control. Co-treatment with either ATI-450 or AZD8931 attenuated this cytokine-induced upregulation, suggesting that these inhibitors may delay the onset of senescence by blocking pro-inflammatory signaling pathways. Cytokine-stress reduced the relative expression of the β-cell identity/function genes Ucn3 and MafA by ~2.0-fold and ~1.5-fold, respectively, compared to DMSO control. Co-treatment with either ATI-450 or AZD8931 attenuated the cytokine-induced downregulation of Ucn3 and MafA, indicating that these compounds may help preserve β-cell functional identity.

### Conclusion
These findings suggest that both ATI-450 and AZD8931 can protect MIN6 cells from cytokine-induced dysfunction in vitro by reducing expression of the senescence-related marker p21cip1 and preserving key β-cell identity/function genes such as Ucn3 and MafA. This provides mechanistic insights for the in vivo effects of these inhibitors to reduce T1D incidence in NOD mice, revealing specific inflammatory pathways in β-cells that might be targeted for β-cell preservation. Since both inhibitors demonstrated favorable safety profiles in clinical trials for other diseases, these compounds could be investigated for preventing T1D in islet autoantibody-positive individuals.

ATI-450 and AZD8931 Protect MIN6 Cells from Cytokine-Induced Dysfunction

### Background
Retinopathy of prematurity (ROP), a leading cause of childhood blindness, involves abnormal vascular proliferation and retinal detachment. Known risk factors include supplemental oxygen exposure, low gestational age (GA), and low birth weights (BW). Emerging evidence suggests early-life gut dysbiosis may contribute to ROP progression via the gut-retina axis and subsequent inflammatory pathways. Our group previously identified distinct gut microbial profiles in infants with severe ROP compared to those without. Systemic antibiotics are major disruptors of the gut microbiome, yet few studies have explored antibiotic exposure as a risk factor for ROP due to early-life gut dysbiosis. This study investigated the association of antibiotic exposure and clinical factors with ROP severity, focusing on high-risk preterm infants that developed ROP not requiring treatment compared to infants with severe ROP that required lasers/injections.

### Methods
This retrospective cohort study included high-risk preterm infants (≤27 weeks GA or ≤750 g BW) admitted to a level III NICU who underwent routine ROP screening. Subjects were stratified into two groups: those requiring treatment for severe ROP (Stage 3 type 1) and those with mild ROP not requiring intervention (Stage 1-2, Stage 3 type 2). Clinical variables including BW, EGA, weight gain rate, days on ventilation, and diagnoses of bronchopulmonary dysplasia (BPD) or necrotizing enterocolitis (NEC) were compared. The Shapiro-Wilk test assessed normality. Continuous variables were analyzed with t-tests or Wilcoxon rank-sum, and categorical variables with Fisher’s exact test. 

### Results
Thirty-four infants met inclusion criteria (23 no treatment, 11 treatment). No statistically significant differences were observed between groups in BW, EGA, weight gain rate, days on ventilation, delivery method, or incidence of BPD or NEC. However, infants requiring treatment for severe ROP had a median of 29 days of antibiotic exposure, compared to 9.0 days in the no treatment group with ROP (p<0.05, Wilcoxon rank-sum). The significant association between prolonged antibiotic exposure and ROP requiring treatment suggests a potential role for microbiome disruption or immune modulation in ROP pathogenesis. 

### Conclusion
These findings suggest that extended antibiotic exposure in high-risk pre-term infants may be associated with increased ROP severity requiring intervention. Alterations in the gut microbiome, potentially mediated by antibiotic use, may trigger downstream effects on immune regulation and signaling pathways. As the gut-retina axis continues to emerge as a key mediator of retinal vascular development, future studies should integrate microbiome profiling and metabolomics to elucidate this mechanistic relationship. 


Prolonged Antibiotic Exposure Associated with Increased Severity of Retinopathy of Prematurity (ROP) Requiring Treatment

### Introduction
Accelerated brain aging can lead to cognitive decline, as morphological changes occur in the brain. We hypothesize that lower social engagement and higher geriatric depression in older adults pose a greater risk for accelerated brain aging and thus a higher brain age gap (BAG).

### Methods
Participants in the AGES study, aged 66 to 96, were surveyed on depression and social engagement at baseline and again after approximately five years. The Geriatric Depression Scale and monthly leisure activity participation were used as measures. Depression scores of 0–5 were categorized as normal/low risk, and scores of 6–15 as moderate/severe risk. For social engagement, each point on the leisure variable corresponded to four leisure activities per month; then categorized into four groups: None (0), Low (0–2), Medium (2–5), and High (5+). Each measure was analyzed using BAG as the dependent variable. 

### Results
Depression predicted higher BAG at baseline (P< 0.013), follow up (P <0.01) and longitudinally (P< 0.005). Leisure was associated with higher BAG at baseline (P < 0.002), however not at follow-up. A post hoc Tukey test confirmed individuals in the "None" category differed significantly from those in the other leisure groups (P < 0.01). No significance was found longitudinally for leisure on BAG.

### Conclusion
Depression has a significant impact on BAG in healthy older adults. Social engagement significantly influences brain aging at baseline, though this effect is not sustained over time; suggesting early intervention may be protective.


Psychosocial Predictors of Accelerated Brain Aging: A Study of Depression and Social Engagement in Healthy Older Adults

### Background
Anxiety disorders affect one in three people worldwide, yet current treatments, centered on brain neurotransmitters, fail many patients and often cause undesirable side effects. While these therapies act centrally, growing evidence suggests that emotional states are also influenced by signals from peripheral organs. We identify asprosin, a fasting-induced hormone secreted by adipose tissue, as a direct endocrine driver of anxiety. Asprosin crosses the blood-brain barrier and binds protein tyrosine phosphatase receptor delta (PTPRD), a neuronal receptor enriched in hippocampal neurons and genetically linked to anxiety risk. This work defines the first hormone–receptor circuit linking energy state to emotional behavior, one that is peripheral, mechanistically distinct, and therapeutically actionable.

### Methods
We manipulated the asprosin-Ptprd signaling axis in mice using five approaches: (1) viral overexpression of asprosin (Ad5-FBN1 or AAV8-asprosin); (2) peripheral neutralization with an anti-asprosin monoclonal antibody (mAb); (3) genetic loss-of-function models, including Fbn1NPS/+ mice (asprosin-deficient) and Ptprd+/- mice; (4) pharmacologic inhibition using 7-butoxy-illudalic acid (7-BIA), a selective Ptprd inhibitor; and (5) stereotactic Cre-mediated deletion of Ptprd in specific brain regions. Anxiety-like behavior was quantified across well-validated assays: open field, light–dark, and elevated plus maze, under both basal conditions and chronic stress paradigms. Asprosin binding was assessed using alkaline phosphatase-tagged ligands, and whole-cell patch-clamp electrophysiology evaluated neuronal excitability.

### Results
Reducing asprosin signaling through - genetic asprosin deficiency, pharmacologic sequestration with a monoclonal antibody, partial Ptprd loss and pharmacologic Ptprd inhibition - reduced baseline anxiety-like behavior across multiple assays. Conversely, elevating asprosin with viral overexpression increased baseline anxiety. When anxiety was induced using chronic stress paradigms, circulating asprosin surged, found to be driven by catecholamine release. Mechanistically, recombinant asprosin depolarized ventral CA1 pyramidal neurons and doubled their firing rate via a Ptprd-dependent, synapse-independent process. Region-specific deletion studies confirmed that Ptprd in ventral CA1 was necessary for stress-induced anxiety, identifying this subregion as the key node mediating asprosin-driven emotional changes.

### Conclusion
This study reframes anxiety as a hormonally gated state regulated by a defined adipose-to-brain endocrine axis. The asprosin–Ptprd pathway operates independently of classical neurotransmission, offering dual therapeutic targets: a peripheral hormone and its central receptor. Our findings highlight the body’s peripheral pathways as an untapped source of insight and innovation in neuropsychiatric disease. It establishes the mechanistic foundation for the first hormone-based anxiolytic, a strategy that is translatable, safe, and designed to reach the millions of patients for whom current drugs fall short.


A hormone circuit from fat to hippocampus drives a novel, druggable anxiety pathway

Vaccination remains one of the most effective strategies of modern medicine in controlling infectious disease outbreaks. However, numerous case reports have described ocular adverse events following administration of COVID-19, influenza, and herpes zoster vaccines. These manifestations range from mild inflammation to vision-threatening complications, including Graves’ orbitopathy, uveitis, optic neuropathies, acute retinal necrosis, retinal vascular occlusions, corneal graft rejection, and cranial nerve palsies. This systematic review was conducted according to PRISMA 2020 guidelines and included 143 studies retrieved from PubMed in February 2025. Articles were screened and categorized by anatomical location and type of ocular manifestation. Many cases resolved with corticosteroids, antivirals, or conservative management; however, a subset of patients experienced persistent vision loss, structural damage, or recurrence. While most cases showed a temporal association rather than definitive causality, proposed mechanisms include molecular mimicry, bystander T-cell activation, and dysregulated cytokine responses in genetically predisposed individuals. Although rare, clinicians should remain aware of these pos-sible adverse effects and monitor high-risk patients accordingly.

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Machine Learning-Guided Design of Next-Generation Triple Agonist Peptide Therapeutics for Metabolic Disease

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