Faculty Bibliography

BACKGROUND/UNASSIGNED:This study is part of the Undiagnosed Diseases Network (UDN). The UDN is designed to improve diagnostic evaluation for patients who have defied diagnosis as well as to identify the underlying mechanism of disease. We explored recommendations made as part of the UDN evaluation, the number and type of specialists involved in that evaluation, and factors related to changes in care following the UDN visit. We used two datasets: visit wrap-up documents and post-evaluation surveys. We created distinct statistical models for each dataset to further understand the patient experience after a multidisciplinary rare disease visit. RESULTS/UNASSIGNED:Across datasets, the most common primary symptom category was neurology. The mean number of evaluations per participant was 3.8 with the most common being Genetics. The mean number of recommendations per participant was 4.9; 81.5 % had ≥ 1 recommendation. The most common recommendation was referral to a medical provider. Having a diagnosis within 3 months of the UDN visit was associated with more evaluations, but fewer recommendations. CONCLUSION/UNASSIGNED:UDN visits typically involve evaluations by multiple specialists, potentially resulting in recommendations for downstream care. In the survey sample, over half the participants cited their intention to follow the recommendations made. Maximizing communication about ongoing care management following the UDN visit may also optimize care. Future research can explore how and why such characteristics matter.

Zoonotic influenza viruses, including highly pathogenic avian influenza and swine-origin variants, continue to cause sporadic human infections with, in some cases, high case fatality rates and potential for sustained human-to-human transmission. The COVID-19 pandemic underscored both the possibilities of rapid vaccine innovation and the persistent challenges in equitable access and public trust. This paper synthesizes the vaccine-related priorities from the 2024 update of the World Health Organization Public Health Research Agenda for Influenza, integrating evidence from systematic literature reviews commissioned, expert consultations, and analysis of lessons learned from recent health emergencies, to outline a research and policy roadmap for zoonotic and pandemic influenza vaccine preparedness. Key research priorities identified include development of broadly protective animal and human vaccines; improved understanding of correlates of protection; rapid and scalable manufacturing platforms; predictive modelling for strain selection; and targeted communication strategies to strengthen uptake. Experts have considered that implementing these priorities will require One Health integration, sustained investment, harmonized regulatory frameworks, and proactive community engagement to ensure that advances in vaccine science translate into timely, equitable public health protection.

BACKGROUND/OBJECTIVES/OBJECTIVE:Persistent pulmonary nodules are at higher risk of developing into lung cancers. Assessing their future cancer risk is essential for successful interception. We evaluated the performance of two risk prediction models for persistent nodules in hospital-based cohorts: the Brock model, based on clinical and radiological characteristics, and the Sybil model, a novel deep learning model for lung cancer risk prediction. METHODS:= 301) cohorts. We analyzed the correlations between demographic factors, nodule characteristics, and Brock scores and assessed the performance of both models. We also built machine learning models to refine the risk assessment for our cohort. RESULTS:< 0.001). Family history, nodule size ≥10 mm, part-solid nodule types, and spiculation were associated with the risks of lung cancer. The Brock model had an AUC of 0.679, and Sybil's AUC was 0.678. We tested five machine learning models, and the logistic regression model achieved the highest AUC at 0.729. CONCLUSIONS:For patients with persistent pulmonary nodules in real-world cancer hospital-based cohorts, both the Brock and Sybil models had values and limitations for lung cancer risk prediction. Optimizing predictive models in this population is crucial for improving early lung cancer detection and interception.

PURPOSE/OBJECTIVE:Lisfranc injuries present diagnostic and therapeutic challenges, particularly in elite athletes. The 2024 International Foot and Ankle Sports Consensus (IFASC) conducted an expert consensus and systematic review to establish evidence-based guidelines for the identification, classification and nonoperative management of these injuries in high-performance athletes. METHODS:A modified Delphi process involving 32 international orthopaedic foot and ankle surgeons was conducted through four iterative survey rounds. Consensus thresholds were general (75%-85%), strong (86%-99%) and unanimous (100%). A concurrent systematic review was performed, encompassing clinical studies reporting outcomes for bony and ligament Lisfranc injuries in athletes. RESULTS:Seven consensus statements were unanimous, and six were strong. Diagnostic agreement included: (1) mechanism of injury via axial compression or twisting through a plantarflexed foot; (2) midfoot tenderness, pain with squeeze test and inability to bear weight; (3) bilateral weight-bearing radiographs for initial imaging and (4) computed tomography (CT) or magnetic resonance imaging (MRI) for low-grade instability. Experts unanimously agreed that stable, nondisplaced injuries with intact ligaments on MRI may be managed nonoperatively with close monitoring. Systematic review findings demonstrated that ligament injuries predominated in male athletes, with 96.8% returning to sport at 2.8 versus 4.5 months for bony injuries. CONCLUSION/CONCLUSIONS:Lisfranc injuries in elite athletes remain challenging to diagnose and manage due to low-grade injury presentations and high return-to-play demands. This consensus and systematic review establish clear diagnostic and nonoperative treatment guidelines, emphasizing the importance of mechanism-based suspicion, thorough physical examination and early weight-bearing imaging. Stable, nondisplaced ligament injuries without significant MRI findings can be treated nonoperatively, with most athletes safely returning to sport within 6-10 weeks and minimal complications. In contrast, unstable or displaced injuries continue to require surgical fixation to restore alignment and prevent long-term dysfunction. Collectively, these findings provide a standardized framework that supports accurate diagnosis, evidence-based decision-making and efficient recovery in athletes with Lisfranc injuries. LEVEL OF EVIDENCE/METHODS:Level V.

Despite the emerging public health concern related to the use of electronic cigarette vapors (ECV), its impact on lung cancer is poorly understood. We assessed the effect of ECV on lung tumorigenesis in a mouse model of lung adenocarcinoma. Mice were exposed to either room air, combustible cigarette smoke (CCS), or ECV 2 hours daily for 8 weeks at which lung samples were harvested and studied for different outcomes. We found that CCS, but not ECV, led to a significant increase in tumor burden. Immunophenotyping of both CCS- and ECV-exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased CD4+ IFNγ+ and CD8+ GZMB+ T cells along with an elevated CD4+ FOXP3+ regulatory T cells. However, differential changes in myeloid cells were observed between CCS and ECV-exposed lungs. A microbiome profiling of matched stool and lung samples showed differences in the relative abundance of lung Pseudomonadotas, while gut Bacillota, particularly Turicibacter, and Ileibacterium were increased by CCS and ECV. We conclude that both CCS and ECV exposure under the applied regimen lead to a protumor immune suppressive lung microenvironment although with different magnitudes and slightly different phenotypes that might explain their differential effects on tumor burden warranting further studies.

INTRODUCTION/UNASSIGNED:K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. One of the lynchpins of chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3). METHODS/UNASSIGNED:mutant lung cancer mouse model (CC-LR). RESULTS/UNASSIGNED:. DISCUSSION/UNASSIGNED:Our results highlight the importance of STAT3 in driving early tumorigenesis and offer a preventative treatment window for high-risk individuals and patients with early-stage KM-LUAD.

While studies have documented neural correlates of language delay in toddlers with developmental conditions, those at genetic risk for language delay, and those born premature, no studies have examined neural correlates in toddlers exhibiting early language delay without known etiology. This study examines brain morphometry in toddlers with and without early language delay. To do so, we collected magnetic resonance imaging on toddlers with language delay (LD; n=7, M_age=19.67 months, 3 female, 2 Hispanic, 4 non-caucasian) and a typically developing (TD; n=17, M_age=22.73 months, 8 female, 2 Hispanic, 3 non-caucasian) comparison group. Exploratory analyses examined group differences in total brain volume, cortical thickness, and cortical surface area using both a whole-brain and region of interest (Broca's and Wernicke's areas) approach. Results showed no gross brain anatomical differences between groups. However, there were group differences in cortical surface area in the temporal cortex (including Wernicke's area and left middle temporal gyrus, hedges' g= -.35) and Broca's area thickness. Results are reported using multiple analytic methods, age matching, and exclusion of children later diagnosed with autism. While this exploratory study has a limited sample size, it provides novel findings that can be utilized to guide hypothesis-driven imaging studies on toddler language delay.