Digital Commons Network^™

Detection Of Cancers Three Years Prior To Diagnosis Using Plasma Cell-Free Dna, Yuxuan Wang, Corinne E Joshu, Samuel D Curtis, Christopher Douville, Vernon A Burk, Meng Ru, Maria Popoli, Janine Ptak, Lisa Dobbyn, Natalie Silliman, Josef Coresh, Eric Boerwinkle, Anna Prizment, Chetan Bettegowda, Kenneth W Kinzler, Nickolas Papadopoulos, Elizabeth A Platz, Bert Vogelstein

Faculty, Staff and Student Publications

To explore how early can cancers be detected prior to clinical signs or symptoms, we assessed prospectively collected serial plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) test. All eight participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six …

The Causal Pivot: A Structural Approach To Genetic Heterogeneity And Variant Discovery In Complex Diseases, Chad A Shaw, C J Williams, Taotao Tan, Daniel Illera, Nicholas Di, Joshua M Shulman, John W Belmont

Center on Aging Staff Publications

We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT’s robust power and …

Implementing A Training Resource For Large-Scale Genomic Data Analysis In The All Of Us Researcher Workbench, Jasmine Baker, Erik Stricker, Julie Coleman, Shamika Ketkar, Taotao Tan, Ashley M Butler, Laterrica Williams, Latanya Hammonds-Odie, Debra Murray, Brendan Lee, Kim C Worley, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

A lack of representation in genomic research and limited access to computational training create barriers for many researchers seeking to analyze large-scale genetic datasets. The All of Us Research Program provides an unprecedented opportunity to address these gaps by offering genomic data from a broad range of participants, but its impact depends on equipping researchers with the necessary skills to use it effectively. The All of Us Biomedical Researcher (BR) Scholars Program at Baylor College of Medicine aims to break down these barriers by providing early-career researchers with hands-on training in computational genomics through the All of Us Evenings with …

Dietary And Consumer Behaviors In Individuals Currently Using Substances: A Cross-Sectional Study Based On Nhanes (2013 - 2018), A Sarah Cohen, Marylou Cardenas-Turanzas, Audrey Lopez, Tiffany Champagne-Langabeer

Faculty, Staff and Student Publications

Background: Substance use disorders (SUD) are associated with metabolic dysregulation and nutritional deficiencies. Studies show that incorporating nutrition interventions into treatment may improve physical and psychological health. This study sought to explore dietary and consumer behavior in individuals currently using substances.

Methods: Data from the 2013 - 2018 National Health and Nutrition Examination Survey were used for this cross-sectional study. Individuals 18 - 69 who were currently using marijuana, cocaine, heroin, methamphetamines, or injected unprescribed drugs were compared with individuals not using substances. Dietary and consumer behavior, including alcohol consumption was assessed. Analyses were performed using Stata I/C version 15. …

An Allele-Agnostic Mutant-Kras Inhibitor Suppresses Tumor Maintenance Signals And Reprograms Tumor Immunity In Pancreatic Cancer, Kathleen M Mcandrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra

Faculty, Staff and Student Publications

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse …

An Isoform-Specific Runx1c-Btg2 Axis Governs Aml Quiescence And Chemoresistance, Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl Mckenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang

Faculty, Staff and Student Publications

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. …

Nebulization Of An Mrna-Encoded Monoclonal Antibody For Passive Immunization Of Foals Against Rhodococcus Equi, Rebecca M Legere, Jeannine A Ott, Cristina Poveda, Daryll Vanover, Karin E R Borba, Jae Yeon Joo, Cameron L Martin, Bibiana P Da Silveira, Jocelyne M Bray, Kerstin Landrock, Gus A Wright, J Chistensen Blazier, Andrew E Hillhouse, Ashley L Benham-Duret, Brandon Mistretta, Rafaela L Klein, Sarah M Thompson, Amelia R Woolums, Michael F Criscitiello, Luc R Berghman, Angela I Bordin, Philip J Santangelo, Jeroen Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence-associated protein A (VapA) directly into the lungs. VapA-specific memory B cells from an immunized horse were used to identify and select the sequence for an equine immunoglobulin (Ig)G1 mAb. In vitro-transcribed mRNA encoding this sequence expressed …

Amoxicillin Vs Ceftriaxone To Treat Pneumonia Caused By Amoxicillin-Non-Susceptible Streptococcus Pneumoniae, Daniel M Musher

Faculty, Staff and Students Publications

Although the article by J Càmara, I Grau, A González-Díaz, N Santos, et al. (Antimicrob Agents Chemother 69:e00237-25, 2025, https://doi.org/10.1128/aac.00237-25) suggests that ceftriaxone is greatly superior to amoxicillin in treating pneumonia due to pneumococci with an MIC > 2 mg/L, much of the difference in efficacy of the two drugs may have been due to dosage, route, and times of administration of the amoxicillin.

Persistent Na+ Current Couples Spreading Depolarization To Seizures In Scn8a Gain-Of-Function Mice, Isamu Aiba, Yao Ning, Jeffrey L Noebels

Faculty, Staff and Students Publications

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. Although SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (IKM) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure–SD complexes in the awake mouse cortex.

Here we find that enhanced persistent Na+ current attributable to gain-of-function mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic direct-current (DC)-band EEG recording detected spontaneous bilateral seizure–SD complexes accompanied by seizures with …

Gellan Gum Formulations Containing Natural Polyphenolic Compounds To Treat Oral Candidiasis, Narchonai Ganesan, Lewis Oscar Felix, Biswajit Mishra, Liyang Zhang, Charilaos Dellis, Fadi Shehadeh, Danielle Wu, Lissette A Cruz, R M Arce, Eleftherios Mylonakis

Faculty, Staff and Student Publications

Oral candidiasis (OC) is caused by Candida albicans, targeting immunocompromised individuals and developing drug resistance, highlighting the need for advanced therapeutics. Polyphenols such as caffeic acid phenethyl ester (CAPE) and ellagic acid (EA) display antifungal and immune-modulating properties. Incorporating CAPE and EA in gellan gum (GG) formulation enhances their applicability and effectiveness against OC. We developed GG-based formulations loaded with CAPE (1,000 µg/mL), EA (1,000 µg/mL), or CAPE + EA (1,000 µg/mL each) against C. albicans. GG formulations containing gellan (0.6% and 1.0%), genipin (5 mM), polyethylene glycol 400 (0.5%), and sorbitan monooleate 80 (0.5%) demonstrated enhanced release …

Transcutaneous Spinal Stimulation Paired With Visual Feedback Facilitates Retention Of Improved Weight Transfer Toward The Affected Side In People Post-Stroke, Hyunje Park, Beom-Chan Lee, Dimitry Sayenko, Sheng Li, Seoung Hoon Park

The Brown Foundation: Institute of Molecular Medicine

Background: Many individuals with hemiparesis after stroke are reluctant to transfer their body weight toward the affected side and rely more heavily on the unaffected leg while walking. Although visual feedback (VF) has been utilized to improve their weight transfer during walking, the effects of transcutaneous spinal stimulation (TSS) paired with VF during locomotor training in people post-stroke remain largely unexplored. The purpose of this study, therefore, was to determine whether phasic TSS paired with VF regarding weight shifting to the affected leg during treadmill walking would enhance weight transfer toward the affected side.

Methods: Eleven individuals post-stroke participated in …

Scenario Projections Of Covid-19 Burden In The Us, 2024-2025, Sara L Loo, Sung-Mok Jung, Lucie Contamin, Emily Howerton, Samantha J Bents, Harry Hochheiser, Michael C Runge, Claire P Smith, Erica C Carcelén, Katie Yan, Joseph C Lemaitre, Emily Przykucki, Clifton D Mckee, Koji Sato, Allison L Hill, Matteo Chinazzi, Jessica T Davis, Clara Bay, Alessandro Vespignani, Shi Chen, Rajib Paul, Daniel Janies, Jean-Claude Thill, Sean M Moore, T Alex Perkins, Ajitesh Srivastava, Majd Al Aawar, Kaiming Bi, Shraddha Ramdas Bandekar, Anass Bouchnita, Spencer J Fox, Lauren Ancel Meyers, Przemyslaw Porebski, Srinivasan Venkatramanan, Bryan Lewis, Jiangzhuo Chen, Madhav Marathe, Michal Ben-Nun, James Turtle, Pete Riley, Katriona Shea, Cécile Viboud, Justin Lessler, Shaun Truelove

Faculty, Staff and Student Publications

Importance: COVID-19 remains a disease with high burden in the US, prompting continued debate about optimal targets for annual vaccination.

Objective: To project COVID-19 burden in the US for April 2024 to April 2025 under 6 scenarios of immune escape (20% and 50% per year) and levels of vaccine recommendation (no recommendation, vaccination for individuals at high risk only, vaccination for all eligible groups) and to assess the potential benefit of vaccine recommendations in reducing disease burden.

Design, setting, and participants: For this decision analytical model, the US Scenario Modeling Hub, a collaborative modeling effort, convened 9 teams to provide …

Optimal Medical Care And Coronary Flow Capacity-Guided Myocardial Revascularization Vs Usual Care For Chronic Coronary Artery Disease: The Century Trial, K Lance Gould, Nils P Johnson, Amanda E Roby, Richard Kirkeeide, Mary Haynie, Tung Nguyen, Linh Bui, Monica B Patel, Danai Kitkungvan, Patricia Mendoza, Dejian Lai, Ruosha Li, Stefano Sdringola, David Mcpherson, Jagat Narula

Faculty, Staff and Student Publications

Background and aims: The randomized CENTURY trial tested the hypothesis that a comprehensive strategy integrating intense lifestyle modification and aggressive medical management to goals with revascularization reserved for severely reduced coronary flow capacity (CFC) by positron emission tomography (PET) would reduce risk factors, subsequent revascularization, death and myocardial infarction (MI) compared with standard of care in chronic stable coronary artery disease (CAD).

Methods: Participants were randomly assigned to standard or comprehensive care groups. Rest-stress PET quantified CFC for physiological CAD severity at baseline, 2, 5, and up to 11 years. The comprehensive care group reviewed PET results with frequent clinic …

Targeting Aldh16a1 Mediated Thioredoxin Lysosomal Degradation To Enhance Ferroptosis Susceptibility In Smarca4-Deficient Nsclc, Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan

Faculty, Staff and Student Publications

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that …

Inhibition Of Mcl-1 And Mek Overcomes Mek Inhibitor Resistance In Triple-Negative And Inflammatory Breast Cancers, Mohd Mughees, Moises Tacam, Alex W Tan, Mary Kathryn Pitner, Lakesla R Iles, Xiaoding Hu, Emilly S Villodre, Bisrat G Debeb, Takahiro Kogawa, Bora Lim, Rachel M Layman, Wendy A Woodward, Naoto T Ueno, Debu Tripathy, Savitri Krishnamurthy, Yuan Qi, Lajos Pusztai, Jian Wang, Varsha Gandhi, Geoffrey Bartholomeusz, Chandra Bartholomeusz

Faculty, Staff and Student Publications

The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that the MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and …

Trends In Radiation Use From 2004 To 2020 Among Adolescents And Young Adults With Hodgkin Lymphoma, Kelsey L Corrigan, Amy M Berkman, Jillian Gunther, Clark R Andersen, Susan Wu, Amber Gibson, Branko Cuglievan, Miriam B Garcia, Gohar Manzar, Penny Fang, Brian De, Sairah Ahmed, Cesar Nunez, Michelle A T Hildebrandt, David C Mccall, Susan K Parsons, Michael E Roth

Faculty, Staff and Student Publications

Background: Hodgkin lymphoma has excellent survival rates in adolescents and young adults (AYA, diagnosed between ages 15 and 39 years). However, survivors are at risk of treatment-related late effects. Whereas radiotherapy (RT) de-escalation/omission has emerged as an approach to minimize late effects, no prior studies have evaluated RT use over time in AYAs with Hodgkin lymphoma.

Methods: Using the National Cancer Database, we identified 40,717 AYAs diagnosed with Hodgkin lymphoma between 2004 and 2020. Differences in sociodemographic and clinical variables were assessed using a two-sample two-sided t test or χ2 test. RT use was summarized per year by frequency with …

Efficacy Of Atr Kinase Inhibitor Elimusertib Monotherapy Or Combination In Tumors With Dna Damage Response Pathway And Other Genomic Alterations, Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P Diperi, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam

Faculty, Staff and Student Publications

The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia-mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR), ≥30% decrease in TV; ≥20% increase in TV, progressive disease; and non-PR/progressive disease, stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. …

Chp1 Promotes Lipid Droplet Growth And Regulates The Localization Of Key Enzymes For Triacylglycerol Synthesis, Guang Yang, Ximing Du, Dougall Norris, Armella Zadoorian, Yuyuan Zheng, Mingming Gao, Andrew J Brown, Shane T Grey, Chun Zhou, Hongyuan Yang

Faculty, Staff and Student Publications

The glycerol-3-phosphate (G-3-P) pathway is central to the synthesis of triacylglycerols (TAGs) and glycerophospholipids, essential for membrane biogenesis and lipid storage. The first and rate-limiting step in this pathway is catalyzed by glycerol-3-phosphate acyltransferases (GPATs), with microsomal GPAT3 and GPAT4 being evolutionarily conserved and predominant in most tissues. While previous studies have implicated Calcineurin B homologous protein 1 (CHP1) as a cofactor for GPAT4, the broader role of CHP1 in regulating microsomal GPATs and TAG biosynthesis remains unclear. Here, we demonstrate that CHP1 is a critical regulator of both GPAT3 and GPAT4, essential for their stability, enzymatic activity, and lipid …

Functional Connectivity Predicting Transdiagnostic Treatment Outcomes In Internalizing Psychopathologies, Kai Zhang, Heide Klumpp, Jagan Jimmy, K Luan Phan, Mohammed R Milad, Zhenfu Wen

Faculty, Staff and Student Publications

Importance: Predicting treatment outcomes for internalizing psychopathologies (IPs), such as depression and anxiety, holds promise for advancing precision medicine. The extent to which whole-brain functional connectivity (FC) can predict treatment responses for patients with IPs across different therapeutic modalities remains unclear.

Objective: To examine whether pretreatment FC patterns predict multidimensional treatment outcomes in patients with IPs and whether predictive performance generalizes across diagnoses and treatment modalities.

Design, setting, and participants: This prognostic study analyzed baseline neuroimaging and clinical data from patients with IPs enrolled in 1 of 2 randomized clinical trials (conducted from December 2013 to February 2018 and September …

Identification Of An Rsph4a Founder Variant And Newborn Screening For Primary Ciliary Dyskinesia, Wilfredo De Jesús-Rojas, Katherine P Guerra-Torres, Alondra J Rosado-Ayala, Edwin L Acevedo-Soto, Marcos J Ramos-Benitez, Ricardo A Mosquera

Faculty, Staff and Student Publications

This cross-sectional study estimates the prevalence of an RSPH4A variant identified in Puerto Rico in an effort to evaluate the feasibility of targeted newborn screening for primary ciliary dyskinesia (PCD).

Barriers And Facilitators To Surgical Trainee Psychological Safety, Jennifer H Chen, Alyssa A Pradarelli, Julie Evans, Niki Matusko, Norah N Naughton, Roy Phitayakorn, John T Mullen, Lily Chang, Melissa Johnson, Thavam Thambi-Pillai, Jon Ryckman, Melissa Alvarez-Downing, Nell Maloney Patel, Sebastiano Cassaro, Felicia Ivascu, David T Hughes, Gurjit Sandhu

Faculty, Staff and Students Publications

Importance: Although psychological safety has been shown to be imperative for effective learning, specific factors associated with its presence in surgical training have not been well characterized.

Objective: To identify barriers and facilitators to psychological safety for surgical trainees in the clinical learning environment.

Design, setting, and participants: This qualitative study was conducted from February 20 to May 2, 2024, among 25 trainees in general surgery and 3 surgical subspecialty programs at 9 teaching hospitals-4 university-based, 3 community-based, and 2 community-based, university-affiliated hospitals.

Exposure: Participation in surgical training.

Main outcomes and measures: Participants were asked to share their perspectives and …

Commensal Colonization Of Candida Albicans In The Mouse Gastrointestinal Tract Is Mediated Via Expression Of Candidalysin And Adhesins, Kelsey E Mauk, Pedro Miramón, Michael C Lorenz, Léa Lortal, Julian R Naglik, Bernhard Hube, Lynn Bimler, Farrah Kheradmand, David B Corry

Faculty, Staff and Students Publications

The ubiquitous fungal pathogen Candida albicans has the potential to either asymptomatically colonize the gastrointestinal (GI) tract or become an invasive pathogen through mechanisms that remain incompletely understood. Here we explored the fungal, host, and environmental factors that influence the ability of C. albicans to colonize the mouse GI tract using a representative clinical strain, CLCA10. After a single gavage challenge (5 × 106 CFU C. albicans), specific pathogen-free (SPF) mice remained colonized with C. albicans strain CLCA10, but not other Candida species, for at least 58 days with the fungus confined largely to the gut luminal …

Encapsulation Of Disease-Causing And Commensal Mitis Group Non-Pneumococcal Streptococci, Daniel M Musher, Mathias Müsken, M John Hicks, Lesley Mcgee, Bernard Beall

Faculty, Staff and Students Publications

Background: Mitis group non-pneumococcal streptococci (MGNPS), specifically Streptococcus mitis, Streptococcus infantis and Streptococcus oralis, have recently been shown to cause pneumonia and/or bacteremia. These organisms often have capsular (cps) operons resembling those in pneumococci, and some express cps-generated polysaccharides that antigenically cross-react with pneumococcal capsular serotypes. But, to date, a series of MGNPS isolates has not been studied by electron microscopy (EM) for the presence of a capsule.

Methods: We studied 21 MGNPS; 11 were isolated from sputum and determined to have caused pneumonia, 3 were isolated from blood, and 7 were commensal isolates cultured …

Genome-Wide Insights Into The Genes And Pathways Shaping Human Foveal Development: Redefining The Genetic Landscape Of Foveal Hypoplasia, Callum Hunt, Ha-Jun Yoon, Alvin Lirio, Kayesha Coley, Jun Wang, Nick Shrine, Jianming Shao, Gail D E Maconachie, Zhanhan Tu, Jonathan H Zippin, Pirro G Hysi, Christopher J Hammond, Omar A Mahroo, Mariya Moosajee, Michel Michaelides, Andrew R Webster, Ala Moshiri, Rui Chen, Martin D Tobin, Chiara Batini, Mervyn G Thomas, Uk Biobank Eye And Vision Consortium

Faculty, Staff and Students Publications

Purpose: To define the genetic architecture of foveal morphology and explore its relevance to foveal hypoplasia (FH), a hallmark of developmental macular disorders.

Methods: We applied deep-learning algorithms to quantify foveal pit depth from central optical coherence tomography (OCT) B-scans in 61,269 UK Biobank participants. A genome-wide association study (GWAS) was conducted using REGENIE, adjusting for age, sex, height, and ancestry. Rare coding variants (frequency < 1%) were analyzed in an exome-wide rare-variant association study (RVAS). Candidate genes were prioritized using integrative mapping; pathway, cross-ancestry, and genetic-correlation analyses were exploratory.

Results: GWAS identified 126 sentinel variants, including 47 novel associations. Integrative mapping prioritized 129 putative causal genes, with 64 not previously implicated in foveal biology. Enriched pathways included retinoic acid metabolism (e.g., CYP26A1), photoreceptor differentiation …

Ontology Accelerates Few-Shot Learning Capability Of Large Language Model: A Study In Extraction Of Drug Efficacy In A Rare Pediatric Epilepsy, Pedram Golnari, Katrina Prantzalos, Veronica Hood, Mary Anne Meskis, Lori L Isom, Karen Wilcox, Jack M Parent, Dennis Lal, Samden D Lhatoo, Howard P Goodkin, Elaine C Wirrell, Kelly G Knupp, Manisha Patel, Jeffrey A Loeb, Joseph E Sullivan, Lauren Harte-Hargrove, Brandy E Fureman, Jeffrey Buchhalter, Satya S Sahoo

Faculty, Staff and Student Publications

OBJECTIVE: Dravet Syndrome (DS) is a developmental and epileptic encephalopathy that is characterized by severe, prolonged motor seizures and high resistance to multiple antiseizure medications (ASMs) with multiple comorbidities. Evaluating the efficacy of new drugs in DS preclinical models and mapping them to human phenotypes of DS through analysis of published literature is an important goal for improving outcomes in this rare pediatric epilepsy.

MATERIALS AND METHODS: Large language models (LLM) have demonstrated great promise in parsing published literature; however, the performance of LLMs falls short in medical applications. In this study, we investigate the effectiveness of domain ontology developed …

Looking Beyond Hospital Discharge: One-Year Mortality Following Tracheostomy Creation In Traumatically Injured Older Adults, Heather R Kregel, Jan-Michael Van Gent, Fatimah Sunez, Michael W Wandling, Krislynn M Mueck, Bryan A Cotton, David E Meyer, Laura J Moore, Lillian S Kao, Thaddeus J Puzio

Faculty, Staff and Student Publications

Introduction: We aimed to evaluate long-term outcomes following tracheostomy in older trauma patients and hypothesized that 1-year survival decreases with older age.

Methods: This was a descriptive analysis of intensive care unit patients ≥65 y old who underwent tracheostomy from 2015 to 2020. The National Death Index was accessed to determine time from tracheostomy creation to death. Groups were categorized by age. The primary outcome was 1-year mortality. Survival by age strata was analyzed using the Kaplan-Meier method.

Results: Of 205 eligible patients, 125 (61%) were 65-74, 68 (33%) were 75-84, and 12 (6%) were >85 y old. Median injury …

Exploring Boundaries With Food, Substances, And People In Substance Use Recovery: A Qualitative Analysis, Tiffany Champagne-Langabeer, Audrey Sarah Cohen, Kriti Shrestha, Jie Zhu, Audrey Lopez, Alisha Campbell, Christine Bakos-Block

Faculty, Staff and Student Publications

Background: In the United States, over 47 million youth and adults live with a substance use disorder (SUD). These individuals are frequently malnourished and have metabolic dysregulation as a result. Nutrition interventions incorporating a mindfulness-based approach help recovery efforts that are physical and mental.

Objective: The objective of this study was to explore and analyze the perspectives and experiences of individuals with SUD regarding emotional regulation and nutrition. The study used a mixed methods approach to generate insights for improving recovery support and developing future interventions.

Design: In 2024, an exploratory mixed methods study was conducted based on a large …

Synthetic Zfta Fusions Pinpoint Disordered Protein Domain Acquisition As A Mechanism Of Brain Tumorigenesis, A Arabzade, H K Shirnekhi, S Varadharajan, S M Ippagunta, A H Phillips, N Laboe, D W Baggett, Wahiduzzaman, M Jo, T Zheng, R Pathak, D Gee, D Bhimsaria, H Wu, X Gao, J Liu, E Emanus, A Bland, A Kardian, A Hancock, B Holcomb, T Wright, T Bugbee, H Sun, M Zhai, E Caesar, M Park, S Tripathi, A Shirinifard, K Lowe, A Khalighifar, R A Petersen, S King, D Stabley, A Pitre, G E Campbell, C-G Park, W T Freyaldenhoven, B Chandra, Y Xia, E Bonten, A Achari, S Kandikonda, A Carisey, S B Pounds, J Xu, D W Ellison, B Deneen, K C Bertrand, R W Kriwacki, S C Mack

Children’s Nutrition Research Center Staff Publications

Over 95% of ependymomas that arise in the cortex are driven by a gene fusion involving the zinc finger translocation-associated (ZFTA) protein. Here, using super-resolution and lattice light-sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA-RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis studies of ZR reveal a key intrinsically disordered region (IDR) in RELA that governs condensate formation. Condensate-modulating IDR mutations introduced into ZR impaired its genomic occupancy at oncogenic loci and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic …

Randomized Trial: Peppermint Oil (Menthol) Pharmacokinetics In Children And Effects On Gut Motility In Children With Functional Abdominal Pain: 540 Mg Vs. 900 Mg Dose Comparison, Robert J Shulman, Bruno P Chumpitazi, Daniel Gonzalez, Uttam Garg, Salma Musaad, Jiali Wen, Gregory L Kearns

Children’s Nutrition Research Center Staff Publications

Aims: There is a paucity of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of menthol, the active ingredient in peppermint oil (PMO). We studied the PK of menthol (540 and 900 mg) in children and measured their effects on gut transit/contractility.

Methods: Children 7-12 years of age with functional abdominal pain underwent wireless motility capsule (WMC) testing. One week later, they were randomized to 540 mg or 900 mg of oral enteric-coated PMO. Blood was sampled over 24 h to determine menthol PK. The WMC test was repeated while they took their respective dose (180 mg thrice or 180 …

Replication Of Blood Dna Methylomic Signatures Associated With Cerebrospinal Fluid Levels Of Ykl-40 And Nfl Biomarkers, Timo Kaleck, Rafael Campos-Martin, Amanda Cano, Maria Victoria Fernández, Pamela Martino-Adami, Luca Kleineidam, Victor M Andrade Fuentes, Kumar P Tripathi, Kayenat Parveen, Raquel Puerta, Itziar De Rojas, Kishore A Ravichandran, Oliver Peters, Julian Hellmann-Regen, Josef Priller, Maria Gemenetzi, Anja Schneider, Jens Wiltfang, Emrah Düzel, Katharina Buerger, Robert Perneczky, Stefan Teipel, Christoph Laske, Frederic Brosseron, Marta Marquié, Daniel La Van Den Hove, Mercè Boada, Michael T Heneka, Michael Wagner, Natalie Marchant, Jean-Charles Lambert, Ruth Frikke-Schmidt, Frank Jessen, Agustín Ruiz, Alfredo Ramirez

Faculty, Staff and Student Publications

No abstract provided.