Digital Commons Network^™

Cd8 Trm-Like T Cells Expressing Perforin And Ifn-Γ Define A Pediatric Activated T-Cell Acute Liver Failure Endotype., Tamir Diamond, Catherine A. Chapin, Caroline J. Diorio, Sarah Mccuaig, Michelle Lau, Niansheng Chu, Nora M. Gibson, Portia A. Kreiger, Simon Horslen, Kathleen M. Loomes, Anna M. Banc-Husu, Jaime Chu, M Kyle Jensen, Daniel H. Leung, Amrita Narang, Beth A. Carter, Scott Elisofon, Ryan T. Fischer, Steven J. Lobritto, Mike Leonis, Anna L. Peters, Norberto Rodriguez-Baez, Rene Romero, Philip Rosenthal, David Rudnick, James Squires, Shikha Sundaram, Kyla M. Tolliver, Pamela Valentino, Valerie Durkalski, Estella M. Alonso, Edward M. Behrens

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Activated T-cell pediatric acute liver failure (TC-PALF) is the most common cause of non-acetaminophen PALF, with poor transplant-free survival. Livers in TC-PALF are infiltrated by effector cytotoxic T lymphocytes with markers of tissue-resident memory function (CD8 Trm) and an interferon gamma (IFNγ) transcriptional signature. The PALF-Immune Response Network (PALF-IRN) and the prospective TReatment for ImmUne-Mediated PathopHysiology (TRIUMPH) clinical trial (NCT04862221) aim to characterize the TC-PALF immune pathology and utility of T-cell directed therapy to improve transplant-free survival.

METHODS: TRIUMPH patients with TC-PALF were compared with healthy children and disease controls utilizing multiparameter flow cytometry and 3' single-cell RNA sequencing …

Factors Associated With Child Protective Services Referrals In Young Children With Isolated Skull Fractures., Karli Breeden-Carino, Joanne N. Wood, Cindy W. Christian, Tagrid M. Ruiz-Maldonado, Daniel M. Lindberg, Angela Bachim, Lori Frasier, Terra N. Frazier, Nancy S. Harper, Sara E. Kruczek, Farah Brink, Jennifer E. Wolford, Jan Leonard, M Katherine Henry

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Many young children with isolated skull fractures are referred to child protective services (CPS) despite being assessed to have a low likelihood of abuse. We sought to identify factors associated with CPS referrals in this population and to quantify hospital-level variation.

METHODS: We performed a multicenter retrospective cross-sectional study of children < 2 years with skull fractures with or without a small underlying intracranial hemorrhage (ICH) and no additional injuries undergoing a child abuse pediatrics (CAP) subspecialty evaluation. We explored associations between demographic factors, clinical characteristics, psychosocial risk factors, and hospital site with CPS referral status. We performed multivariable logistic regression, adjusting for transfer status and all significant covariates from unadjusted analyses. We utilized marginal standardization to calculate the estimated probability of CPS referrals at each site, adjusting for all factors in the final model.

RESULTS: Of 528 children, 303 (57.4%) were referred to CPS, with 86.5% referred before CAP consultation. In multivariable logistic regression, presence of psychosocial risk factors (OR 4.00; 95% CI 2.25, 7.11), in-person CAP consult (OR 3.93; 1.61, 9.62), inflicted or no trauma history provided (OR 6.15; 3.30, 11.45), …

Understanding Atomoxetine Exposure Variability In Children And Adolescents With Adhd Through Population Pharmacokinetics., Kevin V. Tobin, Addison M. Pritchett Ms, J Steven Leeder, Joga Gobburu, Allison Dunn

Manuscripts, Articles, Book Chapters and Other Papers

Atomoxetine, a selective norepinephrine reuptake inhibitor, is a nonstimulant alternative to treat attention-deficit/hyperactivity disorder in children and adolescents. Atomoxetine exposure is highly variable due to cytochrome P450 polymorphism; however, the impact of these genetic variations has not been adequately characterized in the pediatric population. A population pharmacokinetic (PK) model was developed to evaluate steady-state atomoxetine exposures after oral administration in a large, heterogeneous population of children and adolescents with different metabolic phenotypes. Due to the highly variable and complex absorption between subjects and occasions, a two-stage approach was implemented, treating each participant/occasion as a separate individual. First, the individual atomoxetine …

Phenome-Wide Analysis Of Copy Number Variants In 470,727 Uk Biobank Genomes, Xueqing Zoe Zou, Fengyuan Hu, Haiyi Lou, Oliver S Burren, Xiaoyin Li, Karyn Megy, Eleanor Wheeler, Qiang Wu, Santosh S Atanur, Marcin Karpinski, Douglas Loesch, Zammy Fairhurst-Hunter, Sri V V Deevi, Erin Oerton, Sean Wen, Xiao Jiang, Cecilia Salvoro, Jonathan Mitchell, Abhishek Nag, Ben Hollis, Amanda O'Neill, Jen Harrow, Stewart Macarthur, Sebastian Wasilewski, Sean O'Dell, Lifeng Tian, Katherine R Smith, Guillermo Del Angel, Margarete Fabre, Ryan S Dhindsa, Quanli Wang, Slavé Petrovski, Keren Carss

Duncan NRI Faculty and Staff Publications

Copy number variants (CNVs) are key drivers of human diversity and disease risk1. Here we evaluate the role of CNVs across a broad range of human phenotypes and diseases by analysing CNVs from 470,727 UK Biobank whole-genome sequences and conducting a variant- and gene-level phenome-wide association study (PheWAS) with 2,941 plasma protein abundance measurements, 13,336 binary clinical phenotypes and 1,911 quantitative traits. Proteomic analyses validated functional associations of CNVs with nearby genes (cis-protein quantitative trait loci; cis-pQTLs)—with deletions and duplications typically associated with reduced and increased protein levels, respectively—and uncovered previously unknown protein–protein interactions …

Dominant Clones Leverage Developmental Epigenomic States To Drive Ependymoma, Alisha S Kardian, Hua Sun, Siri Ippagunta, Nicholas Laboe, Srinidhi Varadharajan, Kwanha Yu, Hsiao-Chi Chen, Erik Emanus, Tuyu Zheng, Riley M Deneen, Jon P Connelly, Yong-Dong Wang, Jiangshan Zhan, Hengxi Liu, Kimberley Lowe, Taylor Bugbee, Rakesh Pathak, Amanda Bland, Sanya Mehta, Sophie Cochiolo, Amir Arabzade, Blake Holcomb, Kaitlin M Budd, Gabriele Kembuan, Tristen Wright, Emma Caesar, Maxwell Park, Amelia Hancock, David Gee, Joel Murdoch, Yi Xiao, Samuel K Mcbrayer, Thomas E Merchant, Jun Qi, Adam D Durbin, Lindsay A Schwarz, Li Wang, Andrew M Donson, Nicholas K Foreman, Sameer Agnihotri, Alfonso Lavado, Suzanne J Baker, David W Ellison, Hyun Kyoung Lee, Shondra M Pruett-Miller, Kelsey C Bertrand, Benjamin Deneen, Stephen C Mack

Faculty, Staff and Students Publications

ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse …

A Comprehensive Review Of Tear Fluid Proteome Alterations In Dry Eye Disease: Insights Into Pathophysiology And Biomarker Potential, Saleh Ahmed, Steven Safille, Victoria Clifton, Shruti Sharma, Cintia S De Paiva, Ashok Sharma

Faculty, Staff and Students Publications

Tear fluid is a highly specialized and dynamic biofluid composed of proteins, lipids, mucins, and electrolytes that is essential for maintaining ocular surface integrity, immune defense, and tear film stability. Growing evidence from tear proteomic studieshas revealed extensive alterations in protein composition in dry eye disease (DED), reflecting a complex interplay between local ocular surface pathology and systemic inflammatory influences. This review summarizes proteomic findings from 50 published studies to identify tear proteins that are consistently upregulated or downregulated in DED and to interpret their biological relevance in the context of ocular surface homeostasis. Across studies, proteins upregulated in DED …

Comprehensive Profiling Of The Human Tear Fluid Mirnome Using Small Rna Sequencing, Garrett Jones, Drew Mayernik, Saleh Ahmed, Eliza Williams, Jeremy Altman, Tae Jin Lee, Amy Estes, Cintia S De Paiva, Pamela Martin, Shruti Sharma, Ashok Sharma

Faculty, Staff and Students Publications

Purpose: To generate a comprehensive profile of microRNAs (miRNAs) present in human tear fluid using next-generation sequencing (NGS), establish a reference miRNome for healthy human tear fluid, and investigate whether miRNA expression varies by sex, race, or age.

Methods: Tear samples were collected from 32 adults using Schirmer strips. RNA was isolated using the miRNeasy Serum/Plasma Kit, and cDNA libraries were prepared using the QIAseq miRNA Library Kit. Barcoded libraries were sequenced on the NovaSeq 6000 platform. Bioinformatic analyses included adapter trimming, alignment to miRBase, normalization with DESeq2, and functional annotation using multiMiR and clusterProfiler. Differential expression analysis was performed …

Rexinoid Net-3ib Promotes Resident Macrophage Gene Expression And Mitigates Desiccation-Induced Ocular Surface Disease, Jehan Alam, Yangluowa Qu, Jianming Shao, Ebru Yaman, Karen Zheng, Hiroki Kakuta, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To evaluate the effects of rexinoid NEt-3IB on desiccating stress-induced dry eye, as well as monocyte/macrophage gene expression and cellular trajectory.

Methods: Eyes were topically treated with rexinoid NEt-3IB (5 µM) or vehicle three times a day for 5 days of desiccating stress-induced dry eye. Single-cell RNA sequencing (RNA-seq) profiled gene expression in conjunctival immune cells. RNA-seq was also used to evaluate gene expression in lipopolysaccharide (LPS)-stimulated, dexamethasone-treated (Dex, 1 µM), or NEt-3IB-treated (1-1000 nM) cultured monocytes. Cellular state trajectory and latent time were inferred with scVelo, and latent-time-associated genes were identified using Monocle 3. Permeability to Oregon Green-labeled …

Development And Internal Validation Of A Pretransplant Biomarker Panel For Mortality Prediction Following Liver Transplant, Guergana G Panayotova, Sopio Simonishvili, Lianhua Jin, Duc T Nguyen, Edward A Graviss, Yong Qin, Anastasia Xynogala, Tumininu Ayorinde, Laurie J Minze, Alexander Lemenze, Krupa R Mysore, Julie M Corkrean, Linda W Moore, Flavio Paterno, Ashish Saharia, Constance M Mobley, Arpit Amin, Mark J Hobeika, Xian C Li, Paul J Gaglio, R Mark Ghobrial, James V Guarrera, Keri E Lunsford

Faculty, Staff and Students Publications

Importance: Current pretransplant clinical scoring systems fail to accurately estimate post-liver transplant (LT) survival, making recipient selection challenging. Persistent immune dysfunction contributes to early LT recipient mortality but is not captured by existing models.

Objective: To identify plasma biomarkers of pretransplant immune dysfunction and to develop a biomarker-based pre-LT risk stratification tool to predict post-LT mortality.

Design, setting, and participants: Prospective biomarker analysis of consecutively enrolled adult LT recipients was conducted. Healthy controls were included for baseline comparison. Patients undergoing LT at Houston Methodist Hospital (October 1, 2013, to December 31, 2017) and Rutgers/University Hospital (January 1, 2019, to March …

The International Pediatric Headache Didactic Series: A Novel Curriculum Innovation, Sara Pavitt, Sruthi Ilangovan, Zoë Allen, Samantha L Irwin, Irene Patniyot

Faculty, Staff and Students Publications

Objectives: The International Pediatric Headache Didactic Series (IPHDS) was developed to provide free, comprehensive pediatric headache education to healthcare professionals worldwide. The objective of this study was to describe the design, implementation, and impact of this prospective educational intervention.

Background: Headache is the most common neurological symptom within the pediatric population. Yet, only nine fellowships are offered in pediatric headache medicine. Limitations in access to education and training are often cited as reasons for diagnostic and management barriers. To address this gap, the IPHDS was established in July 2022.

Methods: IPHDS is a recurring series consisting of 23 biweekly lectures. …

Confessions In Cases Of Child Physical Abuse-A Capnet Study, Margaret R Russell, Antoinette L Laskey, Henry T Puls, Suzanne P Starling, Joanne N Wood, Daniel M Lindberg, Nancy S Harper, Caitlin R Mcnamara, Angela N Bachim, Farah W Brink, Lori D Frasier, James D Anderst, Porcia Vaughn, Kristine A Campbell

Faculty, Staff and Students Publications

Objective: Prior research on confessions of physical abuse (PA) has explored mechanisms of injury. Little is known about conditions supporting a confession of abuse or how confessions may influence case outcomes.

Methods: This cross-sectional study of suspected PA in children aged < 10 years at 10 centers participating in CAPNET, a multicenter child PA research network, included children with in-person Child Abuse Pediatrics (CAP) consultations between February 2021 and December 2022 and excluded children without injury. Our focus was a confession of inflicted injury known to the CAP during clinical involvement. We compared child and clinical characteristics, out-of-home (OOH) placements, and arrests between cases with and without confessions. Multivariable models using generalized estimating equations (GEE) produced adjusted predicted probabilities (APP) clustering by CAPNET site.

Results: Confessions were known to CAPs in 115/4297 (2.7%) cases, with significant site variability. In a multivariable GEE model, confessions were more likely in cases with injuries with high specificity for abuse (APP 6.0% vs 1.6%, P < .001), near-fatality (APP 5.6% vs 2.3%, P < .001), and older children (APP 4.8% vs 2.5%, P = .025). OOH placements and arrests were more common in cases with confessions. CAP awareness of confessions, OOH placements, and arrests did not follow racial or ethnic patterns seen in the US child welfare system. Lower socioeconomic status was associated with OOH placements and arrests but not with CAP awareness of confessions.

Conclusions: Our findings highlight differences in case characteristics and outcomes where a confession is known to the CAP and raise questions about …

Distinct Effects Of Complement C4a And C4b Copy Numbers In Systemic Sclerosis Serological And Clinical Subtypes, Javier Martínez-López, Carlos Rangel-Peláez, Inmaculada Rodriguez-Martin, Alfredo Guillen-Del-Castillo, Carmen P Simeón-Aznar, José L Callejas, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Marta E Alarcon-Riquelme, Lorenzo Beretta, Shervin Assassi, Christopher P Denton, Maureen D Mayes, Javier Martin, Marialbert Acosta-Herrera, Martin Kerick

Faculty, Staff and Student Publications

Objective: Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV-K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes.

Methods: We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA+]; 2,200 anti-topoisomerase I [ATA+]; 577 anti-RNA polymerase [ARA+]; 1,078 triple-negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous …

How I Do It: The Transtracheal Approach For Awake Cricopharyngeal Botulinum Toxin Injection, Andrew Tritter, Alexander Simko, Karim Asi

Faculty, Staff and Student Publications

This transtracheal technique for cricopharyngeal botulinum toxin injection is a safe and effective option for chemodenervation of this muscle in the awake patient. Its advantages include reduced risk of toxin spread to intrinsic laryngeal muscles, the ability to administer higher doses of botulinum toxin, improved access to the entire length of the cricopharyngeus, and avoidance of general anesthesia.

Growth Failure And Early Recurrence In Congenital Diaphragmatic Hernia: An International Cohort Study, Rachel C Bordelon, Kylie I Holden, Charles C Miller, Ashley H Ebanks, Kevin P Lally, Matthew T Harting, Allison L Speer, Representing The Congenital Diaphragmatic Hernia Study Group

Faculty, Staff and Student Publications

Purpose: The primary objective was to determine whether growth failure (GF) is associated with early recurrence in congenital diaphragmatic hernia (CDH). The secondary objective was to characterize the prevalence and severity of GF in CDH survivors.

Background: GF is common among CDH survivors, yet it is unclear how growth challenges affect overall morbidity, including hernia recurrence. CDH-specific nutritional guidelines include high calorie and protein targets during periods of acute illness but may benefit from clarifying the relationship between growth and adverse outcomes in this population.

Methods: This multicenter cohort study retrospectively analyzed prospectively collected data from the CDH Study Group …

Neutrophil-Microglia Interaction Drives Motor Dysfunction In A Neuromyelitis Optica Model Induced By Subarachnoid Aqp4-Igg, Fangfang Qi, Vanda A Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M Bartley, Tingjun Chen, Claudia F Lucchinetti, Long-Jun Wu

Faculty, Staff and Student Publications

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron microscopy-based reconstructions revealed …

Gompertz Growth With A Shared Carrying Capacity Optimally Simulates Primary And Metastatic Tumor Growth Dynamics, Pirmin Schlicke, Preethi Korangath, Xiaoxi Pan, Caner Ercan, Kathleen Gabrielson, Lyndsey Werhane, Yinyin Yuan, Sébastien Benzekry, Robert Ivkov, Heiko Enderling

Faculty, Staff and Student Publications

Background: Cancer is a systemic disease with most deaths attributed to metastatic burden. Primary and metastatic tumors, albeit at different anatomic locations, are interconnected through multiple biological processes. Pre-clinical and clinical observations of growth acceleration of metastases after surgery, or abscopal effects outside the radiation field are widely reported, yet reliably triggering favorable and avoiding unfavorable systemic responses remains an unmet clinical need. Understanding local and systemic tumor interaction dynamics will help guide future treatments.

Methods: We analyze the data of multiple in vivo tumor models. We formalize the systemic interplay of tumors as mathematical differential equation and calibrate parameters …

Structural-Functional Analyses Of The Huntingtin/Hap40 Complex In Drosophila And Humans, Stephen M Farmer, Amanda Solbach, Shiyu Xu, Beatriz Rios, Xin Ye, Amy Gao, Daniela Covarrubias, Yue Yu, Lili Ye, Vicky Chuong, Erin Furr Stimming, Haiqing Zhao, Sheng Zhang

Faculty, Staff and Student Publications

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG expansion in the Huntingtin (HTT) gene. Given its simple genetic cause but complex pathogenic mechanisms, interest in targeting HTT for HD treatment is growing, necessitating a clear understanding of HTT regulation. HTT protein primarily exists in a core complex with HAP40, forming a highly ordered structure with two large globular domains connected by a bridge. We previously demonstrated that HAP40 is conserved in

Pharmvar Genefocus: Nat2-Genetic Variation And Updated Nomenclature., Georgia Papanikolaou, Estella S. Poloni, José A G Agúndez, Raquel L F Teixeira, Erin C. Boone, Adalberto Rezende Santos, Michelle Whirl-Carrillo, Katrin Sangkuhl, Teri E. Klein, Mariam R. Habil, Giannoulis Fakis, Rodney F. Minchin, David W. Hein, Sotiria Boukouvala, Andrea Gaedigk

Manuscripts, Articles, Book Chapters and Other Papers

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human N-acetyltransferase 2 (NAT2) gene. NAT2 metabolizes several clinically used drugs including isoniazid, hydralazine, amifampridine, procainamide, and sulfonamides such as dapsone, and also some highly carcinogenic arylamines. Systematic nomenclature describing NAT2 variation is essential for pharmacogenetic testing, genotype interpretation, and translation to phenotype in research and clinical settings. This GeneFocus provides an overview of NAT2 variation and describes important changes to its star allele-based nomenclature that were made as it was transitioned to PharmVar in March 2024. We also highlight and discuss challenges regarding the characterization of allelic variation …

A Topic Modeling Analysis Of Stigma Dimensions, Social, And Related Behavioral Circumstances In Clinical Notes Among Patients With Hiv, Ziyi Chen, Yiyang Liu, Mattia Prosperi, Krishna Vaddiparti, Robert L Cook, Jiang Bian, Yi Guo, Yonghui Wu

Faculty, Staff and Student Publications

Objective: To characterize stigma dimensions, social, and related behavioral circumstances in people living with HIV (PLWHs) seeking care, using natural language processing methods applied to a large collection of electronic health record (EHR) clinical notes from a large integrated health system in the southeast United States.

Methods: We identified a cohort of PLWHs from the University of Florida (UF) Health Integrated Data Repository and performed topic modeling analysis using Latent Dirichlet Allocation (LDA) to uncover stigma-related dimensions and related social and behavioral contexts. Domain experts created a seed list of HIV-related stigma keywords, then applied a snowball strategy to iteratively …

Neighborhood Physical Disinvestment And Incident Diabetes Between Visits 1 And 2 Of The Hispanic Community Health Study/Study Of Latinos (Hchs/Sol)., Cara M. Smith, Elizabeth W. Spalt, Linda C. Gallo, Jordan A. Carlson, Matthew Allison, Bharat Thyagarajan, Earle C. Chambers, Amber Pirzada, Martha Daviglus, Christina Cordero, Qibin Qi, Elena Austin, Amanda M. Fretts, India Ornelas, Robert Kaplan, Joel D. Kaufman, Stephen J. Mooney

Manuscripts, Articles, Book Chapters and Other Papers

Neighborhood-scale environmental factors, including disinvestment in infrastructure, may impact cardiometabolic disease risk. To our knowledge, no prior studies have investigated the association between neighborhood disinvestment and incident diabetes. We used a virtual street audit of Google Street View Imagery to generate a neighborhood disinvestment score for participants' residential addresses in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). An item response theory model was fit to indicators (litter, graffiti, under-maintained buildings, bars on windows, and abandoned buildings) to form a scale measuring a latent level of disinvestment. Ordinary kriging was used to estimate levels for each residential address within the …

Unraveling The Nexus: Tumor Mutational Burden, Pd-L1 Expression, And Oncogenic Alterations In Non-Small Cell Lung Cancer Cytology Specimens, Min Dai, Francis Anthony San Lucas, Hector Alvarez, Leomar Ballester, Hui Chen, Keyur P Patel, Asif Rashid, Shun Rao, Mark J Routbort, Gloria Sura, Keith Sweeney, Gokce Toruner, Peng Wei, Richard Yang, Hyvan Dang, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

Methods: Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

Results: …

Baseline Parp-1 Pet Imaging In Patients With Advanced Solid Tumors With Dna Damage Response Mutations, Tarek Daoud, Jiansong Chen, Peng Wei, Franklin Wong, Timothy A Yap, Lilie L Lin

Faculty, Staff and Student Publications

Purpose: Inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme with numerous roles in DNA damage response signaling, represent a class of anti-cancer drugs approved for treating solid tumors with defects in the DNA damage response. However, additional methods for identifying patients who would benefit from the use of PARP inhibitors are urgently needed. We evaluated a novel radiotracer, 18F-FluorThanatrace ([18F]-FTT), to noninvasively assess PARP activity with PET/CT before treatment and determine associations between uptake, tumor mutation status, and prior receipt of therapy including PARP inhibitors.

Methods: Fifty-two patients with solid tumors underwent whole-body (skull base to thigh) [18F]-FTT PET/CT scans before …

Dyadic Associations Between Stress And Sleep Quality And Moderating Effects Of Emotional Intimacy And In Survivors Of Young Adult Cancer And Their Spouses: An Observational Study, Haejeong An, Seokhun Kim, Michael Roth, Kathrin Milbury, Dalnim Cho

Faculty, Staff and Student Publications

Background: Survivors of young adult (YA) cancer often experience substantial stress during the transition to survivorship, which may impair sleep. Although the stress-sleep link is well established, its role within survivor-spouse dyads remains unclear. Emotional intimacy may influence how couples regulate stress and affect sleep. This study examined dyadic associations between stress and sleep among survivors of YA cancer and their spouses and significant others (hereafter spouses) and tested emotional intimacy as a moderator.

Methods: A total of 103 survivor of YA cancer-spouse dyads completed self-reported measures of stress, emotional intimacy, and sleep quality. An actor-partner interdependence moderation model was …

Diagnostic Criteria And Management Of Melas And Stroke-Like Episodes: Consensus-Based Statements, Michelangelo Mancuso, Marcello Bellusci, Valerio Carelli, Irenaeus De Coo, Daria Diodato, Felix Distelmaier, Omar Hikmat, Michio Hirano, Rita Horvath, Amel Karaa, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Chiara La Morgia, Piervito Lopriore, Mika Henrik Martikainen, Robert Mcfarland, Olimpia Musumeci, Robert D S Pitceathly, Guido Primiano, Shamima Rahman, Fernando Scaglia, Andrew Schaefer, Manuel Schiff, Luisa Semmler, Costanza Lamperti, Serenella Servidei

Faculty, Staff and Student Publications

Background and purpose: Mitochondrial Encephalomyopathy, Lactic acidosis and Stroke-like episodes (MELAS) is a rare multisystem mitochondrial disorder with clinical heterogeneity. Diagnostic criteria and management strategies for MELAS and mitochondrial stroke-like episodes (SLE) remain inconsistent. This work provides international consensus recommendations on the definition, diagnosis, and management of MELAS and SLE in pediatric and adult populations.

Methods: An international Delphi consensus process was conducted within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD), in collaboration with the US Mitochondrial Medicine Society, the ERN for Hereditary Metabolic Disorders (MetabERN), and patient representatives. Following a systematic literature review, 54 statements addressing diagnostic …

Associations Between Sociodemographic Predictors And Age Of Referral For Autism Spectrum Disorder (Asd) Diagnosis Since The Beginning Of The Covid-19 Pandemic, Mallika Mathur, Ruosha Li, Sandra Mckay, Christine Markham, Deepali K Ernest, Shreela Sharma

Faculty, Staff and Student Publications

Purpose: Sociodemographic characteristics, such as race and ethnicity, are associated with delays in ASD diagnosis. However, limited literature has examined the characteristics associated with delayed diagnosis since the start of the COVID-19 pandemic. This study aimed to identify the individual and aggregate sociodemographic characteristics associated with the age at which a child receives a referral for a diagnosis (from March 2020 to May 2023) and evaluate the impacts of the pandemic on this association.

Methods: Using cross-sectional data obtained from patients' electronic health records and the U.S. Census Bureau, we examined associations using linear regressions (N = 507). A subgroup …

Physical Activity For Public Health In The 21st Century, Deborah Salvo, Inacio Crochemore-Silva, Andrea Wendt, Jakob Tarp, Eric J Shiroma, Richard J Simpson, I-Min Lee, Ulf Ekelund, Ester Cerin, Youssouf Keita, Adrian Bauman, Pedro C Hallal, Andrea Ramirez Varela, Michael Pratt, Rodrigo Reis, Erica Hinckson, Ding Ding, Harold W Kohl, James Sallis

Faculty, Staff and Student Publications

With over 5 million attributed deaths per year, physical inactivity is a major global public health issue. Although the importance of physical activity is well recognized within the scope of obesity and cardiometabolic disease prevention and control, its broader benefits for the health of individuals and societies are yet to be fully harnessed. Furthermore, the role of active leisure, active transport and active labor-primary domains of physical activity-in supporting or hindering social and health equity has been largely overlooked. Here we (1) used a health equity lens to describe global domain-specific physical activity inequalities through an analysis of World Health …

Outcomes After Pulmonary Artery Flow Reducer Implantation In High-Risk Neonates With Congenital Heart Disease And Pulmonary Overcirculation, Cihangir Buyukgoz, Shyam Sathanandam, Neil Tailor, Ashley Molloy, Thomas Spentzas, Karthik Ramakrishnan, Christopher Knott-Craig, Umar Boston

Faculty, Staff and Student Publications

Background: Surgical outcomes in neonates with complex congenital heart disease (CHD) and pulmonary overcirculation (POC) initially palliated with pulmonary flow reducers (PFRs) were evaluated.

Methods: This was a retrospective study conducted between January 1, 2020 and December 31, 2023. Eleven neonates underwent PFR palliation. Fenestrated Medtronic microvascular plugs (PFRs) were delivered into the branch pulmonary artery (PA). The target surgical procedure involved the removal of PFRs and biventricular repair (n = 9) or single-ventricle palliation (n = 2).

Results: Patients were deemed high risk on the basis of prematurity (n = 5), early gestational age (n = 5), heterotaxy (n …

Probability Of Fentanyl Adulteration In Cocaine Selectively Decreases Cocaine Demand, Cecilia Nunez, Jin H Yoon, James Mackillop, Margaret C Wardle

Faculty, Staff and Student Publications

Fentanyl-related, cocaine-overdose deaths have drastically increased, yet research on how people who use cocaine perceive fentanyl adulteration is limited. This study developed the novel Adulterated Cocaine Purchasing Task (ACocPT), a modification of the original Cocaine Purchasing Task, to quantify how people respond to fentanyl adulteration in cocaine. In the ACocPT, participants indicated how much cocaine they would purchase when cocaine had no (0%) vs. some (10%) probability of fentanyl adulteration. Study aims were: 1) determine how possible fentanyl adulteration affects cocaine demand, and 2) determine which individual characteristics predict continued demand for cocaine despite fentanyl adulteration. This Amazon Mechanical Turk …

A Treat-To-Target Approach For Obesity Management: A Post Hoc Analysis Of The Surmount-5 Trial., Carel W Le Roux, Luca Busetto, Louis Aronne, Deborah Bade Horn, Georgios K Dimitriadis, Beverly Falcon, Luis-Emilio Garcia-Perez, Elisa Gomez Valderas, Theresa Hunter Gibble, Cagri Senyucel, Julia P Dunn

Faculty, Staff and Student Publications

Introduction: With new advancements in obesity medicine, clarity on goals and expectations for successful disease management is limited. This post hoc analysis assessed application of proposed treat-to-target (TtT) thresholds for obesity to the outcome measures of SURMOUNT-5, which randomised participants with obesity to tirzepatide or semaglutide.

Methods: The proportion of participants in each treatment group reaching proposed TtT thresholds for waist to height ratio (WHtR) < 0.53, body mass index (BMI) < 27 kg/m2, or a combination was evaluated. The associations between the thresholds and achieving low disease activity to remission (meeting goals for at least four of five defined cardiometabolic risk parameters) and normalisation or improvement in SF-36v2 physical component score (PCS) from baseline to week 72 were explored.

Results: About 23.1%-33.9% of participants treated with tirzepatide and 14.2%-20.7% treated with semaglutide reached the TtT thresholds, with greater weight reduction than the overall population. About 77% of participants who reached WHtR < 0.53 achieved low disease activity to remission, with an odds ratio of 2.31 (p < 0.001) compared to those who did not reach this target. The BMI threshold was not statistically associated with the assessed outcomes for SF-36v2 PCS.

Conclusion: In this …

Confessions In Cases Of Child Physical Abuse-A Capnet Study., Margaret R. Russell, Antoinette L. Laskey, Henry T. Puls, Suzanne P. Starling, Joanne N. Wood, Daniel M. Lindberg, Nancy S. Harper, Caitlin R. Mcnamara, Angela W. Bachim, Farah W. Brink, Lori D. Frasier, James Anderst, Porcia Vaughn, Kristine A. Campbell

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OBJECTIVE: Prior research on confessions of physical abuse (PA) has explored mechanisms of injury. Little is known about conditions supporting a confession of abuse or how confessions may influence case outcomes.

METHODS: This cross-sectional study of suspected PA in children aged < 10 years at 10 centers participating in CAPNET, a multicenter child PA research network, included children with in-person Child Abuse Pediatrics (CAP) consultations between February 2021 and December 2022 and excluded children without injury. Our focus was a confession of inflicted injury known to the CAP during clinical involvement. We compared child and clinical characteristics, out-of-home (OOH) placements, and arrests between cases with and without confessions. Multivariable models using generalized estimating equations (GEE) produced adjusted predicted probabilities (APP) clustering by CAPNET site.

RESULTS: Confessions were known to CAPs in 115/4297 (2.7%) cases, with significant site variability. In a multivariable GEE model, confessions were more likely in cases with injuries with high specificity for abuse (APP 6.0% vs 1.6%, P < .001), near-fatality (APP 5.6% vs 2.3%, P < .001), and older children (APP 4.8% vs 2.5%, P = .025). OOH placements and arrests were more common in cases with confessions. CAP awareness of confessions, OOH placements, and arrests did not follow racial or ethnic patterns seen in the US child welfare system. Lower socioeconomic status was associated with OOH placements and arrests but not with CAP awareness of confessions.

CONCLUSIONS: Our findings highlight differences in case characteristics and outcomes where a confession is known to the CAP and raise questions about …