Digital Commons Network^™

Speeding Up Interval Estimation For R2-Based Mediation Effect Of High-Dimensional Mediators Via Cross-Fitting, Zhichao Xu, Chunlin Li, Sunyi Chi, Tianzhong Yang, Peng Wei

Faculty, Staff and Student Publications

Mediation analysis is a useful tool in investigating how molecular phenotypes such as gene expression mediate the effect of exposure on health outcomes. However, commonly used mean-based total mediation effect measures may suffer from cancellation of component-wise mediation effects in opposite directions in the presence of high-dimensional omics mediators. To overcome this limitation, we recently proposed a variance-based R-squared total mediation effect measure that relies on the computationally intensive nonparametric bootstrap for confidence interval estimation. In the work described herein, we formulated a more efficient two-stage, cross-fitted estimation procedure for the R2 measure. To avoid potential bias, we performed …

Nutrition Support Adequacy In Children With Biliary Atresia After Liver Transplant, Nicole Knebusch, Manpreet Virk, Moreshwar S Desai, Marwa Mansour, Stacey Beer, Brittany Pearo, Kelby Fuller, Krupa Mysore, John Goss, Thomas Fogarty, Fernando Stein, Jorge A Coss-Bu

Faculty, Staff and Students Publications

No abstract provided.

Treatment Patterns For Genitourinary Syndrome Of Menopause: A Trinetx Analysis, Anushka Ghosh, Maria D'Amico, Yash B. Shah, Whitney R. Smith, Mihir S. Shah, Costas D. Lallas, Alana M. Murphy

Department of Urology Faculty Papers

BACKGROUND: Genitourinary syndrome of menopause (GSM) is a highly prevalent, underdiagnosed condition that can significantly impair quality of life (QoL). This study evaluates real-world treatment trends for GSM to better understand current management practices and highlight ongoing gaps in care. The background is in a different font than the rest of the abstract.

METHODS: We queried the TriNetX database for patients with a diagnosis of postmenopausal atrophic vaginitis (ICD N95.2) and treatment information from 2004-2024. A combination of RxNorm and International Classification of Diseases-10 (ICD) codes was used to classify disease and treatment type, including topical estrogen (RxNorm 4083, 4099), …

Mental Health And Beliefs About Abortion Access Following Changes To Reproductive Healthcare Laws In 2022: Findings From Oklahoma, Munjireen Sifat, Laili K. Boozary, Tina N. Le, Julia Mcquoid, Brittany Zaring-Hinkle, Sarah Tonkin, Lizbeth Benson, Bingjing Mao, Motolani Ogunsanya, Ruosi Shao, Amy M. Cohn, Allyson Shortle, Darla E. Kendzor

Department of Medical Oncology Faculty Papers

INTRODUCTION: A secondary analysis of cross-sectional survey data was conducted to characterize beliefs about abortion access in Oklahoma, measure stress associated with the overturn of Roe vs. Wade (2022), and evaluate the potential relationship between post-Roe stress (PR stress) and mental health.

METHODS: From August through September 2022, adult Oklahomans (N = 1793) were surveyed about their sociodemographic characteristics, beliefs about abortion access, frequency of past-month stress related to the overturn of Roe vs. Wade, and mental health. Beliefs about abortion access were characterized overall and within sociodemographic groups. The relationship between PR stress and mental health was evaluated, and …

Subgroup Analyses Of The Phase 3 Focus Study Of Melphalan/Hepatic Delivery System In Patients With Unresectable Metastatic Uveal Melanoma, Jonathan S. Zager, Marlana Orloff, Pier Francesco Ferrucci, Junsung Choi, David J. Eschelman, Evan S. Glazer, Aslam Ejaz, Erika Richtig, Sebastian Ochsenreither, Sunil A. Reddy, Michael C. Lowe, Georgia M. Beasley, Anja Gesierich, Martin Gschnell, Reinhard Dummer, Ana Arance, Stephen William Fenwick, Joseph J. Sacco, Johnny John, Matthew Wheater, Christian H. Ottensmeier

Department of Medical Oncology Faculty Papers

PURPOSE: To assess efficacy and safety in subgroups of patients treated with Melphalan/Hepatic Delivery System (melphalan/HDS), a drug/device combination for liver-directed treatment of metastatic UM (mUM) patients. Previously reported FOCUS study results indicated melphalan/HDS treatment provides a clinically meaningful response rate and favorable benefit-risk ratio in patients with unresectable mUM.

METHODS: Patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) every 6-8 weeks for up to 6 cycles. Post hoc analyses of efficacy and safety were conducted for patient subgroups based on demographic and baseline disease characteristics.

RESULTS: 102 patients with mUM were enrolled; treatment was attempted …

Sex Differences In Bile Acid Homeostasis And Excretion Underlie The Disparity In Liver Cancer Incidence Between Males And Females, Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate …

Tumor Biology And Access To Care And Metastatic Breast Cancer Outcomes, Matthew R. Dunn, Sarah C. Van Alsten, Marc A. Emerson, Katherine Reeder-Hayes, Terry Hyslop, Melissa A. Troester

Kimmel Cancer Center Faculty Papers

PURPOSE: To understand how access to care influences metastatic breast cancer burden (MBC) while accounting for molecular tumor characteristics, and identify interventions to reduce metastatic disease burden.

METHODS: The Carolina Breast Cancer Study is a population-based cohort with invasive breast cancer (diagnosed 2008-2013). Both de novo metastasis (stage IV at diagnosis) and distant recurrence were evaluated (12 years of follow-up. Tumor data were from medical records, pathology reports, and RNA expression data. Social variables and access to care were from participant surveys. Generalized linear models were used to estimate associations of biological and access characteristics with MBC; Cox models were …

Using A Heuristic Tool To Improve Symptom Self-Management In Adolescents And Young Adults With Cancer: Protocol For A Randomized Controlled Trial., Suzanne Ameringer, Grace Hodges, R K Elswick, Lauri Linder, Catherine Fiona Macpherson, Kristin Stegenga

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Adolescents and young adults (AYAs) with cancer experience multiple distressing symptoms during treatment, yet few developmentally relevant resources have been developed to help them self-manage their symptoms. Empowering patients to have a more active role in self-management during cancer treatment may lessen their symptom severity and distress.

OBJECTIVE: The aim of this study is to test an intervention designed to improve symptom self-management, the Computerized Symptom Capture Tool (C-SCAT), by helping AYAs understand their unique symptom experience and discuss it with their health care providers.

METHODS: We are conducting a multisite, 2-group randomized controlled trial to evaluate the effects …

Coordinated Changes In Stromal And Hematopoietic Cells That Define The Perinatal To Juvenile Transition In The Mouse Thymus, Anusha Vasudev, Colin R Moore, Aparna Calindi, Seung Woo Kang, Bryan R Helm, Jayashree Srinivasan, Siddhartha Shah, Erin Baker, Ruiting Zong, Nandini Singarapu, Scott Casey, Andrew N Macintyre, Ken S Lau, Laura P Hale, Qi Liu, Nancy R Manley, Lauren I R Ehrlich, Ellen R Richie

Faculty, Staff and Student Publications

Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal …

Synergistic Effects Of Gfap With Tnfr1 And Tnfr2 On Conversion To Ad Dementia And Overall Survival Across The Alzheimer’S Disease Spectrum, Laura Alejandra Ramirez Tirado, Ann D. Cohen, C. Elizabeth Shaaban, Cristy Matan, Brian J. Lopresti, Milos D. Ikonomovic, Thomas K. Karikari, Victor L. Villemagne, Oscar L. Lopez

Department of Neurology Faculty Papers

Background: We recently reported synergistic effects of TNFR1 and TNFR2 with
astrogliosis resulting in greater vascular burden and neurodegeneration, particularly in
Aβ+ participants. Here, we aimed to assess the interactions of peripheral inflammation
and astrogliosis on incidence of AD dementia and mortality. We hypothesized
synergistic effects with astrogliosis resulting in increased incidence of dementia, and
mortality, particularly in Aβ+ participants.
Methods: Participants of the Gingko evaluation of memory (GEM) study underwent
PiB-PET scans between 2009-2018. GFAP and peripheral inflammatory markers were
measured in 2009 by immunoassay. We evaluated the relationship of peripheral
markers of inflammation (TNFR1,TNFR2) and astrogliosis (GFAPdementia incidence …

Eif3d And Eif3e Mediate Selective Translational Control Of Hypoxia That Can Be Inhibited By Small Molecules, Stephen C Purdy, Kate Matlin, Christopher Alderman, Amber Baldwin, Natasha Shrivastava, Goksu Sarioglu, Somnath Dutta, Kristofor J Webb, Arthur Wolin, Dillon P Boulton, Annika Gustafson, Jyoti Kapali, John D Landua, Michael T Lewis, M Cecilia Caino, James C Costello, William Old, Xiang Wang, Rui Zhao, Heide L Ford, Neelanjan Mukherjee

Faculty, Staff and Students Publications

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis, effects that are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia-inducible factors (HIFs). However, translational effects in hypoxia, which likely precede transcriptional effects, have remained largely unexplored. Using ribosome profiling, we uncovered a selective translational response in acute hypoxia that is eukaryotic initiation factor (eIF)3d/eIF3e dependent and controls downstream hypoxic responses, including HIF1α accumulation and cellular invasion. We further demonstrated that eIF3e copy number and eIF3e and eIF3d expression signatures are associated with worsened outcomes for patients with breast cancer. Finally, we identified …

Liberal Or Restrictive Postoperative Transfusion In Patients At High Cardiac Risk: The Top Randomized Clinical Trial, Panos Kougias, Sherene E Sharath, Min Zhan, Jeffrey L Carson, L Erin Norman, Zhibao Mi, Rupsi Pal, Hasan Dosluoglu, J Gregory Modrall, George A Sarosi, Peter Nelson, Shipra Arya, Alexandra Scrymgeour, Jade Ollison, Lawrence A Calais, Vijay Nambi, L Parker Gregg, Shuaib M Abdullah, Shirling Tsai, Natasha Becker, Justin C Choi, Louisa Chiu, Salvatore Scali, Neal R Barshes, Samir Awad, Mohammed Moursi, Matthew C Koopmann, Mitchell Sally, Daniel Ihnat, Archana Ramaswamy, Warren Gasper, Edith Tzeng, Mark A Wilson, Gale Tang, Grant Huang, Kousick Biswas

Faculty, Staff and Students Publications

Importance: Postoperative red blood cell transfusion guidelines recommend transfusion for hemoglobin levels less than 7 g/dL. However, the safety of this strategy in patients at high risk of cardiac events undergoing major operations remains unclear.

Objective: To evaluate the risk of death or major ischemic events within 90 days after a liberal transfusion strategy compared with a restrictive transfusion strategy in patients at high risk of cardiac events who had undergone major vascular or general surgery operations and developed postoperative anemia.

Design, setting, and participants: This parallel, single-blind, randomized clinical superiority trial included 1428 veterans (≥18 y) at high cardiac …

Discovery Of Small Molecules And A Druggable Groove That Regulate Dna Binding And Release Of The Ap-1 Transcription Factor Δfosb, Sean Mcneme, Yun Young Yim, Ashwani Kumar, Yi Li, Brandon Hughes, Corey Peyton St Romain, Galina Aglyamova, Jianping Chen, Nghi D Nguyen, Shanghua Fan, Gabriel S Stephens, Wen-Ning Zhao, Samantha Kruzshak, Molly Estill, Corrine Brener, Solange Tofani, Anil Kumar, Earnest P Chen, Nadeen Takatka, Alfred J Robison, Haiying Chen, Reid T Powell, Stephen J Haggarty, Clifford Stephan, Eric J Nestler, Jeannie Chin, Mischa Machius, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct …

Titin-Related Familial Dilated Cardiomyopathy: Factors Associated With Disease Onset, Renee Johnson, Robert A Fletcher, Stacey Peters, Monique Ohanian, Magdalena Soka, Andrei Smolnikov, Katherine E Abihider, Michael J Ackerman, Flavie Ader, Mohammed M Akhtar, Ahmad S Amin, Euan A Ashley, John J Atherton, Rachel Austin, Annette F Baas, Richard D Bagnall, Samantha Barratt Ross, Jean-Louis Blouin, Emily E Brown, Henning Bundgaard, Douglas Cannie, Przemyslaw Chmielewski, Gemma Correnti, Maria Generosa Crespo-Leiro, Matteo Dal Ferro, Lisa M Dellefave-Castillo, Fernando Dominguez, Dennis Dooijes, Anne M Dybro, Youssef Ed Demri, Mohamed El Hachmi, Luis Escobar-Lopez, Sarah Jajesnica Foye, Maria Franaszczyk, Marta Gigli, Esther Gonzalez Lopez, Adeline Goudal, Sharon Graw, Michel Guipponi, Eric Haan, Jan Haas, Daniel J Hammersley, Frederikke G Hansen, Christopher S Hayward, Thomas Morris Hey, Stephane Heymans, Carolyn Y Ho, Arjan C Houweling, Jodie Ingles, Angela Ingrey, Andrew Jabbour, Paul A James, Joeri A Jansweijer, Jan D H Jongbloed, Anne M Keogh, Jose M Larrañaga-Moreira, Ronald H Lekanne Deprez, Ivan Macciocca, Peter S Macdonald, Nicolas Mansencal, Julia Mansour, Cristina Martinez-Veira, Barbara Mcdonough, Julie Mcgaughran, Kristen Medo, Marco Merlo, Ewa Michalak, Lorenzo Monserrat, Helen Mountain, Steven A Muller, Anne M Murphy, Brittney Murray, Emily C Oates, Elizabeth Ormondroyd, Nicholas Pachter, Alessia Paldino, Aurélien Palmyre, Naveen L Pereira, Kermshlise C Picard, Nicola Poplawski, Sanjay Prasad, Julie Proukhnitzky, Jean-Francois Pruny, Patricia Reant, Pascale Richard, Anne Ronan, Farbod Sedaghat-Hamedani, Christopher Semsarian, Garrett Storm, Sophie Stroeks, Petros Syrris, Matthew R G Taylor, Kate Thomson, Tina Thompson, J Peter Van Tintelen, Christoffer Rasmus Vissing, Kathryn E Waddell-Smith, Mathew Wallis, Dominica Zentner, Clare Arnott, Ali J Marian, Jaewon Oh, Siv Fokstuen, Cynthia A James, Roberto Barriales-Villa, Benjamin Meder, Karim Wahbi, John R Giudicessi, Victoria N Parikh, James S Ware, Nicolas Piriou, Caroline Rooryck, Neal K Lakdawala, Luisa Mestroni, Gianfranco Sinagra, Perry M Elliott, Hugh Watkins, Elizabeth M Mcnally, Philippe Charron, Karin Y Van Spaendonck-Zwarts, Pablo Garcia-Pavia, Maria Luisa Peña-Peña, Jens Mogensen, Alex Hoerby Christensen, Zofia T Bilińska, Torsten B Rasmussen, Jonathan G Seidman, Christine E Seidman, Anneline S J M Te Riele, Job A J Verdonschot, Yigal M Pinto, Imke Christiaans, Diane Fatkin

The Brown Foundation: Institute of Molecular Medicine

Background and aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM.

Results: A total of 3158 subjects in 1043 …

Investigating Chronic Toxicity, Diet, Patient-Reported Outcomes And The Microbiome In Immunotherapy-Treated Metastatic Melanoma Survivors: A New Frontier, Margaux Robert, Satabdi Saha, Nazli Dizman, Michelle Rohlfs, Elizabeth Sirmans, Julie Simon, Rodabe N Amaria, Isabella C Glitza Oliva, Hussein A Tawbi, Michael A Davies, Alexandra Ikeguchi, Karen Basen-Engquist, Keri Schadler, Michael E Roth, Wenye Song, Xiaotao Zhang, Nadim J Ajami, Lorenzo Cohen, Jennifer A Wargo, Christine B Peterson, Jennifer L Mcquade, Carrie R Daniel

Faculty, Staff and Student Publications

Background/Objectives: Immune checkpoint blockade (ICB) therapies have significantly improved outcomes in metastatic melanoma. However, immune-related adverse events (irAEs) and persistent chronic toxicities (CTs) among this emerging survivor population likely influence different facets of quality of life. This study characterized CT, patient-reported outcomes (PROs), diet, physical activity and gut microbiome features in a cohort of long-term survivors with a history of ICB-treated metastatic melanoma.

Methods: Forty-eight patients with a history of metastatic melanoma who initiated ICB treatment at least 3 years earlier and were not currently on treatment were prospectively enrolled from a melanoma survivorship clinic. Participants completed screening …

Trait-Like Visual Cortical Hyperactivity In Trait Anxiety, Zhaohan Wu, Yuqi You, Joshua A Brown, Raymond J Dolan, Wen Li

Faculty, Staff and Student Publications

Sensory processing varies across individuals, with some traits-particularly sensory hypersensitivity to basic non-valenced stimuli-linked to emotional traits and psychiatric risk. Traditional accounts attribute this sensory-emotion linkage to limbic or prefrontal modulation, but empirical support is limited. Growing evidence suggests sensory cortex itself flexibly encodes value beyond labeled-line analysis. Across four high-density EEG experiments with multi-wave assessments, we identified reliable visual cortical hyperactivity in high trait anxiety. The effect emerged as early as 46 ms, localized to V1/V2, and was specific to the parvocellular pathway. It was reproducible across arousal states, stimulus valence, extended intervals, and paradigms, and evident for both …

Single-Nucleus Multiomics Reveals The Disrupted Regulatory Programs In Three Brain Regions Of Sporadic Early-Onset Alzheimer’S Disease, Andi Liu, Citu Citu, Nitesh Enduru, Xian Chen, Chia-Hao Tung, Tirthankar Sinha, Sofia E Sepulveda, Astrid M Manuel, Damian Gorski, Brisa S Fernandes, Meifang Yu, Paul E Schulz, Lukas M Simon, Claudio Soto, Zhongming Zhao

Faculty, Staff and Student Publications

Sporadic early-onset Alzheimer’s disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer’s disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type–specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells …

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

P-15 Peptide Enhanced Bone Graft Improves Time To Fusion In Transforaminal Lumbar Interbody Fusion: A Randomized, Controlled, Investigational Device Exemption Study, James S. Harrop, Michael P. Steinmetz, John E. O'Toole, Christopher D Chaput, Rick C. Sasso, K. Brandon Strenge, Greg Maislin, Jeffrey P. Mullin, Thomas B. Freeman, Anthony Guanciale, Howard Lantner, Michael E. Janssen, David G. Schwartz, John M. Small, Wellington K. Hsu, Paul M. Arnold

Department of Neurosurgery Faculty Papers

STUDY DESIGN: Prospective, multicenter, single-blind, randomized, and controlled pivotal study.

OBJECTIVE: Compare time-to-fusion in patients treated with P-15L (PearlMatrix TM P-15 peptide enhanced bone graft) versus local autograft over 24 months and evaluate changes in pain and quality of life at 24 months relative to baseline.

SUMMARY OF BACKGROUND DATA: P-15L, an FDA-designated breakthrough device, is a composite bone graft with P-15, a 15-amino acid polypeptide that promotes cellular adhesion, proliferation, and differentiation to support bone formation.

METHODS: Patients (22-80 y) with degenerative disc disease were randomized to the investigational (P-15L) or control (local autograft) group during single-level transforaminal lumbar …

Clinical Outcomes Of Patients With Unsuccessful Mechanical Thrombectomy Versus Best Medical Management Of Medium Vessel Occlusion Stroke In The Middle Cerebral Artery Territory, Tobias D Faizy, Vivek Yedavalli, Hamza Adel Salim, Dhairya A Lakhani, Basel Musmar, Nimer Adeeb, Muhammed Amir Essibayi, Motaz Daraghma, Kareem El Naamani, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kuhn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Leonard Ll Yeo, Benjamin Yq Tan, Robert W Regenhardt, Jeremy Josef Heit, Nicole M Cancelliere, Aymeric Rouchaud, Jens Fiehler, Sunil A Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Răzvan Alexandru Radu, Mohamad Abdalkader, Piers Klein, Thomas R Marotta, Julian Spears, Takahiro Ota, Ashkan Mowla, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Gaultier Marnat, Hamza Shaikh, Christoph J Griessenauer, David S Liebeskind, Alessandro Pedicelli, Andrea Maria Alexandre, Illario Tancredi, Erwah Kalsoum, Max Wintermark, Boris Lubicz, Aman B Patel, Vitor Mendes Pereira, Adam A Dmytriw, Adrien Guenego, Mad-Mt Investigators

Faculty, Staff and Student Publications

Background: Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown.

Methods: This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. Only patients with occlusion of the distal branches (M2 and M3) of the middle cerebral artery territory were included. Unsuccessful MT was defined as a modified Thrombolysis in Cerebral Infarction score of 0-2a. Propensity score matching …

Adjudicated Cardiovascular Events In Patients With Covid-19: Association With Vaccination Status And Changes Over Time, Behnood Bikdeli, Darsiya Krishnathasan, Antoine Bejjani, Candrika D. Khairani, Nada Hamade, Umberto Campia, Julia Davies, Nicole Porio, Ali Assi, Andre Armero, Anthony Tristani, Marcos D. Ortiz-Rios, Victor Nauffal, Zaid I. Almarzooq, Eric Q. Wei, Bridget Mcgonagle, Mariana Pfeferman, Sina Rashedi, Alyssa Sato, Giovanni Scimeca, Valeria Zuluaga-Sánchez, Mehrdad Zarghami, Aditya Achanta, Sirus Jesudasen, Bruce C. Tiu, Geno J. Merli, Orly Leiva, John Fanikos, Aditya M. Sharma, Samantha M. Rizzo, Ruth B. Morrison, Alec Vishnevsky, Shiavax J. Rao, Sivan Naveh, Abdelghani El Rafei, James Welker, Marc P. Bonaca, Brett J. Carroll, Samuel Z. Goldhaber, Zhou Lan, Gregory Piazza, The Corona-Vte Network Investigators

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Patients with COVID-19 are at risk of thrombotic and cardiovascular complications. Existing risk estimates derive from early COVID-19 experiences. More recent event rates, temporal trends, and the association between vaccination status and cardiovascular outcomes remain unclear.

METHODS: The CORONA-VTE Network (COVID-19 Registry to Assess Frequency, Risk Factors, Management, and Outcomes of Arterial and Venous Thromboembolic Complications) multicenter registry included patients with COVID-19 from March 2020 to February 2024. A composite of venous and arterial thrombotic events and a composite of adjudicated cardiovascular events were assessed at 90 days after COVID-19 diagnosis. Time-to-first-event analyses were stratified by inpatients and outpatients …

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Emotion Regulation Differences Between Gender And Sexuality Groups: A Systematic Review And Meta-Analysis, Jake Camp, Emma Blundell, Patrick Smith, Katharine Rimes

School of Psychology

Gender and sexual minority (GSM) people are at increased risk of mental health difficulties compared to their cisgender-heterosexual peers. This is likely because of exposure to minority stressors. Emotion regulation difficulties have been proposed as an important mechanism for mental health disparities in GSM populations. This systematic review and meta-analysis examined whether GSM groups differ from cisgender and heterosexual groups in global and specific aspects of emotion regulation (e.g., emotion awareness, strategies, impulse control, cognitive appraisal, and emotion suppression), and whether emotion dysregulation mediated the relationship between GSM identity and mental health outcomes. We identified 40 eligible studies, of which …

Extracellular Matrix-Mycaf Signatures Correlate With Resistance To Neoadjuvant Apd-L1 Immune Checkpoint Inhibition With Durvalumab + Metformin In Hpv+ Hnscc, Pablo Llerena, Hani Samarah, Kathryn Nunes, Zhao Lin, Kelly Bridgham, Sruti Tekumalla, Amiti Jain, Larry A. Harshyne, Sanket Kumar Shukla, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, John R. Eisenbrey, Scott W Keith, David Cognetti, Voichita Bar-Ad, Adam J. Luginbuhl, Rita S. Axelrod, Rajanikanth Vadigepalli, Hushan Yang, Diana Whitaker-Menezes, Megan Roche, My G. Mahoney, Athanassios Argiris, Charalambos C. Solomides, Jennifer Johnson, Md, Mouadh Barbirou, Amanda Miller, Andrew P. South, Ramkrishna Mitra, Alban J Linnenbach, Ubaldo E. Martinez-Outshoorn, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

PURPOSE: Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICIs, offering promise to improve response rates. We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.

PATIENTS AND METHODS: Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms. We present …

Transdiagnostic Links Of Reward Processing In Obsessive-Compulsive Disorder And Depression, Kevin M Wagner, Matti Cervin, Jessica S C Cheng, Jasmine Arriaga, Vanessa Zavala Cruz, Dayan Berrones, Josselyn S Muñoz, Renee M Frederick, Jacey L Anderberg, Belinda E Núñez Bracho, Victor R Adorno, Leonardo F Fontenelle, Andrew D Wiese, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), James J Crowley, Eric A Storch

Faculty, Staff and Students Publications

Objectives: Transdiagnostic models aim to uncover shared mechanisms across mental disorders. Reward responsiveness (the ability to experience pleasure from rewarding stimuli) is a plausible, yet underexplored, transdiagnostic mechanism linking obsessive-compulsive disorder (OCD) and depression. This study used network analysis to (1) examine how key reward responsiveness domains are interlinked in individuals with OCD and (2) explore how each domain is uniquely associated with OCD and depression.

Methods: A total of 1345 individuals with a history of OCD symptoms (ages 18-88, 71 % women) from Latino communities in the United States (including Puerto Rico) and nine Latin American countries completed validated …

Methodology For The Pediatric Dose Optimization For Seizures In Emergency Medical Services (Pedidose) Study, Manish I Shah, Kathleen M Adelgais, James M Chamberlain, Henry E Wang, Lindsey A Morgan, James J Riviello, Rana R Said, Joseph E Sullivan, Kimia F Ghaffari, Kathryn M Kothari, Mohsen Saidinejad, Robert A Lowe, Raymond L Fowler, Catherine R Counts, Claudia R Morris, Jonathan R Studnek, Nancy K Glober, Caleb E Ward, Brian M Clemency, Nicholas Patrick, Rachel D Munn, Graham M Brant-Zawadzki, Christian Martin-Gill, Daniel K Nishijima, Kevin Li, Neomi Sepulveda, John M Vanburen

Faculty, Staff and Student Publications

Background: Seizures are one of the most common reasons for emergency medical services (EMS) activation for children, and current EMS practice results in underdosing and delayed delivery of anti-seizure medication. A prehospital evidence-based guideline recommends using intranasal or intramuscular midazolam as first-line treatment for pediatric seizures. Despite attempts to implement these guidelines, one-third of children having a paramedic-witnessed seizure have ongoing seizures on emergency department (ED) arrival; this may be due to inadequate or delayed midazolam dosing. Replacing the error-prone, sequential calculations with age-based midazolam dosing may be simpler, faster, and more effective without compromising safety. The objective of this …

Incomplete (A3) Versus Complete (A4) Thoracolumbar Burst Fractures: Results From A Prospective International Multicenter Cohort Study, Jin W. Tee, Barry T. S. Kweh, Alex R. Vaccaro, Klaus J. Schnake, Mohammad El-Sharkawi, Eugen C. Popescu, Shanmuganathan Rajasekaran, Lorin M. Benneker, Sebastian F. Bigdon, John France, Jerome Paquet, R. Todd Allen, William F. Lavelle, Miguel Hirschfeld, Spyridon Pneumaticos, Richard J. Bransford, Andrei F. Joaquim, Harvinder S. Chhabra, Ulrich Spiegl, Hauri Dimitri, F. Cumhur Oner, Marcel Dvorak, Gregory D. Schroeder, Charlotte Dandurand

Department of Orthopaedic Surgery Faculty Papers

OBJECTIVE: The objective was to compare incomplete (A3) versus complete (A4) thoracolumbar burst fractures managed nonoperatively or operatively with respect to reaching minimal clinically important difference (MCID) in Oswestry Disability Index (ODI) score.

METHODS: A prospective observational international multicenter cohort study was conducted. After stratification using the AO Spine Thoracolumbar Injury Classification System, A3 and A4 outcomes were analyzed separately within nonoperative and operative management groups. Outcomes included absolute and relative improvement in ODI scores between discharge and 12-month follow-up. Kaplan-Meier curves were generated and compared with the log-rank test. Multivariable Cox regression models were constructed. The Cox regression models …

Concurrent Tb And Hiv Therapies Control Tb Reactivation During Co-Infection But Not Chronic Immune Activation, Riti Sharan, Yi Zou, Bindu Singh, Vinay Shivanna, Edward J Dick, Shannan Hall-Ursone, Xi Luo, Guanlin Guo, Shabaana A Khader, Xavier Alvarez, Jyothi Rengarajan, Zhao Lai, Smriti Mehra, Hulin Wu, Deepak Kaushal

Faculty, Staff and Student Publications

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using …

Measurable Imaging-Based Changes In Enhancement Of Intrahepatic Cholangiocarcinoma After Radiotherapy Reflect Physical Mechanisms Of Response, Brian De, Prashant Dogra, Mohamed Zaid, Dalia Elganainy, Kevin Sun, Ahmed M Amer, Charles Wang, Michael K Rooney, Enoch Chang, Hyunseon C Kang, Zhihui Wang, Priya Bhosale, Bruno C Odisio, Timothy E Newhook, Ching-Wei D Tzeng, Hop S Tran Cao, Yun S Chun, Jean-Nicholas Vauthey, Sunyoung S Lee, Ahmed Kaseb, Kanwal Raghav, Milind Javle, Bruce D Minsky, Sonal S Noticewala, Emma B Holliday, Grace L Smith, Albert C Koong, Prajnan Das, Vittorio Cristini, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

Escalated doses of radiotherapy associate with improved local control and overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA), but personalization remains limited because conventional size-based CT criteria correlate poorly with outcomes. We hypothesized that quantitative enhancement measurements would better predict clinical outcomes and guide individualized RT optimization. In a retrospective cohort of 154 patients, we analyzed pre- and post-RT CT scans using quantitative European Association for Study of Liver (qEASL) to derive viable tumor volumes, comparing enhancement-based metrics with size-based RECIST and linking them to outcomes via survival and mathematical modeling. Change in enhancement volume was strongly associated with OS after …