Digital Commons Network^™

Early Estimate Of Nirsevimab Effectiveness For Prevention Of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season - New Vaccine Surveillance Network, October 2023-February 2024., Heidi L. Moline, Ayzsa Tannis, Ariana P. Toepfer, John V. Williams, Julie A. Boom, Janet A. Englund, Natasha B. Halasa, Mary Allen Staat, Geoffrey A. Weinberg, Rangaraj Selvarangan, Marian G. Michaels, Leila C. Sahni, Eileen J. Klein, Laura S. Stewart, Elizabeth P. Schlaudecker, Peter G. Szilagyi, Jennifer E. Schuster, Leah Goldstein, Samar Musa, Pedro A. Piedra, Danielle M. Zerr, Kristina A. Betters, Chelsea Rohlfs, Christina Albertin, Dithi Banerjee, Erin R. Mckeever, Casey Kalman, Benjamin R. Clopper, New Vaccine Surveillance Network Product Effectiveness Collaborators, Meredith L. Mcmorrow, Fatimah S. Dawood

Manuscripts, Articles, Book Chapters and Other Papers

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants agedtrials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, …

Variants In Zfx Are Associated With An X-Linked Neurodevelopmental Disorder With Recurrent Facial Gestalt\, James L Shepherdson, Katie Hutchison, Dilan Wellalage Don, George Mcgillivray, Tae-Ik Choi, Carolyn A Allan, David J Amor, Siddharth Banka, Donald G Basel, Laura D Buch, Deanna Alexis Carere, Renée Carroll, Jill Clayton-Smith, Ali Crawford, Morten Dunø, Laurence Faivre, Christopher P Gilfillan, Nina B Gold, Karen W Gripp, Emma Hobson, Alexander M Holtz, A Micheil Innes, Bertrand Isidor, Adam Jackson, Panagiotis Katsonis, Leila Amel Riazat Kesh, Genomics England Research Consortium;, Sébastien Küry, François Lecoquierre, Paul Lockhart, Julien Maraval, Naomichi Matsumoto, Julie Mccarrier, Josephine Mccarthy, Noriko Miyake, Lip Hen Moey, Andrea H Németh, Elsebet Østergaard, Rushina Patel, Kate Pope, Jennifer E Posey, Rhonda E Schnur, Marie Shaw, Elliot Stolerman, Julie P Taylor, Erin Wadman, Emma Wakeling, Susan M White, Lawrence C Wong, James R Lupski, Olivier Lichtarge, Mark A Corbett, Jozef Gecz, Charles M Nicolet, Peggy J Farnham, Cheol-Hee Kim, Marwan Shinawi

Duncan NRI Faculty and Staff Publications

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included …

Rehabilitation Treatment Specification System For Voice Therapy: Application To Everyday Clinical Care, Jeremy Wolfberg, John Whyte, Patricia Doyle, Shirley Gherson, Jason Muise, Brian Petty, Carol Jorgensen Tolejano, Robert E Hillman, Tara Stadelman-Cohen, Jarrad H Van Stan

Faculty, Staff and Student Publications

PURPOSE: Rehabilitation intervention descriptions often do not explicitly identify active ingredients or how those ingredients lead to changes in patient functioning. The Rehabilitation Treatment Specification System (RTSS) provides guidance to identify the critical aspects of any rehabilitation therapy and supported the development of standardly named ingredients and targets in voice therapy (Rehabilitation Treatment Specification System for Voice Therapy [RTSS-Voice]). This study sought to test the content validity of the RTSS-Voice and determine if the RTSS-Voice can be used to identify commonalities and differences in treatment (criterion validity) across clinicians in everyday clinical practice.

METHOD: Five speech-language pathologists from different institutions …

Implementing Services For Pediatric Cystic Fibrosis Treatment In A Community Hospital., Paige Grube, Heather Nichols, Sarah Ferrell Pharmd, Denise Gilham Pnp, Allyson Gaylor Pharmd, Bcpps, Karen Dunkelberger Bs Pharm, Mshi, Cpps

Pharmacy Residency

This project aimed to describe how the pharmacy department prepared to care for pediatric patients with cystic fibrosis, a new population being cared for at the institution.

PURPOSE: Our community hospital was recently charged with providing care for pediatric people with cystic fibrosis (PwCF). Pediatric PwCF generally need a higher level of care than is required by other pediatric patients cared for at our institution. This project aimed to prepare the pharmacy department to care for this specialized population safely and efficiently.

SUMMARY: The implementation process was divided into 3 phases to accomplish the larger purpose. These phases were as …

Target: A Randomized, Noninferiority Trial Of A Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling For Prostate Cancer Germline Testing, Stacy Loeb, Scott Keith, Heather Cheng, Amy Leader, Laura Gross, Tatiana Sanchez Nolasco, Nataliya Byrne, Rebecca Hartman, Lauren Brown, Christopher Pieczonka, Leonard Gomella, William Kevin Kelly, Costas Lallas, Nathan Handley, Patrick Mille, James Mark, Gordon Brown, Sameer Chopra, Alexandra Mcclellan, David Wise, Lucas Hollifield, Veda Giri

Department of Urology Faculty Papers

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services.

METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at …

Protein Biomarkers And Alternatively Methylated Cell-Free Dna Detect Early Stage Pancreatic Cancer, Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin

Faculty, Staff and Student Publications

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially …

Enhancing Prognostic Power In Multiple Myeloma Using A Plasma Cell Signature Derived From Single-Cell Rna Sequencing, Jian-Rong Li, Shahram Arsang-Jang, Yan Cheng, Fumou Sun, Anita D'Souza, Binod Dhakal, Parameswaran Hari, Quillan Huang, Paul Auer, Yong Li, Raul Urrutia, Fenghuang Zhan, John D Shaughnessy, Siegfried Janz, Jing Dong, Chao Cheng

Faculty, Staff and Students Publications

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum …

Liax Is A Surrogate Marker For Cell Envelope Stress And Daptomycin Non-Susceptibility In Enterococcus Faecium, Dierdre B Axell-House, Shelby R Simar, Diana Panesso, Sandra Rincon, William R Miller, Ayesha Khan, Orville A Pemberton, Lizbet Valdez, April H Nguyen, Kara S Hood, Kirsten Rydell, Andrea M Detranaltes, Mary N Jones, Rachel Atterstrom, Jinnethe Reyes, Pranoti V Sahasrabhojane, Geehan Suleyman, Marcus Zervos, Samuel A Shelburne, Kavindra V Singh, Yousif Shamoo, Blake M Hanson, Truc T Tran, Cesar A Arias

Faculty, Staff and Student Publications

Daptomycin (DAP) is often used as a first-line therapy to treat vancomycin-resistant

Inactivation Of Adenosine Receptor 2a Suppresses Endothelial-To-Mesenchymal Transition And Inhibits Subretinal Fibrosis In Mice, Qiuhua Yang, Yongfeng Cai, Qian Ma, Albert Xiong, Peishan Xu, Zhidan Zhang, Jiean Xu, Yaqi Zhou, Zhiping Liu, Dingwei Zhao, John Asara, Wei Li, Huidong Shi, Ruth B Caldwell, Akrit Sodhi, Yuqing Huo

Faculty, Staff and Students Publications

Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury–induced CNV or mice with a deficiency in the …

Single-Cell Cd4 And Cd8 T-Cell Secretome Profiling Reveals Temporal And Niche Differences In Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy, Jessica L Root, Poonam N Desai, Christopher Ly, Bofei Wang, Fatima Zahra Jelloul, Jing Zhou, Sean Mackay, Mansour Alfayez, Jairo Matthews, Sherry Pierce, Patrick K Reville, Naval Daver, Hussein A Abbas

Faculty, Staff and Student Publications

UNLABELLED: Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T-cell antileukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of patients with relapsed/refractory (RelRef) AML treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy …

Proteomic Associations Of Adverse Outcomes In Human Heart Failure, Marie-Joe Dib, Ahmed Diab, Ali Javaheri, Douglas L Mann, Et Al.

2020-Current year OA Pubs

BACKGROUND: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization.

METHODS AND RESULTS: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant …

Endovascular Thrombectomy For Large Ischemic Stroke Across Ischemic Injury And Penumbra Profiles, Amrou Sarraj, Ameer E Hassan, Michael G Abraham, Santiago Ortega-Gutierrez, Scott E Kasner, Muhammad Shazam Hussain, Michael Chen, Leonid Churilov, Hannah Johns, Clark W Sitton, Vignan Yogendrakumar, Felix C Ng, Deep K Pujara, Spiros Blackburn, Sophia Sundararajan, Yin C Hu, Nabeel A Herial, Juan F Arenillas, Jenny P Tsai, Ronald F Budzik, William J Hicks, Osman Kozak, Bernard Yan, Dennis J Cordato, Nathan W Manning, Mark W Parsons, Andrew Cheung, Ricardo A Hanel, Amin N Aghaebrahim, Teddy Y Wu, Pere Cardona Portela, Chirag D Gandhi, Fawaz Al-Mufti, Natalia Pérez De La Ossa, Joanna D Schaafsma, Jordi Blasco, Navdeep Sangha, Steven Warach, Timothy J Kleinig, Faris Shaker, Faisal Al Shaibi, Gabor Toth, Mohammad A Abdulrazzak, Gagan Sharma, Abhishek Ray, Jeffrey Sunshine, Amanda Opaskar, Kelsey R Duncan, Wei Xiong, Edgar A Samaniego, Laith Maali, Colleen G Lechtenberg, Arturo Renú, Nirav Vora, Thanh Nguyen, Johanna T Fifi, Stavropoula I Tjoumakaris, Pascal Jabbour, Georgios Tsivgoulis, Vitor Mendes Pereira, Maarten G Lansberg, Michael Degeorgia, Cathy A Sila, Nicholas Bambakidis, Michael D Hill, Stephen M Davis, Lawrence Wechsler, James C Grotta, Marc Ribo, Greg W Albers, Bruce C Campbell

Faculty, Staff and Student Publications

Importance: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.

Objective: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.

Design, setting, and participants: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 …

Endovascular Thrombectomy For Large Ischemic Stroke Across Ischemic Injury And Penumbra Profiles., Amrou Sarraj, Ameer E Hassan, Michael G Abraham, Santiago Ortega-Gutierrez, Scott E Kasner, Muhammad Shazam Hussain, Michael Chen, Leonid Churilov, Hannah Johns, Clark W Sitton, Vignan Yogendrakumar, Felix C Ng, Deep K Pujara, Spiros Blackburn, Sophia Sundararajan, Yin C Hu, Nabeel A Herial, Juan F Arenillas, Jenny P Tsai, Ronald F Budzik, William J Hicks, Osman Kozak, Bernard Yan, Dennis J Cordato, Nathan W Manning, Mark W Parsons, Andrew Cheung, Ricardo A Hanel, Amin N Aghaebrahim, Teddy Y Wu, Pere Cardona Portela, Chirag D Gandhi, Fawaz Al-Mufti, Natalia Pérez De La Ossa, Joanna D Schaafsma, Jordi Blasco, Navdeep Sangha, Steven Warach, Timothy J Kleinig, Faris Shaker, Faisal Al Shaibi, Gabor Toth, Mohammad A Abdulrazzak, Gagan Sharma, Abhishek Ray, Jeffrey Sunshine, Amanda Opaskar, Kelsey R Duncan, Wei Xiong, Edgar A Samaniego, Laith Maali, Colleen G Lechtenberg, Arturo Renú, Nirav Vora, Thanh Nguyen, Johanna T Fifi, Stavropoula I Tjoumakaris, Pascal Jabbour, Georgios Tsivgoulis, Vitor Mendes Pereira, Maarten G Lansberg, Michael Degeorgia, Cathy A Sila, Nicholas Bambakidis, Michael D Hill, Stephen M Davis, Lawrence Wechsler, James C Grotta, Marc Ribo, Greg W Albers, Bruce C Campbell

Neuroscience Articles

IMPORTANCE: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.

OBJECTIVE: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.

DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 …

Potential Protein Signatures For Recurrence Prediction Of Ischemic Stroke, Chengyi Zhang, Yang Liu, Huimin Zhu, Xinying Huang, Cang Guo, Si Cheng, Meng Yuan, Yong Jiang, Xia Meng, S Claiborne Johnston, Yongjun Wang, Wei-Na Jin, Fu-Dong Shi

Faculty, Staff and Student Publications

Background: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence.

Methods and results: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke …

The Epigenetic Evolution Of Glioma Is Determined By The Idh1 Mutation Status And Treatment Regimen., Tathiane M Malta, Thais S Sabedot, Natalia S Morosini, Indrani Datta, Luciano Garofano, Wies Vallentgoed, Frederick S Varn, Kenneth Aldape, Fulvio D'Angelo, Spyridon Bakas, Jill S Barnholtz-Sloan, Hui K Gan, Mohammad Hasanain, Ann-Christin Hau, Kevin C Johnson, Simona Cazacu, Ana C Decarvalho, Mustafa Khasraw, Emre Kocakavuk, Mathilde C M Kouwenhoven, Simona Migliozzi, Simone P Niclou, Johanna M Niers, D Ryan Ormond, Sun Ha Paek, Guido Reifenberger, Peter A Sillevis Smitt, Marion Smits, Lucy F Stead, Martin J Van Den Bent, Erwin G Van Meir, Annemiek Walenkamp, Tobias Weiss, Michael Weller, Bart A Westerman, Bauke Ylstra, Pieter Wesseling, Anna Lasorella, Pim J French, Laila M Poisson, Roel G W Verhaak, Antonio Iavarone, Houtan Noushmehr

Faculty Research 2024

UNLABELLED: Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator …

Germline Genetic Testing And Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From The Children's Oncology Group, Bailey A Martin-Giacalone, He Li, Michael E Scheurer, Dana L Casey, Shannon Dugan-Perez, Deborah A Marquez-Do, Donna Muzny, Richard A Gibbs, Donald A Barkauskas, David Hall, Douglas R Stewart, Joshua D Schiffman, Matthew T Mcevoy, Javed Khan, David Malkin, Corinne M Linardic, Brian D Crompton, Jack F Shern, Stephen X Skapek, Rajkumar Venkatramani, Douglas S Hawkins, Aniko Sabo, Sharon E Plon, Philip J Lupo

Faculty, Staff and Students Publications

IMPORTANCE: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma.

OBJECTIVE: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023.

EXPOSURE: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set …

Intraoperative Evaluation Of Breast Tissues During Breast Cancer Operations Using The Masspec Pen, Kyana Y Garza, Mary E King, Chandandeep Nagi, Rachel J Dehoog, Jialing Zhang, Marta Sans, Anna Krieger, Clara L Feider, Alena V Bensussan, Michael F Keating, John Q Lin, Min Woo Sun, Robert Tibshirani, Christopher Pirko, Kirtan A Brahmbhatt, Ahmed R Al-Fartosi, Alastair M Thompson, Elizabeth Bonefas, James Suliburk, Stacey A Carter, Livia S Eberlin

Faculty, Staff and Students Publications

IMPORTANCE: Surgery with complete tumor resection remains the main treatment option for patients with breast cancer. Yet, current technologies are limited in providing accurate assessment of breast tissue in vivo, warranting development of new technologies for surgical guidance.

OBJECTIVE: To evaluate the performance of the MasSpec Pen for accurate intraoperative assessment of breast tissues and surgical margins based on metabolic and lipid information.

DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic study conducted between February 23, 2017, and August 19, 2021, the mass spectrometry-based device was used to analyze healthy breast and invasive ductal carcinoma (IDC) banked tissue samples from adult …

Epivar Browser: Advanced Exploration Of Epigenomics Data Under Controlled Access., David R. Lougheed, Hanshi Liu, Katherine A. Aracena, Romain Grégoire, Alain Pacis, Tomi Pastinen, Luis B. Barreiro, Yann Joly, David Bujold, Guillaume Bourque

Manuscripts, Articles, Book Chapters and Other Papers

MOTIVATION: Human epigenomic data has been generated by large consortia for thousands of cell types to be used as a reference map of normal and disease chromatin states. Since epigenetic data contains potentially identifiable information, similarly to genetic data, most raw files generated by these consortia are stored in controlled-access databases. It is important to protect identifiable information, but this should not hinder secure sharing of these valuable datasets.

RESULTS: Guided by the Framework for responsible sharing of genomic and health-related data from the Global Alliance for Genomics and Health (GA4GH), we have developed an approach and a tool to …

Adipose Triglyceride Lipase Is A Therapeutic Target In Advanced Prostate Cancer That Promotes Metabolic Plasticity, Dominik Awad, Pham Hong Anh Cao, Thomas L Pulliam, Meredith Spradlin, Elavarasan Subramani, Tristen V Tellman, Caroline F Ribeiro, Riccardo Muzzioli, Brittany E Jewell, Hubert Pakula, Jeffrey J Ackroyd, Mollianne M Murray, Jenny J Han, Mei Leng, Antrix Jain, Badrajee Piyarathna, Jingjing Liu, Xingzhi Song, Jianhua Zhang, Albert R Klekers, Justin M Drake, Michael M Ittmann, Cristian Coarfa, David Piwnica-Worms, Mary C Farach-Carson, Massimo Loda, Livia S Eberlin, Daniel E Frigo

Faculty, Staff and Students Publications

UNLABELLED: Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate …

Adipose Tissue Dysfunction And Energy Balance Paradigms In People Living With Hiv, Claudia E Ramirez Bustamante, Neeti Agarwal, Aaron R Cox, Sean M Hartig, Jordan E Lake, Ashok Balasubramanyam

Faculty, Staff and Students Publications

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral …

Postconcussive Symptoms After Early Childhood Concussion, Dominique Dupont, Ken Tang, Cindy Beaudoin, Fanny Dégeilh, Isabelle Gagnon, Keith Owen Yeates, Sean C Rose, Jocelyn Gravel, Brett Burstein, Antonia S Stang, Rachel M Stanley, Roger L Zemek, Miriam H Beauchamp, Perc Koala Study

Faculty, Staff and Student Publications

IMPORTANCE: Research on postconcussive symptoms (PCS) following early childhood concussion has been hindered by a lack of measures suitable for this age group, resulting in a limited understanding of their evolution in young children.

OBJECTIVE: To document PCS in the first 3 months after early childhood concussion using a developmentally appropriate measure.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data collected at 3 Canadian and 1 US urban pediatric emergency departments (EDs) and 8 Canadian daycares from December 2018 to December 2022 as part of the Kids' Outcomes and Long-Term Abilities (KOALA) project, a prospective, multicenter, longitudinal cohort study. …

Differential Treatment Effects Of Subgroup Analyses In Phase 3 Oncology Trials From 2004 To 2020, Alexander D Sherry, Andrew W Hahn, Zachary R Mccaw, Joseph Abi Jaoude, Ramez Kouzy, Timothy A Lin, Bruce Minsky, C David Fuller, Tomer Meirson, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

IMPORTANCE: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited.

OBJECTIVE: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov.

MAIN OUTCOMES AND MEASURES: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard …

The Epigenetic Evolution Of Glioma Is Determined By The Idh1 Mutation Status And Treatment Regimen, Tathiane M Malta, Thais S Sabedot, Natalia S Morosini, Indrani Datta, Luciano Garofano, Wies Vallentgoed, Frederick S Varn, Kenneth Aldape, Fulvio D'Angelo, Spyridon Bakas, Jill S Barnholtz-Sloan, Hui K Gan, Mohammad Hasanain, Ann-Christin Hau, Kevin C Johnson, Simona Cazacu, Ana C Decarvalho, Mustafa Khasraw, Emre Kocakavuk, Mathilde C M Kouwenhoven, Simona Migliozzi, Simone P Niclou, Johanna M Niers, D Ryan Ormond, Sun Ha Paek, Guido Reifenberger, Peter A Sillevis Smitt, Marion Smits, Lucy F Stead, Martin J Van Den Bent, Erwin G Van Meir, Annemiek Walenkamp, Tobias Weiss, Michael Weller, Bart A Westerman, Bauke Ylstra, Pieter Wesseling, Anna Lasorella, Pim J French, Laila M Poisson, Consortium The Glass, Roel G W Verhaak, Antonio Iavarone, Houtan Noushmehr

Faculty, Staff and Student Publications

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of …

Lilrb3 Supports Immunosuppressive Activity Of Myeloid Cells And Tumor Development, Ryan Huang, Xiaoye Liu, Jaehyup Kim, Hui Deng, Mi Deng, Xun Gui, Heyu Chen, Guojin Wu, Wei Xiong, Jingjing Xie, Cheryl Lewis, Jade Homsi, Xing Yang, Chengcheng Zhang, Yubo He, Qi Lou, Caroline Smith, Samuel John, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the …

Differential Treatment Effects Of Subgroup Analyses In Phase 3 Oncology Trials From 2004 To 2020, Alexander D Sherry, Andrew W Hahn, Zachary R Mccaw, Joseph Abi Jaoude, Ramez Kouzy, Timothy A Lin, Bruce Minsky, C David Fuller, Tomer Meirson, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited.

Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials.

Design, setting, and participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov.

Main outcomes and measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard …

Physical Activity Patterns Within Dementia Care Dyads, N Farina, R Mcardle, Rg Lowry, S Banerjee

Peninsula Medical School

Previous research has explored the physical activity habits of people with dementia and their family carers separately, with little consideration of how physical habits are associated within dyads. In this observational study, we sought to explore the relationship between people with dementia and their carers' physical activity, at a group level and at a dyadic level. Twenty-six participant dyads (persons with dementia and their carer spouses) were asked to wear an accelerometer for 30 days continuously. Comparisons were made at a group level and a dyadic level. People with dementia did not participate in significantly more moderate to vigorous physical …

The Immunopathological Landscape Of Human Pre-Tcrα Deficiency: From Rare To Common Variants., Marie Materna, Ottavia M Delmonte, Marita Bosticardo, Mana Momenilandi, Peyton E Conrey, Bénédicte Charmeteau-De Muylder, Clotilde Bravetti, Rebecca Bellworthy, Axel Cederholm, Frederik Staels, Christian A Ganoza, Samuel Darko, Samir Sayed, Corentin Le Floc'h, Masato Ogishi, Darawan Rinchai, Andrea Guenoun, Alexandre Bolze, Taushif Khan, Adrian Gervais, Renate Krüger, Mirjam Völler, Boaz Palterer, Mahnaz Sadeghi-Shabestari, Anne Langlois De Septenville, Chaim A Schramm, Sanjana Shah, John J Tello-Cajiao, Francesca Pala, Kayla Amini, Jose S Campos, Noemia Santana Lima, Daniel Eriksson, Romain Lévy, Yoann Seeleuthner, Soma Jyonouchi, Manar Ata, Fatima Al Ali, Anna Stittrich, Caroline Deswarte, Anaïs Pereira, Jérôme Mégret, Tom Le Voyer, Paul Bastard, Laureline Berteloot, Michaël Dussiot, Natasha Vladikine, Paula P Cardenas, Emmanuelle Jouanguy, Mashael Alqahtani, Amal Hasan, Thangavel Alphonse Thanaraj, Jérémie Rosain, Fahd Al Qureshah, Vito Sabato, Marie Alexandra Alyanakian, Marianne Leruez-Ville, Flore Rozenberg, Elie Haddad, Jose R Regueiro, Maria L Toribio, Judith R Kelsen, Mansoor Salehi, Shahram Nasiri, Mehdi Torabizadeh, Hassan Rokni-Zadeh, Majid Changi-Ashtiani, Nasimeh Vatandoost, Hossein Moravej, Seyed Mohammad Akrami, Mohsen Mazloomrezaei, Aurélie Cobat, Isabelle Meyts, Etsushi Toyofuku, Madoka Nishimura, Kunihiko Moriya, Tomoyuki Mizukami, Kohsuke Imai, Laurent Abel, Bernard Malissen, Fahd Al-Mulla, Fowzan Sami Alkuraya, Nima Parvaneh, Horst Von Bernuth, Christian Beetz, Frédéric Davi, Daniel C Douek, Rémi Cheynier, David Langlais, Nils Landegren, Nico Marr, Tomohiro Morio, Mohammad Shahrooei, Rik Schrijvers, Sarah E Henrickson, Hervé Luche, Luigi D Notarangelo, Jean-Laurent Casanova, Vivien Béziat

Faculty Research 2024

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre–a T cell receptor (pre-TCRa) expression. Low circulating naive ab T cell counts at birth persisted over time, with normal memory ab and high gd T cell counts. Their TCRa repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue ab T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive ab T cell …

Genome-Wide Association Study Identifies Human Genetic Variants Associated With Fatal Outcome From Lassa Fever., Dylan Kotliar, Siddharth Raju, Shervin Tabrizi, Ikponmwosa Odia, Augustine Goba, Mambu Momoh, John Demby Sandi, Parvathy Nair, Eric Phelan, Ridhi Tariyal, Philomena E Eromon, Samar Mehta, Refugio Robles-Sikisaka, Katherine J Siddle, Matt Stremlau, Simbirie Jalloh, Stephen K Gire, Sarah Winnicki, Bridget Chak, Stephen F Schaffner, Matthias Pauthner, Elinor K Karlsson, Sarah R Chapin, Sharon G Kennedy, Luis M Branco, Lansana Kanneh, Joseph J Vitti, Nisha Broodie, Adrianne Gladden-Young, Omowunmi Omoniwa, Pan-Pan Jiang, Nathan Yozwiak, Shannon Heuklom, Lina M Moses, George O Akpede, Danny A Asogun, Kathleen Rubins, Susan Kales, Anise N Happi, Christopher O Iruolagbe, Mercy Dic-Ijiewere, Kelly Iraoyah, Omoregie O Osazuwa, Alexander K Okonkwo, Stefan Kunz, Joseph B Mccormick, S Humarr Khan, Anna N Honko, Eric S Lander, Michael B A Oldstone, Lisa Hensley, Onikepe A Folarin, Sylvanus A Okogbenin, Stephan Günther, Hanna M Ollila, Ryan Tewhey, Peter O Okokhere, John S Schieffelin, Kristian G Andersen, Steven K Reilly, Donald S Grant, Robert F Garry, Kayla G Barnes, Christian T Happi, Pardis C Sabeti

Faculty Research 2024

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa …

Evaluation Of A Novel Mechanical Venous Thromboembolism Compression Device In Trauma Patients: A Pilot Study., Kellie Girardot, Jan Powers, Lisa Morgan, Lisa Hollister

Emergency Medicine and Trauma

BACKGROUND: Venous thromboembolism (VTE) is the fourth most common preventable hospital-acquired complication for hospitalized trauma patients. Mechanical prophylaxis, using sequential compression or intermittent pneumatic compression (IPC) devices, is recommended alongside pharmacologic prophylaxis for VTE prevention. However, compliance with device use is a barrier that reduces the effectiveness of mechanical prophylaxis.

OBJECTIVE: This study aimed to determine whether using the Movement and Compressions (MAC) system compared with an IPC device impacts compliance with mechanical VTE prophylaxis in trauma patients.

METHODS: This study used a before-and-after design with historical control at a Level II trauma center with a convenience sample of adult …

Near-Infrared Spectroscopy Data For Foot Skin Oxygen Saturation In Healthy Subjects, Mehmet A Suludere, Arthur Tarricone, Bijan Najafi, Lee Rogers, Michael C Siah, Gu Eon Kang, Lawrence A Lavery

Center on Aging Staff Publications

Our objective was to evaluate normative data for near‐infrared spectroscopy (NIRS) in 110 healthy volunteers by Fitzpatrick skin type (FST) and region of the foot. We obtained measurements of the dorsum and plantar foot using a commercially available device (SnapshotNIR, Kent Imaging, Calgary Canada). On the dorsum of the foot, people with FST6 had significantly lower oxygen saturation compared to FST1‐5 (p <  0.001), lower oxyhaemoglobin compared to FST2‐5 (p = 0.001), but there was no difference in deoxyhaemoglobin. No differences were found on the plantar foot. When comparing dorsal and plantar foot, there was higher oxyhaemoglobin (0.40 ± 0.09 vs. 0.51 ± 0.12, p <  0.001) and deoxyhaemoglobin (0.16 ± 0.05 vs. 0.21 ± 0.05, p …