Digital Commons Network^™

The Volume And Characteristics Of Research On Gastrointestinal Symptoms In ‘Natural’ Peri- And Postmenopause:: A Scoping Review, Naomi Shaw, Rebecca Abbott, Clare Pettinger

School of Health Professions

BACKGROUND: Menopause has been linked to an array of symptoms, often with adverse effects on quality of life, work and relationships. Despite evidence of economic and social impacts, and a growing population of menopausal individuals, there are significant gaps in knowledge regarding menopause. Gastrointestinal (GI) symptoms in peri- and postmenopause are areas of uncertainty that warrant further investigation.

OBJECTIVES: Following JBI guidance, this scoping review aimed to systematically map research on GI symptoms in 'natural' peri- and postmenopause, exploring the volume and conduct of research, and variables investigated that could influence symptom experience.

ELIGIBILITY CRITERIA: Studies assessing GI symptoms (constipation, …

Using The Electronic Health Record To Facilitate Drug Allergy Delabeling., Matthew J Molloy, Adam P Yan, Averi E Wilson, Jonathan Beus, Lauren M Hess

Faculty, Staff and Students Publications

Purpose of review: There is a growing number of allergy delabeling programs across diverse clinical specialties and care settings. The electronic health record (EHR) can be leveraged to facilitate allergy delabeling. The purpose of this review is to describe EHR tools that have been used in allergy delabeling programs. We also provide recommendations for organizations considering EHR-based allergy delabeling workflows that incorporate clinical informatics best practices.

Recent findings: Recent literature describes several EHR tools used in delabeling. These tools can be organized around the steps of the allergy delabeling workflow: 1. Identify eligible patients, 2. Risk stratify, 3. Evaluation and …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Positron Emission Tomography Reveals Increased Myocardial Glucose Uptake In A Subset Of Friedreich Ataxia Patients, R Mark Payne, Thomas M O'Connell, P Melanie Pride, Gregg R Wagner, George J Eckert, Tiffany R Johnson, Weinian Shou, Gary D Hutchins

Faculty, Staff and Student Publications

Why some but not all patients with the rare disease Friedreich ataxia (FRDA) are at increased risk of poor cardiovascular outcome and death is unclear and unpredictable. We investigated the hypothesis that mitochondrial dysfunction in FRDA leads to altered patterns of myocardial metabolic substrate utilization. We recruited 5 healthy controls (Ctl) and 11 FRDA participants. All underwent fasting myocardial positron emission tomography (PET scan) with 15O–H2O, 18F-FDG, and 11C-Palmitate. We conducted cardiac transcriptomics on mice with ablation of the Frda gene in heart to explore mechanisms of fuel substrate utilization. Five (45%) FRDA participants had an LV mass index (LVMi) …

Transdiagnostic Alterations In White Matter Microstructure Associated With Suicidal Thoughts And Behaviours In The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Lejla Colic, Zuriel Ceja, Maria R Dauvermann, Luca M Villa, Hannah S Savage, Yara J Toenders, Niousha Dehestani, Alyssa H Zhu, Adrian I Campos, Lauren E Salminen, Martin Alda, Ingrid Agartz, Nina Alexander, Rosa Ayesa-Arriola, Elizabeth D Ballard, Nerisa Banaj, Carlotta Barkhau, Zeynep Başgöze, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Katharina Brosch, Manuel Canal-Rivero, Simon Cervenka, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Philippe Courtet, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Jeremy Deverdun, Ana M Diaz-Zuluaga, Lorielle M F Dietze, Jennifer W Evans, Negar Fani, Kira Flinkenflügel, Naomi P Friedman, Ian H Gotlib, Nynke A Groenewold, Dominik Grotegerd, Tomas Hajek, Alexander S Hatoum, Marco Hermesdorf, Ian B Hickie, Yoshiyuki Hirano, Tiffany C Ho, Yuki Ikemizu, Frank Iorfino, Jonathan C Ipser, Yuko Isobe, Andrea P Jackowski, Fabrice Jollant, Tilo Kircher, Melissa Klug, Sheri-Michelle Koopowitz, Anna Kraus, Axel Krug, Emmanuelle Le Bars, Elisabeth J Leehr, Meng Li, Elizabeth T C Lippard, Carlos Lopez-Jaramillo, Ivan I Maximov, Andrew M Mcintosh, Katie A Mclaughlin, Sean R Mcwhinney, Susanne Meinert, Elisa Melloni, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Stener Nerland, Emilie Olie, Victor Ortiz-García De La Foz, Pedro M Pan, Fabricio Pereira, Fabrizio Piras, Federica Piras, Sara Poletti, Andrew E Reineberg, Gloria Roberts, Rafael Romero-García, Matthew D Sacchet, Giovanni A Salum, Anca-Larisa Sandu, Carl M Sellgren, Eiji Shimizu, Harry R Smolker, Jair C Soares, J Douglas Steele, Frederike Stein, Dan J Stein, Benjamin Straube, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Romain Valabregue, Johanna Valencia-Echeverry, Gerd Wagner, Gordon Waiter, Martin Walter, Heather C Whalley, Mon-Ju Wu, Tony T Yang, Carlos A Zarate, Andre Zugman, Giovana B Zunta-Soares, Kees Van Heeringen, Sanne J H Van Rooij, Nic Van Der Wee, Steven Van Der Werff, Paul M Thompson, Hilary P Blumberg, Anne-Laura Van Harmelen, Miguel E Rentería, Neda Jahanshad, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of …

Distinct Spatiotemporal Patterns Of White Matter Hyperintensity Progression, Jinyong Chung, Gilsoon Park, Wi-Sun Ryu, Dawid Schellingerhout, Hang-Rai Kim, Dong-Seok Gwak, Elizabeth Haddad, Neda Jahanshad, Beom Joon Kim, Keun-Sik Hong, Hyerin Oh, Sang-Wuk Jeong, Joon-Tae Kim, Man Seok Park, Kang-Ho Choi, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Yong-Jin Cho, Byung-Chul Lee, Philip M Bath, Joanna M Wardlaw, Hee-Joon Bae, Hosung Kim, Dong-Eog Kim

Faculty, Staff and Student Publications

White matter hyperintensity, a key imaging biomarker for brain health, has prognostic implications for stroke. Using a multicenter MRI dataset of 9179 stroke patients plus the UK Biobank (n = 36,210 low/high risk controls), we employ Subtype and Stage Inference modeling and identify three distinct white matter hyperintensity progression subtypes: fronto-parietal, radial, and temporo-occipital. Longitudinal validation confirms classification stability. The fronto-parietal subtype shows delayed onset and more hypertension, while the temporo-occipital subtype has more atrial fibrillation and coronary heart disease. The fronto-parietal and radial subtypes are linked to small vessel stroke, while the temporo-occipital subtype is linked to cardioembolism. The …

Leptin As A Key Driver For Organ Fibrogenesis, Xue-Nan Sun, Shiuhwei Chen, Shangang Zhao, Jan-Bernd Funcke, Megan Virostek, Line Pedersen, Chao Li, Chanmin Joung, Qian Lin, Yan Li, Ayanna Cobb, May-Yun Wang, Kyounghee Min, Lisandro Maya-Ramos, Giovanna Degasperi, Junquan Liu, Ningyan Zhang, Zhiqiang An, Diana R Tomchick, R Max Wynn, Da Young Oh, Philipp E Scherer

Faculty, Staff and Student Publications

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting …

Lorbin: Efficient Binning Of Long-Read Metagenomes By Multiscale Adaptive Clustering And Evaluation, Wei Xue, Zuo Liu, Yaozhong Zhang, Waseem Raza, Yarong Li, Li Jiang, Ye Tao, Jun Qian, Jousset Alexandre, Fang-Jie Zhao, Yangchun Xu, Fritz Sedlazeck, Qirong Shen, Gaofei Jiang, Zhong Wei

Faculty, Staff and Students Publications

Long-read sequencing has transformed metagenomics and improved the quality of metagenome-assembled genomes (MAGs). However, current binning methods struggle with identifying unknown species and managing imbalanced species distributions. Here, we present LorBin, an unsupervised binner specially designed to reconstruct MAGs in natural microbiomes. LorBin deploys a two-stage multiscale adaptive DBSCAN and BIRCH clustering with evaluation decision models using single-copy genes to maximize MAG recovery. LorBin outperforms six competing binners in both simulated and real microbiomes, including oral, gut, and marine samples. LorBin generated 15-189% more high-quality MAGs with high serendipity and identified 2.4-17 times more novel taxa than state-of-the-art binning methods. …

Racial Disparities In Clonal Hematopoiesis And Their Impact On Hematologic Malignancies, Zijian Zhang, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Developing The Professional Knowledge Of Librarians Through A Webinar Series, Katie Pierce Farrier, Sandra Desjardins, Laura Haygood

Library Staff Publications

Background: The Early Career Librarians Initiative of the South Central Chapter of the Medical Library Association (ECLI) offered a webinar series that addressed topics of interest to new professionals such as networking, goal setting, and salary negotiation. Additionally, the ECLI assessed participant feedback on the series through a program evaluation survey.

Case presentation: ECLI partnered with the Network of the National Library of Medicine (NNLM), Region 3, to offer six webinars over the course of two years. Attendees were asked to complete a survey. Quantitative results were analyzed, and qualitative free-text responses were thematically coded. A total of 567 people …

Xpert Mtb/Rif Ultra Assay For Tuberculosis Disease And Rifampicin Resistance In Children, Alexander W Kay, Maia Madison, Katie Scandrett, Tara Ness, Pauline Amuge, Leeberk Raja Inbaraj, Mukesh Kumar Sathya Narayanan, Lucia González Fernández, Michael Eisenhut, Nazir Ismail, Alexei Korobitsyn, Sabine E Verkuijl, Annemieke Brands, Kerri Viney, Tiziana Masini, Anna M Mandalakas, Karen R Steingart, Yemisi Takwoingi

Faculty, Staff and Students Publications

Background: In 2023, an estimated 1.3 million children (aged 0-14 years) became ill with tuberculosis, and 166,000 children (aged 0-15 years) died from the disease. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that detects Mycobacterium tuberculosis complex and rifampicin resistance. This is an update of a Cochrane review first published in 2020 and last updated in 2022. Parts of the current update informed the 2024 WHO updated guidance for the diagnosis of tuberculosis.

Objectives: To assess the diagnostic accuracy of Xpert Ultra for detecting pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and …

Cdk4/6 Inhibitors In Breast Cancer-Who Should Receive Them?, Anran Chen, Ze-Yi Zheng, Meenakshi Anurag, Ahmed Elkhanany, Natalie C Chen, Eric C Chang

Faculty, Staff and Students Publications

More than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 …

Acute Mastoiditis In Children During The Covid Era: A Systematic Review And Meta-Analysis, Erin Briggs, Isabelle J. Chau, Shaun A. Nguyen, Justin C. Pelic, Erin A. Harvey, Ted A. Meyer

SKMC Student Presentations and Publications

OBJECTIVE: Explore the impact of the COVID-19 pandemic on pediatric acute mastoiditis (AM).

DATA SOURCES: CINAHL, Cochrane Library, PubMed, Scopus.

METHODS: Literature was searched from 2014 to 2025 for articles reporting AM in children. Specific outcomes included clinical presentation, bacterial epidemiology, complications, and management. Primary outcome measures included continuous measures (mean), proportions (%), mean difference (Δ), and relative risk (RR) with 95 % confidence intervals (CI).

RESULTS: There were seven included studies (N = 1001 children) with 632 patients in the pre-COVID cohort and 369 in the COVID-era cohort. There was a significant difference in the proportion of intracranial complications …

Increasing Opportunities For Community Input In Harm Reduction Program Development Using Iterative Engagement., Nicole M. Wagner, Jordan A. Carlson, Meagan Bean, Amy Wineland, Joshua Blum, Scott A. Cardona, Sheila Covarrubias, Allison Kempe, Abby C. King, Amy G. Huebschmann

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Incorporating people who use substances into a community-engaged research process can support the implementation and evaluation of evidence-based harm reduction programs. Attending to their voice ensures those who need these programs will use them. Yet, ongoing co-learning with people who use substances, often the ideal for community engaged research, poses a challenge for recruitment, ongoing participation, and obtaining diverse perspectives. We need novel strategies to support flexibility among populations experiencing legal and social instability so that community engaged work includes more diverse perspectives. In this paper, we describe a novel community engagement approach called Effective Adaptable and Sustainable in …

Enhancing Cyberattack Resiliency Through The Radiotherapy Backup And Recovery Dashboard Tool, Justin Pijanowski, Eric Nguyen, Yasin Abdulkadir, Justin Hink, Yevgeniy Vinogradskiy, James Lamb

Department of Radiation Oncology Faculty Papers

PURPOSE: Radiation Oncology departments impacted by recent cyberattacks were unable to access data backups or their Record and Verify (R&V) system and therefore faced challenges to resume patient treatments in a timely manner. We present a novel software tool that backs-up critical radiotherapy treatment information and displays essential information for on-treatment patients in an intuitive and accessible dashboard allowing clinics to continue radiotherapy treatments. The purpose of this report is to describe implementation details, challenges, and share open-source code to facilitate radiation oncology clinics' efforts to develop tools to improve cyberattack resiliency.

METHODS: The Radiotherapy Backup and Recovery Dashboard Tool …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

Mir147 Promotes Mucosal Integrity And Healing In Intestinal Inflammation, Agnieszka K Czopik, Arash Dabiri, Chia-Hao Tung, Victoria Vaughn, Xiangsheng Huang, Jinlian Wang, Hui Li, Nicolas F Moreno, Natalia V Piwko, Katherine Figarella, Hongfang Liu, Zhongming Zhao, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and …

Lifestyle Data-Based Multiclass Obesity Prediction With Interpretable Ensemble Models Incorporating Shap And Lime Analysis, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

Obesity is a major public health concern. Predicting obesity risk from lifestyle data can guide targeted interventions, but current models remain limited. This study first evaluates ensemble learning methods and then combines approaches to improve prediction accuracy and generalizability. Four ensemble techniques-boosting, bagging, stacking, and voting-were tested. Five boosting and five bagging models were constructed alongside voting and stacking models. Hyperparameter tuning optimized performance, and feature importance analysis guided potential feature elemination. In phase two, hybrid stacking and voting models integrated the best-performing boosting and bagging models to enhance predictive capability. Model robustness was ensured through k-fold cross-validation and statistical …

A Quantitative, Bayesian-Informed Approach To Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification Of Tp53 Germline Variants For Li-Fraumeni Syndrome, Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel De La Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar De Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P Macfarland, Jamie L Maciaszek, Kara Maxwell, Kelly Mcgoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle

Faculty, Staff and Students Publications

Background: Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods: The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of …

Genome-Wide Association Study Of Childhood B-Cell Acute Lymphoblastic Leukemia Reveals Novel African Ancestry-Specific Susceptibility Loci, Cindy Im, Andrew R Raduski, Lauren J Mills, Kashi Raj Bhattarai, Robert J Mobley, Kelly R Barnett, Zhanni Lu, Kenneth Liao, Nathan Anderson, Rebecca A Johnson, Erica Langer, Anthony J Hooten, Alix E Seif, Kathrin M Bernt, Matthew Tsang, Brandon A Mamou, Luis Gil-De-Gómez, Julie A Wolfson, Danielle N Friedman, Neerav Shukla, Laura J Klesse, Erin L Marcotte, Lingyun Ji, Alice Dang, Minjie Luo, Yiming Zhong, Jalen Langie, Charleston W K Chiang, Adam De Smith, Joseph L Wiemels, Andrew Dewan, Xiaomei Ma, Catherine Metayer, Zhaoming Wang, Heather H Nelson, Nathan Pankratz, Tianzhong Yang, Saonli Basu, Lucie M Turcotte, Jun J Yang, Daniel Savic, Michael E Scheurer, Logan G Spector

Faculty, Staff and Students Publications

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P <  5 × 10−8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10−3). Novel risk variants were also associated with subtype-specific disease (P <  0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower …

A Knowledge-Driven Deep Learning Framework For Organoid Morphological Segmentation And Characterization, Yiming Qin, Jiajia Li, Yin Heng, Zheyuan Wang, Dezhi Wu, Mahi Rahman, Pengwei Hu, Tobias Plötz, Alexander Hopp, Nicholas Kurniawan, Mathias Winkel, Philipp Harbach, Chunling Tang, Feng Tan

Publications

BACKGROUND: Organoids have great potential to revolutionize various aspects of biomedical research and healthcare. Researchers typically use the fluorescence-based approach to analyse their dynamics, which requires specialized equipment and may interfere with their growth. Therefore, it is an open challenge to develop a general framework to analyse organoid dynamics under non-invasive and low-resource settings.

RESULTS: In this paper, we present a knowledge-driven deep learning system named TransOrga-plus to automatically analyse organoid dynamics in a non-invasive manner. Given a bright-field microscopic image, TransOrga-plus detects organoids through a multi-modal transformer-based segmentation module. To provide customized and robust organoid analysis, a biological knowledge-driven …

A Standard-Based Taxonomy Of Features That Affect User Response To Clinical Decision Support Alerts, Siru Liu, Allison B Mccoy, Dean F Sittig, Josh F Peterson, Thomas A Lasko, Adam Wright

Faculty, Staff and Student Publications

Objective: The objective of this work is to develop a standard-based taxonomy of features that might affect user response to alerts using evidence from literature and public alert logic repositories.

Methods: We developed a taxonomy of features using multiple sources: (1) the Agency for Healthcare Research and Quality (AHRQ) CDS Connect Repository, (2) alert logic from commercial electronic health record (EHR) customers, and (3) published literature. Three categories (patient, provider, environment/context) were used a priori to develop the taxonomy. The final taxonomy was mapped to the Fast Healthcare Interoperability Resources (FHIR) standard for development of standardized CDS services.

Results: Aggregating …

Emergency Department-Initiated Palliative Care Screening Among Older Adults: A Systematic Review And Meta-Analysis Protocol, Dimitri E Lin, Satheesh Gunaga, Fabrice I Mowbray, Eric D Isaacs, Daniel Markwalter, Naomi George, Alison E Hay, Rita Manfredi, Erica Westlake, Murtaza Akhter, Jason K Bowman, Naomi Rebollo-Lee, Brian Gacioch, Alexander D Ginsburg, Justin Kenneth Brooten, Sarah Pajka, Katie Selman, Paul Bain, Joshua J Davis, Shan Liu, Kei Ouchi

Faculty, Staff and Students Publications

Introduction: The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer's disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient's trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. …

Everolimus And Low-Dose Tacrolimus After Heart Transplant In Children: A Randomized Clinical Trial, Christopher S Almond, Kevin P Daly, Erin L Albers, Juan C Alejos, Rebecca Ameduri, Scott R Auerbach, Lynsey Barkoff, Aliessa P Barnes, Matthew J Bock, Arene Butto, Waldemar F Carlo, Chesney D Castleberry, Maryanne R Chrisant, Shriprasad R Deshpande, William J Dreyer, Melanie D Everitt, Brian Feingold, Selena Gonzales, Seth A Hollander, Steven J Kindel, Gloria L Klein, Ashwin K Lal, Jacqueline M Lamour, Joanne Lee, Minmin Lu, Irene D Lytrivi, Shelley D Miyamoto, Elfriede Pahl, David M Peng, Thomas D Ryan, Tajinder P Singh, Jennifer A Su, David L Sutcliffe, A Marian Ybarra, Steven Zangwill, Joseph W Rossano, Lynn A Sleeper

Faculty, Staff and Students Publications

Importance: Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.

Objective: To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in …

Apoa1 Binding Protein Promotes Lymphatic Cell Fate And Lymphangiogenesis By Relieving Caveolae-Mediated Inhibition Of Vegfr3 Signaling, Jun-Dae Kim, Surbhi Chaudhary, Weiqing Chen, Jonathan Astin, Philip S Crosier, Pengchun Yu, John P Cooke, Henry J Pownall, Hugo J Bellen, Nhat-Tu Le, Daniel L Kiss, Guangyu Wang, Stanley G Rockson, Hong Chen, Longhou Fang

Faculty, Staff and Students Publications

The lymphatic system maintains tissue fluid balance, and its dysfunction can result in lymphedema. Although cholesterol is essential for cellular function, its role in lymphatic development has remained unknown. Here, we identify APOA1 binding protein (AIBP) as a key regulator that promotes lymphatic endothelial cell fate specification and lymphangiogenesis. Mechanistically, AIBP reduces plasma membrane cholesterol content, thereby enhancing VEGFR3 signaling by disrupting caveolae—small plasma membrane invaginations formed by the scaffolding protein caveolin-1 (CAV-1)—and relieving CAV-1–mediated inhibition. In zebrafish and mice, AIBP loss impairs VEGFR3 signaling and lymphatic development, defects that can be rescued by CAV-1 deletion or by a VEGFR3 …

Influences On Emergency Clinician Use Of Health Information Exchange: Interview Study, Brian E. Dixon, Umesh Ghimire, Benjamin Richter, Corinne Bowditch, Saurabh Rahurkar, John T. Finnell, Joshua R. Vest

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Health information exchange (HIE) supports clinical decision-making in emergency medicine settings. Despite evidence and policies that encourage the adoption of HIE, use by clinicians is limited. Moreover, few studies examine HIE use years after adoption by hospitals or clinics.

OBJECTIVE: This study aims to examine the perceptions and use of a mature, operational HIE system by emergency department clinicians years after its implementation.

METHODS: We interviewed 21 clinicians in various roles (eg, attending physician and nurse practitioner) across multiple health systems that participate in a statewide HIE network. We asked questions about their use of the HIE system and …

Insights, Opportunities, And Challenges Provided By Large Cell Atlases, Martin Hemberg, Federico Marini, Shila Ghazanfar, Ahmad Al Ajami, Najla Abassi, Benedict Anchang, Bérénice A Benayoun, Yue Cao, Ken Chen, Yesid Cuesta-Astroz, Zachary Debruine, Calliope A Dendrou, Iwijn De Vlaminck, Katharina Imkeller, Ilya Korsunsky, Alex R Lederer, Jessica Jingyi Li, Pieter Meysman, Clint L Miller, Kerry A Mullan, Uwe Ohler, Pratibha Panwar, Nikolaos Patikas, Jonas Schuck, Jacqueline H Y Siu, Timothy J Triche, Alex Tsankov, Sander W Van Der Laan, Masanao Yajima, Jean Yang, Fabio Zanini, Ivana Jelic

Faculty, Staff and Student Publications

The field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome.

Biallelic Loss-Of-Function Variants In C19orf44 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen

Faculty, Staff and Students Publications

Background: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.

Methods: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to …

Global Age-Sex-Specific All-Cause Mortality And Life Expectancy Estimates For 204 Countries And Territories And 660 Subnational Locations, 1950–2023: A Demographic Analysis For The Global Burden Of Disease Study 2023, Gbd 2023 Demographics Collaborators

Faculty, Staff and Students Publications

BACKGROUND: Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of …