Medicine and Health Sciences Commons^™

Age Modulates The Predictive Value Of Self-Reported Sleepiness For All-Cause Mortality Risk: Insights From A Comprehensive National Database Of Veterans, Arash Maghsoudi, Mehrnaz Azarian, Amir Sharafkhaneh, Melissa B Jones, Hoormehr Nozari, Meir Kryger, Amin Ramezani, Javad Razjouyan

Faculty, Staff and Students Publications

Study objectives: Excessive daytime sleepiness is prevalent and overwhelmingly stems from disturbed sleep. We hypothesized that age modulates the association between excessive daytime sleepiness and increased all-cause mortality.

Methods: We utilized the Veterans' Health Administration data from 1999-2022. We enrolled participants with sleep related International Classification of Diseases 9/10 codes or sleep services. A natural language processing pipeline was developed and validated to extract the Epworth Sleepiness Scale (ESS) as a self-reported tool to measure excessive daytime sleepiness from physician progress notes. The natural language processing's accuracy was assessed through manual annotation of 470 notes. Participants were categorized into normal-ESS …

Genetic Risk Factors In Isolated Dystonia Escape Genome-Wide Association Studies, Björn-Hergen Laabs, Katja Lohmann, Eva-Juliane Vollstedt, Tobias Reinberger, Lisa-Marie Nuxoll, Gamze Kilic-Berkmen, Joel S Perlmutter, Sebastian Loens, Carlos Cruchaga, Andre Franke, Valerija Dobricic, Frauke Hinrichs, Anne Grözinger, Eckart Altenmüller, Steven Bellows, Sylvia Boesch, Susan B Bressman, Kevin R Duque, Alberto J Espay, Andreas Ferbert, Jeanne S Feuerstein, Samuel Frank, Thomas Gasser, Bernhard Haslinger, Robert Jech, Frank Kaiser, Christoph Kamm, Katja Kollewe, Andrea A Kühn, Mark S Ledoux, Ebba Lohmann, Abhimanyu Mahajan, Alexander Münchau, Trisha Multhaupt-Buell, Alexander Pantelyat, Sarah E Pirio Richardson, Deborah Raymond, Stephen G Reich, Rachel Saunders Pullman, Barbara Schormair, Nutan Sharma, Azadeh Hamzehei Sichani, Kristina Simonyan, Jens Volkmann, Aparna Wagle Shukla, Juliane Winkelmann, Laura J Wright, Michael Zech, Kirsten E Zeuner, Simone Zittel, Meike Kasten, Yan V Sun, Tobias Bäumer, Norbert Brüggemann, Laurie J Ozelius, Hyder A Jinnah, Christine Klein, Inke R König

Faculty, Staff and Students Publications

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.

Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.

Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.

Results: This GWAS identified no common genome-wide significant …

Shear Stress Induces A Time-Dependent Inflammatory Response In Human Monocyte-Derived Macrophages, Elysa Jui, Griffin Kingsley, Hong Kim T Phan, Kavya L Singampalli, Ravi K Birla, Jennifer P Connell, Sundeep G Keswani, K Jane Grande-Allen

Faculty, Staff and Students Publications

Macrophages are innate immune cells that are known for their extreme plasticity, enabling diverse phenotypes that lie on a continuum. In a simplified model, they switch between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes depending on surrounding microenvironmental cues, which have been implicated in disease outcomes. Although considerable research has been focused on macrophage response to biochemical cues and mechanical signals, there is a scarcity of knowledge surrounding their behavior in response to shear stress. In this study, we applied varying magnitudes of shear stress on human monocyte-derived macrophages (MDMs) using a cone-and-plate viscometer and evaluated changes in morphology, gene expression, …

Identification Of Single-Cell Blasts In Pediatric Acute Myeloid Leukemia Using An Autoencoder, Alice Driessen, Susanne Unger, An-Phi Nguyen, Rhonda E Ries, Soheil Meshinchi, Stefanie Kreutmair, Chiara Alberti, Pavel Sumazin, Richard Aplenc, Michele S Redell, Burkhard Becher, María Rodríguez Martínez

Faculty, Staff and Students Publications

Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell …

Yield Of Skeletal Surveys In National Network Of Child Abuse Pediatricians: Age Is Key, Caitlin R Mcnamara, Joanne N Wood, Daniel Lindberg, Kristine A Campbell, Spencer Poston, Matthew Valente, Maria Antonucci, Jennifer Wolford, Carmen Coombs, Hannah Sahud, Jennifer Clarke, Farah W Brink, Angela Bachim, Lori D Frasier, Nancy S Harper, John D Melville, Natalie Laub, James Anderst, Rachel P Berger

Faculty, Staff and Students Publications

Background: Skeletal surveys (SS) are recommended for the evaluation of suspected physical abuse in children < 2 years old. No guidelines exist for SS completion in children between 2 and 5 years old.

Objective: To determine rates of SS completion by age and examine variables associated with occult fracture identification in older children.

Participants and setting: Observational cross-sectional multi-center study of 10 US pediatric centers 2/2021-9/2022 including children < 6 years old evaluated for physical child abuse.

Methods: The principal outcome is occult fracture identified on SS. Non-parametric tests were conducted from comparison between age groups and those with and without occult fractures.

Results: The rate of SS completion declined with increasing age from a high of 91 % in infants < 6 months old to 7 % in children 5-5.9 years old. The proportion of SS with occult fractures also decreased with age. Of 450 children 2-5 years old with a SS, 20 [4 % (95 % CI: 3-8 %)] had an occult fracture. The rate of occult fractures among children 2-5 years old who were diagnosed with abuse and not admitted to the hospital was 0.3 % (95 % CI 0-0.6 %)]. Over 30 % of children 2-5 years old were diagnosed with child abuse by a child abuse pediatrician without completion of a SS.

Conclusion: In children 2-5 years of …

Challenges And Rewards Of In Vivo Synaptic Density Imaging, And Its Application To The Study Of Depression, Ruth H Asch, Chadi G Abdallah, Richard E Carson, Irina Esterlis

Faculty, Staff and Students Publications

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a …

Perivascular Epithelioid Cell-Family Tumors In Children, Adolescents, And Young Adults: Clinicopathologic Features In 70 Cases, Phoebe M Hammer, Angus Toland, Muhammad Shaheen, Archana Shenoy, Ashwini Esnakula, M John Hicks, Mikako Warran, Alyaa Al-Ibraheemi, Jessica L Davis, Serena Y Tan

Faculty, Staff and Students Publications

Context.—: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented.

Objective.—: To describe a multi-institutional series of PEComas in children, adolescents, and young adults.

Design.—: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and the authors' files.

Results.—: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominantly in the kidney (53 of 70), followed by the …

Suppression Of Matrigel-Induced Choroidal Neovascularization By Aav Delivery Of A Novel Anti-Scg3 Antibody, Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block …

An Artificial Intelligence-Generated Model Predicts 90-Day Survival In Alcohol-Associated Hepatitis: A Global Cohort Study, Winston Dunn, Yanming Li, Ashwani K Singal, Douglas A Simonetto, Luis A Díaz, Francisco Idalsoaga, Gustavo Ayares, Jorge Arnold, María Ayala-Valverde, Diego Perez, Jaime Gomez, Rodrigo Escarate, Eduardo Fuentes-López, Carolina Ramirez-Cadiz, Dalia Morales-Arraez, Wei Zhang, Steve Qian, Joseph C Ahn, Seth Buryska, Heer Mehta, Nicholas Dunn, Muhammad Waleed, Horia Stefanescu, Andreea Bumbu, Adelina Horhat, Bashar Attar, Rohit Agrawal, Joaquín Cabezas, Victor Echavaría, Berta Cuyàs, Maria Poca, German Soriano, Shiv K Sarin, Rakhi Maiwall, Prasun K Jalal, Fátima Higuera-De-La-Tijera, Anand V Kulkarni, P Nagaraja Rao, Patricia Guerra-Salazar, Lubomir Skladaný, Natália Kubánek, Veronica Prado, Ana Clemente-Sanchez, Diego Rincon, Tehseen Haider, Kristina R Chacko, Gustavo A Romero, Florencia D Pollarsky, Juan C Restrepo, Luis G Toro, Pamela Yaquich, Manuel Mendizabal, Maria L Garrido, Sebastián Marciano, Melisa Dirchwolf, Victor Vargas, César Jiménez, David Hudson, Guadalupe García-Tsao, Guillermo Ortiz, Juan G Abraldes, Patrick S Kamath, Marco Arrese, Vijay H Shah, Ramon Bataller, Juan Pablo Arab

Faculty, Staff and Students Publications

Background and aims: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model.

Approach and results: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) …

Neighborhood-Level Deprivation Mediates Racial And Ethnic Disparities In Hcc Diagnosis In Texas, Itunu O Sokale, Aaron P Thrift, Hashem B El-Serag, Abiodun O Oluyomi

Faculty, Staff and Students Publications

BACKGROUND: Texas has the highest HCC rates in the United States, and the greatest burden is among Hispanics. Racial and ethnic disparities in HCC incidence have multiple underpinning factors. We conducted a mediation analysis to examine the role of neighborhood disadvantage (Area Deprivation Index) as a potential mediator of the association between neighborhood race and ethnicity distribution and neighborhood HCC case counts in Texas.

METHODS: The primary outcome measure was counts of new HCC diagnoses per census tract based on Texas Department of State Health Services Texas Cancer Registry data. The primary exposure of interest was the race and ethnicity-based …

Trends And Disparities In Coronary Artery Disease And Obesity-Related Mortality In The United States From 1999-2022, Mushood Ahmed, Hira Javaid, Aimen Shafiq, Zain Ali Nadeem, Areeba Ahsan, Abdullah Nofal, Raheel Ahmed, Mahboob Alam, Marat Fudim, Gregg C Fonarow, Mamas A Mamas

Faculty, Staff and Students Publications

BACKGROUND: Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location.

METHODS: The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint …

Pkc-Mediated Phosphorylation Governs The Stability And Function Of Celf1 As A Driver Of Emt In Breast Epithelial Cells, Shebna Massey, Natee Kongchan, Yang Gao, Arindam Chaudhury, Emuejevoke Olokpa, Jason Karch, Anna Malovannaya, Chonghui Cheng, Xiang Zhang, Joel R Neilson

Faculty, Staff and Students Publications

Epithelial to mesenchymal transition (EMT) is believed to be a principal factor contributing to cancer metastasis. The post-transcriptional and post-translational mechanisms underlying EMT are comparatively underexplored. We previously demonstrated that the CELF1 RNA binding protein is necessary and sufficient to drive the EMT of breast epithelial cells, and that the relative protein expression of CELF1 in this context was dictated at the post-translational level. Here, we elucidate the mechanism of this regulation. Mass spectrometric analysis of CELF1 isolated from mesenchymal MCF-10A cells identified multiple sites of serine and threonine phosphorylation on the protein, correlating with the increased stability of this …

Pancreatitis Pain Quality Changes At Year 1 Follow-Up, But Gp130 Remains A Biomarker For Pain, Jami L Saloman, Kristofer Jennings, Kimberly Stello, Shuang Li, Anna Evans Phillips, Kristen Hall, Evan L Fogel, Santhi Swaroop Vege, Dana K Andersen, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Mark D Topazian, Stephen K Van Den Eeden, Jose Serrano, Darwin L Conwell, Liang Li, Dhiraj Yadav

Center for Medical Ethics and Health Policy Staff Publications

Background/objectives: Debilitating abdominal pain is a common symptom affecting patients with chronic pancreatitis (CP). CP pain is dynamic due to multiple underlying mechanisms. The objective of this study was to 1) evaluate changes in pain phenotype at one year follow-up and 2) validate putative pain biomarkers in a prospective cohort study.

Methods: The Neuropathic and Nociceptive PROMIS-PQ questionnaires were used to classify pain for participants with in the PROCEED study. Putative serum biomarkers were measured via immunoassay.

Results: At enrollment, 17.6 % (120/681) subjects with CP reported no pain in the previous year. Of those, 29 % experienced pain during …

Exploring Latent Clusters In Pediatric Ocd Based On Symptoms, Severity, Age, Gender, And Comorbidity, Orri Smárason, Robert R Selles, Davíð R M A Højgaard, John R Best, Karin Melin, Tord Ivarsson, Per Hove Thomsen, Bernhard Weidle, Nicole Michelle Mcbride, Eric A Storch, Daniel Geller, Sabine Wilhelm, Lara J Farrell, Allison M Waters, Sharna Mathieu, Noam Soreni, S Evelyn Stewart, Gudmundur Skarphedinsson

Center for Medical Ethics and Health Policy Staff Publications

Given diverse symptom expression and high rates of comorbid conditions, the present study explored underlying commonalities among OCD-affected children and adolescents to better conceptualize disorder presentation and associated features. Data from 830 OCD-affected participants presenting to OCD specialty centers was aggregated. Dependent mixture modeling was used to examine latent clusters based on their age- and gender adjusted symptom severity (as measured by the Children's Yale-Brown Obsessive-Compulsive Scale; CY-BOCS), symptom type (as measured by factor scores calculated from the CY-BOCS symptom checklist), and comorbid diagnoses (as assessed via diagnostic interviews). Fit statistics favored a four-cluster model with groups distinguished primarily by …

Measuring Perceived Utility Of Genomic Sequencing: Development And Validation Of The Genetic Utility (Gene-U) Scale For Adult Screening, Hadley Stevens Smith, Caryn Kseniya Rubanovich, Jill Oliver Robinson, Ariel N Levchenko, Sarah A Classen, Janet Malek, Adam H Buchanan, Barbara Biesecker, Kyle B Brothers, Benjamin S Wilfond, Christine Rini, Cinnamon S Bloss, Amy L Mcguire, Sara J Knight

Center for Medical Ethics and Health Policy Staff Publications

Purpose: As population-based screening programs to identify genetic conditions in adults using genomic sequencing (GS) are increasingly available, validated patient-centered outcome measures are needed to understand participants' experience. We aimed to develop and validate an instrument to assess the perceived utility of GS in the context of adult screening.

Methods: Informed by a 5-domain conceptual model, we used a 5-step approach to instrument development and validation: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Adults undergoing risk-based or population-based GS who had received GS results as part …

Universal Clinical Decision Support Tool For Thromboprophylaxis In Hospitalized Covid-19 Patients: Post Hoc Analysis Of The Improve-Dd Cluster Randomized Trial, Mark Goldin, Nikolaos Tsaftaridis, Ioannis Koulas, Jeffrey Solomon, Michael Qiu, Tungming Leung, Kolton Smith, Kanta Ochani, Thomas Mcginn, Alex C Spyropoulos

Faculty, Staff and Students Publications

Background: Inpatient and extended postdischarge thromboprophylaxis of COVID-19 patients remains suboptimal despite antithrombotic guidelines.

Objectives: To determine whether a novel electronic health record-agnostic clinical decision support (CDS) tool incorporating the International Medical Prevention Registry on Venous Thromboembolism plus D-dimer (IMPROVE-DD) venous thromboembolism (VTE) scores increases appropriate inpatient and extended postdischarge thromboprophylaxis and improves outcomes in COVID-19 inpatients.

Methods: This post hoc analysis of the IMPROVE-DD cluster randomized trial evaluated thromboprophylaxis CDS among COVID-19 inpatients at 4 New York hospitals between December 21, 2020, and January 21, 2022. Hospitals were randomized 1:1 to CDS (intervention, n = 2) vs no CDS …

Residential Proximity To Oil And Gas Developments And Childhood Cancer Survival, Thanh T Hoang, Rutu A Rathod, Omar Rosales, Maria I Castellanos, Jeremy M Schraw, Elyse Burgess, Erin C Peckham-Gregory, Abiodun O Oluyomi, Michael E Scheurer, Amy E Hughes, Philip J Lupo

Faculty, Staff and Students Publications

Background: Environmental toxicants may impact survival in children with cancer, but the literature investigating these associations remains limited. Because oil and gas developments emit several hazardous air pollutants, the authors evaluated the relationship between residential proximity to oil or gas development and survival across 21 different pediatric cancers.

Methods: The Texas Cancer Registry had 29,730 children (≤19 years old) diagnosed with a primary cancer between 1995 to 2017. Geocoded data were available for 285,266 active oil or gas wells and 109,965 horizontal wells. The authors calculated whether each case lived within 1000 m (yes/no) from each type of oil or …

Evaluation Of Chronic Pancreatitis Prognosis Score In An American Cohort, Soo Kyung Park, Darwin L Conwell, Phil A Hart, Shuang Li, Kimberly Stello, Evan L Fogel, William E Fisher, Christopher E Forsmark, Stephen J Pandol, Walter G Park, Mark Topazian, Jose Serrano, Santhi Swaroop Vege, Stephen K Van Den Eeden, Liang Li, Dhiraj Yadav, Jami L Saloman

Faculty, Staff and Student Publications

Introduction: Chronic Pancreatitis Prognosis Score (COPPS) was developed to discriminate disease severity and predict risk for future hospitalizations. In this cohort study, we evaluated if COPPS predicts the likelihood of hospitalization(s) in an American cohort.

Methods: The Chronic Pancreatitis, Diabetes, and Pancreatic Cancer consortium provided data and serum from subjects with chronic pancreatitis (N = 279). COPPS was calculated with baseline data and stratified by severity (low, moderate, and high). Primary endpoints included number and duration of hospitalizations during 12-month follow-up.

Results: The mean ± SD COPPS was 8.4 ± 1.6. COPPS correlated with all primary outcomes: hospitalizations for any …

Polygenic Risk Scores And Extreme Coronary Artery Calcium Phenotypes (Cac=0 And Cac≥1000) In Adults ≥75 Years Old: The Aric Study, Omar Dzaye, Alexander C Razavi, Zeina A Dardari, Frances M Wang, Yasuyuki Honda, Khurram Nasir, Josef Coresh, Candace M Howard-Claudio, Jin Jin, Bing Yu, Paul S De Vries, Lynne Wagenknecht, Aaron R Folsom, Ron Blankstein, Tanika N Kelly, Seamus P Whelton, Martin Bødtker Mortensen, Ziqiao Wang, Nilanjan Chatterjee, Kunihiro Matsushita, Michael J Blaha

Faculty, Staff and Student Publications

Background: Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. However, the genetic underpinnings of differences in arterial aging remain unclear. We sought to determine the independent association of 2 polygenic scores for coronary heart disease (CHD) with CAC in adults ≥75 years of age.

Methods: There were 1865 ARIC (Atherosclerosis Risk in Communities) participants who underwent genetic testing at visit 1 (1987-1989) and CAC scans …

Metabolic Stress Induces A Double-Positive Feedback Loop Between Ampk And Sqstm1/P62 Conferring Dual Activation Of Ampk And Nfe2l2/Nrf2 To Synergize Antioxidant Defense, Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon

Staff and Researcher Publications

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, …

Update On Pediatric Cancer Surveillance Recommendations For Patients With Neurofibromatosis Type 1, Noonan Syndrome, Cbl Syndrome, Costello Syndrome, And Related Rasopathies, Melissa R Perrino, Anirban Das, Sarah R Scollon, Sarah G Mitchell, Mary-Louise C Greer, Marielle E Yohe, Jordan R Hansford, Jennifer M Kalish, Kris Ann P Schultz, Suzanne P Macfarland, Wendy K Kohlmann, Philip J Lupo, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Marjolijn C J Jongmans, Gail E Tomlinson, Jack Brzezinski, Uri Tabori, Gina M Ney, Karen W Gripp, Andrea M Gross, Brigitte C Widemann, Douglas R Stewart, Emma R Woodward, Christian P Kratz

Center for Medical Ethics and Health Policy Staff Publications

Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which …

Automated Electronic Health Record Data Extraction And Curation Using Extractehr, Tamara P Miller, Kelly D Getz, Edward Krause, Yun Gun Jo, Sandhya Charapala, M Monica Gramatages, Karen Rabin, Michael E Scheurer, Jennifer J Wilkes, Brian T Fisher, Richard Aplenc

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Although the potential transformative effect of electronic health record (EHR) data on clinical research in adult patient populations has been very extensively discussed, the effect on pediatric oncology research has been limited. Multiple factors contribute to this more limited effect, including the paucity of pediatric cancer cases in commercial EHR-derived cancer data sets and phenotypic case identification challenges in pediatric federated EHR data.

Methods: The ExtractEHR software package was initially developed as a tool to improve clinical trial adverse event reporting but has expanded its use cases to include the development of multisite EHR data sets and the support …

Serum Levels Of Total Bile Acids Are Associated With An Increased Risk Of Hcc In Patients With Cirrhosis, Hashem B El-Serag, Aaron P Thrift, Hao Duong, Jing Ning, Saira Khaderi, Amit G Singal, Sumeet K Asrani, Jorge A Marrero, Hannah Powell, Kinza Rizwan, Omar Najjar, Christopher I Amos, Michelle Luster, Abeer Al-Sarraj, Emad Salem, Michael E Scheurer, Jagpreet Chhatwal, Salma Kaochar, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND: Previous studies have reported higher circulating bile acid levels in patients with HCC compared to healthy controls. However, the association between prediagnostic bile acid levels and HCC risk among patients with cirrhosis is unclear.

METHODS: We measured total BA (TBA) concentration in serum samples collected from a prospective cohort of patients with cirrhosis who were followed until the development of HCC, death, or last study date. Competing risk proportional hazard-adjusted models were used to estimate the association between tertiles of serum TBA levels and the risk of developing HCC. We quantified the incremental predictive value of serum bile acid …

Tfeb Controls Syncytiotrophoblast Formation And Hormone Production In Placenta, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Chiara Soldati, Margherita Mutarelli, Sandro Montefusco, Giuseppina Grieco, Lucia Vittoria Sepe, Barbara Rossi, Edoardo Nusco, Giada Rossignoli, Giorgia Panebianco, Fabrizio Merciai, Emanuela Salviati, Eduardo Maria Sommella, Pietro Campiglia, Graziano Martello, Davide Cacchiarelli, Diego Luis Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of …

First Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Settingfirst Interim Results From Fine-Real: A Prospective, Non-Interventional, Phase 4 Study Providing Insights Into The Use And Safety Of Finerenone In A Routine Clinical Setting, Susanne B Nicholas, Ricardo Correa-Rotter, Nihar R Desai, Lixin Guo, Sankar D Navaneethan, Kevin M Pantalone, Christoph Wanner, Stefanie Hamacher, Samuel T Fatoba, Andrea Horvat-Broecker, Antonio Garreta-Rufas, Alain Gay, Martin Merz, David C Wheeler

Center for Medical Ethics and Health Policy Staff Publications

Background: Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). The FINE-REAL study (NCT05348733) aims to evaluate the characteristics and treatment patterns of participants treated with finerenone in clinical practice.

Methods: FINE-REAL is a prospective, single-arm, non-interventional study of patients initiated on finerenone as part of their routine care in accordance with country-approved labels. The study, initiated in June 2022, is expected to be completed by January 2028. The cutoff for this pre-specified interim analysis was June 13, 2023.

Results: Participants were …

Revealing Patterns Of Sars-Cov-2 Variant Emergence And Evolution Using Rbd Amplicon Sequencing Of Wastewater, Xingwen Chen, John Balliew, Cici X Bauer, Jennifer Deegan, Anna Gitter, Blake M Hanson, Anthony W Maresso, Michael J Tisza, Catherine L Troisi, Janelle Rios, Kristina D Mena, Eric Boerwinkle, Fuqing Wu

Faculty, Staff and Student Publications

Objectives: Rapid evolution of SARS-CoV-2 has resulted in the emergence of numerous variants, posing significant challenges to public health surveillance. Clinical genome sequencing, while valuable, has limitations in capturing the full epidemiological dynamics of circulating variants in the general population. This study aimed to monitor the SARS-CoV-2 variant community dynamics and evolution using receptor-binding domain (RBD) amplicon sequencing of wastewater samples.

Methods: We sequenced wastewater from El Paso, Texas, over 17 months, compared the sequencing data with clinical genome data, and performed biodiversity analysis to reveal SARS-CoV-2 variant dynamics and evolution.

Results: We identified 91 variants and observed waves of …

Natural History Of Indeterminate Liver Nodules In Patients With Advanced Liver Disease: A Multicenter Retrospective Cohort Study, Amit G Singal, Neehar D Parikh, Kirti Shetty, Steven-Huy Han, Cassie Xie, Jing Ning, Jo Ann Rinaudo, Ashwini Arvind, Anna S Lok, Fasiha Kanwal, Translational Liver Cancer Investigators

Faculty, Staff and Students Publications

Introduction: Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear.

Methods: We conducted a multicenter retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks.

Results: …

Xenomake: A Pipeline For Processing And Sorting Xenograft Reads From Spatial Transcriptomic Experiments, Benjamin S Strope, Katherine E Pendleton, William Z Bowie, Gloria V Echeverria, Qian Zhu

Faculty, Staff and Students Publications

SUMMARY: Xenograft models are attractive models that mimic human tumor biology and permit one to perturb the tumor microenvironment and study its drug response. Spatially resolved transcriptomics (SRT) provides a powerful way to study the organization of xenograft models, but currently there is a lack of specialized pipeline for processing xenograft reads originated from SRT experiments. Xenomake is a standalone pipeline for the automated handling of spatial xenograft reads. Xenomake handles read processing, alignment, xenograft read sorting, and connects well with downstream spatial analysis packages. We additionally show that Xenomake can correctly assign organism-specific reads, reduce sparsity of data by …

Macrophage Iron Dyshomeostasis Promotes Aging-Related Renal Fibrosis, Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular …

Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab For Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results And Correlative Analyses From Atempt, Paolo Tarantino, Ron Bose, Et Al.

2020-Current year OA Pubs

PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.

METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. …