Digital Commons Network^™

Glymphatic Dysfunction In Multiple Sclerosis And Its Association With Disease Pathology And Disability, Ahmed Bayoumi, Khader M Hasan, Joseph A Thomas, Akram Yazdani, John A Lincoln

Faculty, Staff and Student Publications

Background: The role of the glymphatic system in multiple sclerosis (MS)-related disability remains underexplored. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) offers a non-invasive method to assess glymphatic function.

Objective: To evaluate glymphatic function in MS patients with lower and higher disability.

Methods: This study included 118 MS patients who underwent structural, diffusion-weighted imaging, and clinical assessment. The participants were divided into lower (MS-L, n = 57) and higher disability (MS-H, n = 61) subgroups. Brain parenchymal fraction (BPF), lesion load (LL), and DTI-ALPS index were measured. Subgroup differences and correlations between DTI-ALPS index and other measures were explored. …

Contrasting Association Pattern Of Plasma Low-Density Lipoprotein With White Matter Integrity In Apoe4 Carriers Versus Non-Carriers, Zhenyao Ye, Yezhi Pan, Rozalina G Mccoy, Chuan Bi, Chen Mo, Li Feng, Jiaao Yu, Tong Lu, Song Liu, J Carson Smith, Minxi Duan, Si Gao, Yizhou Ma, Chixiang Chen, Braxton D Mitchell, Paul M Thompson, L Elliot Hong, Peter Kochunov, Tianzhou Ma, Shuo Chen

Faculty, Staff and Student Publications

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer’s disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown.

In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1,917 older adults (aged 65.0–81.0 years; 52.4% female).

Although no main association was observed between either APOE4 or metabolites with …

Consensus Molecular Subtyping Of Metastatic Colorectal Cancer Expands Biomarker-Directed Therapeutic Benefit For Patients With Cms1 And Cms2 Tumors, Saikat Chowdhury, Joanne Xiu, Jennifer R Ribeiro, Theodore Nicolaides, Jian Zhang, W Michael Korn, Kelsey A Poorman, Heinz-Josef Lenz, John L Marshall, Matthew J Oberley, George W Sledge, David Spetzler, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).

Methods: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant).

Results: CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer …

Self-Management Intervention Improves Patient Adherence To Swallowing Exercises During Radiation For Head And Neck Cancer, Eileen H Shinn, Adam S Garden, Minxing Chen, Karen Basen-Engquist, Bryan Fellman, Kate Hutcheson, William H Morrison, Susan Peterson, Liang Li

Faculty, Staff and Student Publications

Background: While preventive swallowing exercises reduce the risk of radiation-associated dysphagia in patients with head and neck cancer, strategies are needed to improve patient adherence.

Methods: Before radiation, all participants were taught preventive swallowing exercises and randomized to either an adherence intervention or enhanced usual care. During radiation, all participants met twice with a speech pathologist for swallowing assessment and reinforcement of exercises. Intervention participants met weekly with a counselor in-person or by phone. At 6-week post-radiation follow-up, all participants completed a follow-up assessment of self-reported adherence, which was then corroborated with medical record documentation.

Results: Newly diagnosed pharyngeal and …

Epigenomic And Transcriptomic Profiling Of Solitary Fibrous Tumors Identifies Site-Specific Patterns And Candidate Genes Regulated By Dna Methylation, Hannah C Beird, Jeffrey M Cloutier, Nalan Gokgoz, Christopher Eeles, Anthony M Griffin, Davis R Ingram, Khalida M Wani, Rossana Lazcano Segura, Luca Cohen, Carl Ho, Jay S Wunder, Irene L Andrulis, P Andrew Futreal, Benjamin Haibe-Kains, Alexander J Lazar, Wei-Lien Wang, Joanna Przybyl, Elizabeth G Demicco

Faculty, Staff and Student Publications

A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and …

Genome-Wide Study Of Gene-By-Sex Interactions Identifies Risks For Cleft Palate, Kelsey Robinson, Randy Parrish, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Jeffrey C Murray, Gary M Shaw, Seth M Weinberg, Harrison Brand, Mary L Marazita, David J Cutler, Michael P Epstein, Jingjing Yang, Elizabeth J Leslie

Faculty, Staff and Student Publications

Structural birth defects affect 3–4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified …

Decitabine, Venetoclax, And Ponatinib For Advanced Phase Chronic Myeloid Leukaemia And Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial, Nicholas J Short, Daniel Nguyen, Elias Jabbour, Jayastu Senapati, Zhihong Zeng, Ghayas C Issa, Hussein Abbas, Cedric Nasnas, Wei Qiao, Xuelin Huang, Gautam Borthakur, Kelly Chien, Fadi G Haddad, Naveen Pemmaraju, Omer S Karrar, Danielle Nguyen, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, …

Genomic Alterations In Dna Mismatch Repair Genes Across Different Cancer Types, Vijaykumar R Holla, Michael P Kahle, Sun-Hee Kim, Arash Ronaghy, Richard K Yang, Keyur P Patel, Mark J Routbort, Michael J Overman, Ecaterina E Dumbrava, Kenna R Mills Shaw, Daniel D Karp, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 …

Boosting Acetylcholine Signaling By Cannabidiol In A Murine Model Of Alzheimer's Disease, Hesam Khodadadi, Évila Lopes Salles, Sahar Emami Naeini, Bidhan Bhandari, Hannah M Rogers, Jules Gouron, William Meeks, Alvin V Terry, Anilkumar Pillai, Jack C Yu, John C Morgan, Kumar Vaibhav, David C Hess, Krishnan M Dhandapani, Lei P Wang, Babak Baban

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a challenging medical issue that requires efficacious treatment options to improve long-term quality of life. Cannabidiol (CBD) is a cannabis-derived phytocannabinoid with potential health benefits, including reports from our laboratory and others showing a therapeutic role in the pre-clinical treatment of AD; however, the mechanisms whereby CBD affects AD progression remain undefined. Innate lymphoid cells (ILCs) are recently discovered immune cells that initiate and orchestrate inflammatory responses. ILC2, a sub-class of ILCs, is proposed to have a role in cognitive function via unknown mechanisms. In this present study, we explored whether CBD ameliorates AD symptoms via …

A Phase I Dose Escalation Study Of The Lrp5 Antagonist Bi 905681 In Patients With Advanced And Metastatic Solid Tumors, D. R. Spigel, J. S. Wang, L. Pronk, B. Muskens, M. Teufel, Babar Bashir, H. Burris

Department of Medical Oncology Faculty Papers

BACKGROUND: The Wnt pathway is involved in proliferation and tissue homeostasis. Aberrant activation promotes cancer cell proliferation and survival. Inhibition of the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptors that regulate Wnt signaling could prevent cancer cell proliferation. BI 905681 is a novel LRP5 antagonist that has demonstrated potent in vivo antitumor activity.

PATIENTS AND METHODS: This was a phase I, dose escalation study (NCT04147247) evaluating BI 905681 in patients with advanced solid tumors over two dosing schedules (schedule A: every 3 weeks, 3-week cycles and schedule B: every 2 weeks, 4-week cycles). The primary endpoint was the maximum tolerated …

Integration Across Biophysical Scales Identifies Molecular And Cellular Correlates Of Person-To-Person Variability In Human Brain Connectivity, Bernard Ng, Shinya Tasaki, Kelsey M Greathouse, Courtney K Walker, Ada Zhang, Sydney Covitz, Matt Cieslak, Audrey J Weber, Ashley B Adamson, Julia P Andrade, Emily H Poovey, Kendall A Curtis, Hamad M Muhammad, Jakob Seidlitz, Ted Satterthwaite, David A Bennett, Nicholas T Seyfried, Jacob Vogel, Chris Gaiteri, Jeremy H Herskowitz

Faculty, Staff and Student Publications

Brain connectivity arises from interactions across biophysical scales, ranging from molecular to cellular to anatomical to network level. To date, there has been little progress toward integrated analysis across these scales. To bridge this gap, from a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well as postmortem dendritic spine morphometric, proteomic and gene expression data from the superior frontal and inferior temporal gyri. Through the integration of the molecular and dendritic spine morphology data, we identified hundreds of proteins that explain interindividual differences in functional connectivity and structural covariation. These proteins are enriched for …

Intra-Tumoral And Peripheral Blood Tigit And Pd-1 As Immune Biomarkers In Nodular Lymphocyte Predominant Hodgkin Lymphoma, Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

Faculty, Staff and Student Publications

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or …

Associations Between Epilepsy, Respiratory Impairment, And Minor Ecg Abnormalities In Children, See Wai Chan, Angela Chun, Linh Nguyen, Beth Bubolz, Anne E Anderson, Yi-Chen Lai

Faculty, Staff and Students Publications

Objective: We sought to examine the effects of acute seizures and respiratory derangement on the cardiac electrical properties reflected on the electrocardiogram (ECG); and to analyze their potential interactions with a diagnosis of epilepsy in children.

Methods: Emergency center (EC) visits with seizure or epilepsy diagnostic codes from 1/2011-12/2013 were included if they had ECG within 24 h of EC visit. Patients were excluded if they had pre-existing cardiac conditions, ion channelopathy, or were taking specific cardiac medications. Control subjects were 1:1 age and gender matched. Abnormal ECG was defined as changes in rhythm, PR, QRS, or corrected QT intervals; …

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 …

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 …

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 …

Synaptic Plasticity In The Injured Brain Depends On The Temporal Pattern Of Stimulation, Quentin S Fischer, Djanenkhodja Kalikulov, Gonzalo Viana Di Prisco, Carrie A Williams, Philip R Baldwin, Michael J Friedlander

Faculty, Staff and Students Publications

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency …

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 …

Time To Treatment Versus Health Care Utilization In Compression Fractures Treated With Vertebral Augmentation: The Vertebral Augmentation Care Pathways Case Series, Emanuel Narcis Husu, Edward S Yoon, Neal H Shonnard, Justine Norwitz, Nell Shonnard, Douglas P Beall

Faculty, Staff and Students Publications

Background: There is little data on the economics of the timing of percutaneous vertebral augmentation (PVA) for vertebral compression fractures (VCFs).

Case report: The purpose of this case series is to compare health care utilization (HCU) costs vs the time to treatment (TTT) of the VCF. The BenchMarket Medical VCF Registry (now Talosix) was utilized. Patients receiving acute or intermediate treatment had the greatest pain and function improvement and the lowest HCU costs. Patients receiving delayed treatment had the least improvement and the highest (3-fold) HCU costs. Any TTT delay resulted in higher HCU costs and diminished benefits. The most …

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 …

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) …

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 …

Dna Methylation Classes Of Stage Ii And Iii Primary Melanomas And Their Clinical And Prognostic Significance, Kathleen Conway, Sharon N Edmiston, Amanda Vondras, Allison Reiner, David L Corcoran, Ronglai Shen, Eloise A Parrish, Honglin Hao, Lan Lin, Jessica M Kenney, Gbemisola Ilelaboye, Caroline E Kostrzewa, Pei Fen Kuan, Klaus J Busam, Cecilia Lezcano, Tim K Lee, Eva Hernando, Paul B Googe, David W Ollila, Stergios Moschos, Ivan Gorlov, Christopher I Amos, Marc S Ernstoff, Anne E Cust, James S Wilmott, Richard A Scolyer, Graham J Mann, Ismael A Vergara, Jennifer Ko, Judy R Rees, Shaofeng Yan, Eduardo Nagore, Marcus Bosenberg, Bonnie Gould Rothberg, Iman Osman, Jeffrey E Lee, Yvonne Saenger, Paul Bogner, Cheryl L Thompson, Meg Gerstenblith, Sheri L Holmen, Pauline Funchain, Elise Brunsgaard, Natalie D Depcik-Smith, Li Luo, Tawny Boyce, Irene Orlow, Colin B Begg, Marianne Berwick, Nancy E Thomas

Faculty, Staff and Students Publications

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.

Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of …

Enhancing Early Detection Of Cognitive Decline In The Elderly: A Comparative Study Utilizing Large Language Models In Clinical Notes, Xinsong Du, John Novoa-Laurentiev, Joseph M Plasek, Ya-Wen Chuang, Liqin Wang, Gad A Marshall, Stephanie K Mueller, Frank Chang, Surabhi Datta, Hunki Paek, Bin Lin, Qiang Wei, Xiaoyan Wang, Jingqi Wang, Hao Ding, Frank J Manion, Jingcheng Du, David W Bates, Li Zhou

Faculty, Staff and Students Publications

           Background: Large language models (LLMs) have shown promising performance in various healthcare domains, but their effectiveness in identifying specific clinical conditions in real medical records is less explored. This study evaluates LLMs for detecting signs of cognitive decline in real electronic health record (EHR) clinical notes, comparing their error profiles with traditional models. The insights gained will inform strategies for performance enhancement.

Methods: This study, conducted at Mass General Brigham in Boston, MA, analysed clinical notes from the four years prior to a 2019 diagnosis of mild cognitive impairment in patients aged 50 and older. We developed prompts for two …

Covid-19 Breakthrough Infection After Vaccination And Substance Use Disorders: A Longitudinal Cohort Of People With And Without Hiv Receiving Care In The United States Veterans Health Administration, Elena M Soyer, Kathleen A Mcginnis, Amy C Justice, Evelyn Hsieh, Maria C Rodriguez-Barradas, Emily C Williams, Lesley S Park

Faculty, Staff and Students Publications

Research regarding HIV, substance use disorders (SUD), and SARS-CoV-2 infections after COVID-19 vaccination is limited. In the Veterans Aging Cohort Study (VACS)-HIV cohort, we followed vaccinated persons with HIV (PWH) and without HIV (PWoH) from 12/2020 to 3/2022 and linked SARS-CoV-2 test results for laboratory-confirmed breakthrough infection through 9/2022. We examined associations of substance use (alcohol use disorder [AUD], other SUD, smoking status) and HIV status and severity with breakthrough infections, using Cox proportional hazards regression hazard ratios (HR). To test for potential interactions between substance use and HIV, we fit survival models with a multiplicative interaction term. Among 24,253 …

Cohort Expansion And Genotype-Phenotype Analysis Of Rab11a-Associated Neurodevelopmental Disorder, Maria Carla Borroto, Heena Patel, Siddharth Srivastava, Lindsay C Swanson, Boris Keren, Sandra Whalen, Cyril Mignot, Xiaodong Wang, Qian Chen, Jill A Rosenfeld, Scott Mclean, Rebecca O Littlejohn, Undiagnosed Diseases Network, Lisa Emrick, Lindsay C Burrage, Ruben Attali, Gaetan Lesca, Cecile Acquaviva-Bourdain, Catherine Sarret, Laurie H Seaver, Konrad Platzer, Tobias Bartolomaeus, Cornelia Wünsch, Susann Fischer, Ana Maria Rodriguez Barreto, Jorge L Granadillo, Elisabeth Schreiner, Theresa Brunet, Ulrich A Schatz, Isabelle Thiffault, Sureni V Mullegama, Jacques L Michaud, Fadi F Hamdan, Elsa Rossignol, Philippe M Campeau

Faculty, Staff and Students Publications

Background: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations.

Methods: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate.

Results: We reinforce the …

Biallelic Loss-Of-Function Variants In Ubap1l And Nonsyndromic Retinal Dystrophies, Ehsan Ullah, Siying Lin, Jiaxiong Lu, Chelsea Bender, Andrew R Webster, Samantha Malka, Savita Madhusudhan, Emma Rees, Denise Williams, Aime R Agather, Catherine A Cukras, Robert B Hufnagel, Rui Chen, Laryssa A Huryn, Gavin Arno, Bin Guan

Faculty, Staff and Students Publications

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

Objective: To provide a clinical and molecular characterization of 6 patients with IRDs with biallelic disease-causing variants in a novel candidate IRD disease gene.

Design, setting, and participants: This multicenter case series study included 6 patients with …

Prognostic Stratification In Dlbcl Patients With Aberrant Myc Gene, Jian-Rong Li, Vikram R Shaw, Abi Parthasarathy, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic …

Identifying High-Risk Multiple Myeloma Patients: A Novel Approach Using A Clonal Gene Signature, Jian-Rong Li, Christiana Wang, Chao Cheng

Faculty, Staff and Students Publications

Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients having poor prognoses. Identifying these patients is crucial for treatment management and strategic decisions. In this study, we developed a novel computational framework to define prognostic gene signatures by selecting genes with expression driven by clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of 22 genes and evaluated in five independent datasets. The CGS provided significant prognostic values after adjusting for well-established factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). Importantly, CGS …

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 …