Digital Commons Network^™

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L Demeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael Lenoir, Changwei Li, Loic Le Marchand, Merry-Lynn N Mcdonald, Caitlin P Mchugh, Alanna C Morrison, Take Naseri, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-Der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice

Faculty, Staff and Student Publications

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

Effects Of Metformin Use On Aneurysmal Subarachnoid Hemorrhage Outcomes, Angel Bueno, Andrea Becerril-Gaitan, Collins Mokua, Kristina Ramirez-Garcia, Justin Nguyen, Faris Shaker, Tien Nguyen, Antonio Dono, Spiros Blackburn, Peng Roc Chen, Mark Dannenbaum, H Alex Choi, Arthur L Day, Jacques J Morcos, Ching-Jen Chen

Faculty, Staff and Student Publications

Background: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.

Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.

Results: A total of 900 patients …

Association Of Clonal Hematopoiesis Of Indeterminate Potential With Cardiovascular Events In Patients With Ckd, Yang Pan, Caitlyn Vlasschaert, Varun Rao, Elvis A Akwo, James E Hixson, Md Mesbah Uddin, Zhi Yu, Do-Kyun Kim, Alexander Bick, Bryan Kestenbaum, Michael Chong, Guillaume Paré, Michael Rauh, Adeera Levin, James P Lash, Manjula Kurella Tamura, Debbie L Cohen, Jiang He, Lee Hamm, Rajat Deo, Zeenat Bhat, Panduranga Rao, Dawei Xie, Pradeep Natarajan, Tanika N Kelly, Cassianne Robinson-Cohen, Matthew B Lanktree

Faculty, Staff and Student Publications

Key Points:

1. In patients with CKD, non-DNMT3A clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events.

2. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race.

3. The protective effect of IL6R p.Asp358Ala on non-DNMT3A CHIP cardiovascular risk was similar to the general population.

Background: Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of …

Cell Type-Specific Multi-Omics Analysis Of Cocaine Use Disorder In The Human Caudate Nucleus, Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja P Völker, Svenja Müller, Anita C Hansson, Thomas D Meyer, Marcella Rietschel, Julia Ladewig, Rainer Spanagel, Ana M M Oliveira, Consuelo Walss-Bass, Rick E Bernardi, Philipp Koch, Stephanie H Witt

Faculty, Staff and Student Publications

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

Faculty, Staff and Student Publications

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …

Can Endothelin-1 Help Address The Diagnostic And Prognostic Challenges In Multimorbid Acute Heart Failure Patients?, Bianca-Ana Dmour, Minerva Codruta Badescu, Cristina Tuchiluș, Corina Maria Cianga, Daniela Constantinescu, Nicoleta Dima, Ștefania Teodora Duca, Awad Dmour, Alexandru Dan Costache, Maria-Ruxandra Cepoi, Adrian Crișan, Sabina Andreea Leancă, Cătălin Loghin, Ionela-Lăcrămioara Șerban, Irina Iuliana Costache-Enache

Faculty, Staff and Student Publications

The management of acute heart failure (AHF) is becoming increasingly complex, especially in patients with multiple comorbidities. Endothelin-1 (ET-1), a vasoconstrictive peptide, is an important mediator of neurohormonal activation, endothelial dysfunction, and cardiac remodeling-key processes involved in the pathogenesis of AHF. The aim of our study was to evaluate the diagnostic and prognostic performance of ET-1 in multimorbid AHF patients, compared to established markers such as amino terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI). We conducted a single-center prospective study including 76 patients; 54 with AHF and 22 serving as controls. Upon admission, all patients …

Geographic Divergence Of Methicillin-Resistant Staphylococcus Aureus St5-Scc Mec I In The Aftermath Of A Major Earthquake And Tsunami: Impact Of A Plasmid Harboring Heavy Metal Resistance Genes, Jose R W Martínez, Manuel Alcalde-Rico, Estefanía Jara-Videla, Jinnethe Reyes, Lina P Carvajal, Sandra Rincon, Rafael Ríos, Lorena Diaz, Ana Quesille-Villalobos, Roberto Riquelme-Neira, Lina Rivas, Ahmed M Moustafa, Blake Hanson, Eduardo A Undurraga, Jorge Olivares-Pacheco, Patricia García, Rafael Araos, Paul J Planet, César A Arias, Jose M Munita

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health menace. The global spread of MRSA is characterized by successive waves of epidemic clones dominating specific geographical regions. The acquisition of genes encoding resistance to heavy metals (HMRGs) is thought to be a key feature in the geographic divergence of MRSA. However, the cause-effect relationship between the presence of HMRGs and the divergence of MRSA clones remains to be clarified. In this study, we assessed the role that HMRGs may have played in the evolutionary divergence of the MRSA ST5-SCCmecI lineage in Latin America. We conducted a genomic characterization …

Gpat4 Sustains Endoplasmic Reticulum Homeostasis In Endocardial Cells And Safeguards Heart Development, Tianyang Zhao, Kuipei Jin, Xiaodong Wang, Xiong Su, Youjun Wang, Mingming Gao, Wen Luo, Hongyuan Yang, Zhongzhou Yang

Faculty, Staff and Student Publications

The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate …

Leveraging Llms To Understand Narratives In Maude Reports, Yuheng Shi, Yang Gong

Faculty, Staff and Student Publications

Interest in using the MAUDE database to investigate adverse events linked to medical devices has been growing. Yet, the narrative sections of these reports remain largely unexplored, leaving valuable insights unutilized and creating an incomplete understanding of these events. To bridge this gap, we employ large language models (LLMs) to analyze and interpret these narratives. Using OpenAI's GPT-4-turbo model, we focused on MAUDE reports involving endoscopic clips to identify uncoded surgical procedures and uncover additional insights. This approach showcases the potential of LLMs in processing narrative content, offering a more efficient and cost-effective alternative to previous methods and supporting the …

A Scoping Review Of Omop Cdm Adoption For Cancer Research Using Real World Data, Liwei Wang, Andrew Wen, Sunyang Fu, Xiaoyang Ruan, Ming Huang, Rui Li, Qiuhao Lu, Heather Lyu, Andrew E Williams, Hongfang Liu

Faculty, Staff and Student Publications

The Observational Medical Outcomes Partnership (OMOP) common data model (CDM) supports large-scale research by enabling distributed network analyses. However, the breadth of its adoption in cancer research is not well understood. We conducted a scoping review to describe the adoption of the OMOP CDM in cancer research. A total of 49 unique articles were included in the review, with 30 on the data analysis theme, and 20 on the infrastructure theme. This review highlighted that while the OMOP CDM ecosystem has enabled successful data support for cancer research, particularly for collaborative studies, ongoing model development and iterative improvement remain needed …

A Folding-Docking-Affinity Framework For Protein-Ligand Binding Affinity Prediction, Ming-Hsiu Wu, Ziqian Xie, Degui Zhi

Faculty, Staff and Student Publications

Accurate protein-ligand binding affinity prediction is crucial in drug discovery. Existing methods are predominately docking-free, without explicitly considering atom-level interaction between proteins and ligands in scenarios where crystallized protein-ligand binding conformations are unavailable. Now, with breakthroughs in deep learning AI-based protein folding and binding conformation prediction, can we improve binding affinity prediction? This study introduces a framework, Folding-Docking-Affinity (FDA), which folds proteins, determines protein-ligand binding conformations, and predicts binding affinities from three-dimensional protein-ligand binding structures. Our experimental results indicate that FDA performs comparably to state-of-the-art docking-free methods. We anticipate that our proposed framework serves as a starting point for integrating …

Alterations In Dna Methylation, Proteomic, And Metabolomic Profiles In African Ancestry Populations With Apol1 Risk Alleles, Xinruo Zhang, Ashley W Scadden, Amarnath Marthi, Victoria L Buchanan, Yishu Qu, Kendra R Ferrier, Brian D Chen, Mariaelisa Graff, Julian Avila, Eric Boerwinkle, Steven Buyske, Clary B Clish, Dan Cruz, Myriam Fornage, Robert E Gerzsten, Christopher R Gignoux, Lashaunta Glover, Lifang Hou, Anne E Justice, Charles Kooperberg, Holly Kramer, Leslie Lange, Ruth J F Loos, Tara Matise, Josyf C Mychaleckyj, Opeyemi A Olabisi, Ulrike Peters, Laura M Raffield, Alex P Reiner, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Bing Yu, Yinan Zheng, Kari E North, Amy K Mottl, Heather M Highland, Maggie A Stanislawski

Faculty, Staff and Student Publications

Key Points:

1. We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which APOL1 variants may be linked to kidney disease.

2. We report distinct methylation profiling between APOL1 risk allele carriers and noncarriers, many near APOL gene family.

3. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers.

Background: The APOL1 high-risk haplotype has been associated with CKD and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated.

Methods: …

Exploring The Impact Of Reduction In Methamphetamine Use On Sexual Risk Behaviors Among Men Who Have Sex With Men And Women: Findings From The Adapt- 2 Trial, Chukwuemeka N Okafor, Jin H Yoon, Ducel Jean-Berluche, Taryn L Mayes, Steve Shoptaw, Madhukar H Trivedi, Jennifer S Potter, Joy Schmitz

Faculty, Staff and Student Publications

Background: Methamphetamine (MA) use has been linked to engaging in sexual risk behaviors (SRBs) that are associated with HIV/STIs, particularly among men who have sex with men (MSM) and men who have sex with men and women (MSMW; hereafter MSM/W). The objectives of this analysis were to determine whether reduced MA is associated with decreases in SRBs in a sample of MSM/W.

Method: Data came from the ADAPT- 2 trial, a randomized, double-blind, two-stage sequential parallel design trial evaluating extended-release injectable naltrexone (NTX) and oral bupropion (BUP) vs. placebo for MA use disorder. In the first 6 weeks of the …

Association Of Age, Sex And Education With Access To The Intravenous Thrombolysis For Acute Ischemic Stroke, Yoona Ko, Beom Joon Kim, Youngran Kim, Jong-Moo Park, Kyusik Kang, Jae Guk Kim, Jae-Kwan Cha, Tai Hwan Park, Kyungbok Lee, Jun Lee, Keun-Sik Hong, Byung-Chul Lee, Kyung-Ho Yu, Dong-Eog Kim, Joon-Tae Kim, Jay Chol Choi, Jee Hyun Kwon, Wook-Joo Kim, Kyu Sun Yum, Sung-Il Sohn, Hyungjong Park, Sang-Hwa Lee, Kwang-Yeol Park, Chi Kyung Kim, Sung Hyuk Heo, Moon-Ku Han, Anjail Z Sharrief, Sunil A Sheth, Hee-Joon Bae

Faculty, Staff and Student Publications

Background: Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients.

Methods: We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed …

Referrals And Repeat Screening For Social Determinants Of Health In Pediatric Primary Care, Ashley Gibson, Rachel Eisenhauer

Faculty, Staff and Student Publications

Background: While healthcare screening for social determinants of health (SDOH) is increasing, not every patient who screens positive receives a referral to care coordination (community health workers, social workers, or case managers). Additionally, the impact of referral on patients' repeat screening is unknown.

Objective: The study aims to identify specific domains of SDOH that are associated with referrals to care coordination and assess the outcome of patients re–screened for SDOH at routine pediatric visits within 1 year. Additionally, this study aims to compare the SDOH needs identified on the initial and repeat screen.

Methods: The population includes patients who screened …

Benchmarking Large Language Models For Biomedical Natural Language Processing Applications And Recommendations, Qingyu Chen, Yan Hu, Xueqing Peng, Qianqian Xie, Qiao Jin, Aidan Gilson, Maxwell B Singer, Xuguang Ai, Po-Ting Lai, Zhizheng Wang, Vipina K Keloth, Kalpana Raja, Jimin Huang, Huan He, Fongci Lin, Jingcheng Du, Rui Zhang, W Jim Zheng, Ron A Adelman, Zhiyong Lu, Hua Xu

Faculty, Staff and Student Publications

The rapid growth of biomedical literature poses challenges for manual knowledge curation and synthesis. Biomedical Natural Language Processing (BioNLP) automates the process. While Large Language Models (LLMs) have shown promise in general domains, their effectiveness in BioNLP tasks remains unclear due to limited benchmarks and practical guidelines. We perform a systematic evaluation of four LLMs-GPT and LLaMA representatives-on 12 BioNLP benchmarks across six applications. We compare their zero-shot, few-shot, and fine-tuning performance with the traditional fine-tuning of BERT or BART models. We examine inconsistencies, missing information, hallucinations, and perform cost analysis. Here, we show that traditional fine-tuning outperforms zero- or …

Alpha-Synuclein Seed Amplification Assays: Data Sharing, Standardization Needed For Clinical Use, Hilal A Lashuel, D James Surmeier, Tanya Simuni, Kalpana Merchant, Byron Caughey, Claudio Soto, Mohamed-Bilal Fares, Roland G Heym, Ronald Melki

Faculty, Staff and Student Publications

Alpha-synuclein seed amplification assays can improve neurodegenerative disease diagnosis and care, but widespread use depends on a framework that standardizes protocols and encourages data sharing.

A Mapping Review And Critique Of The Literature On Translation, Dissemination, And Implementation Capacity Building Initiatives For Different Audiences, Ana A Baumann, Danielle R Adams, Laura-Mae Baldwin, Rachel G Tabak, Sara Malone, Maura M Kepper, Anita D Misra-Hebert, Kathleen R Stevens, Maria E Fernandez, Sunil Kripalani

Faculty, Staff and Student Publications

Background: Capacity building is critical for research and practice as the fields of dissemination, implementation and translation science continue to grow. Some scholars state that capacity building should be grounded in competencies. However, the fields are unclear in determining which competencies are relevant for whom, including the content and appropriate level of information and skills for different roles. The goal of this study was to catalogue competencies across current D&I capacity building initiatives.

Methods: We conducted a mapping review to examine to what extent are theories or frameworks used to guide capacity building, who is being trained, to what extent …

Polygenic Score Analysis Identifies Distinct Genetic Risk Profiles In Alzheimer’S Disease Comorbidities, Carlos F Hernández, Camilo Villaman, Costin Leu, Dennis Lal, Ignacio Mata, Andrés D Klein, Eduardo Pérez-Palma

Faculty, Staff and Student Publications

Alzheimer’s disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients. We show that individuals with higher PGS values showed an elevated risk of developing T2D (OR 2.1, p = 1.07 × 10−11) …

Methylome-Wide Association Analyses Of Lipids And Modifying Effects Of Behavioral Factors In Diverse Race And Ethnicity Participants, Yao Hu, Jeff Haessler, Jessica I Lundin, Burcu F Darst, Eric A Whitsel, Megan Grove, Weihua Guan, Rui Xia, Mindy Szeto, Laura M Raffield, Scott Ratliff, Yuxuan Wang, Xuzhi Wang, Alison E Fohner, Megan T Lynch, Yesha M Patel, S Lani Park, Huichun Xu, Braxton D Mitchell, Joshua C Bis, Nona Sotoodehnia, Jennifer A Brody, Bruce M Psaty, Gina M Peloso, Michael Y Tsai, Stephen S Rich, Jerome I Rotter, Jennifer A Smith, Sharon L R Kardia, Alex P Reiner, Leslie Lange, Myriam Fornage, James S Pankow, Mariaelisa Graff, Kari E North, Charles Kooperberg, Ulrike Peters

Faculty, Staff and Student Publications

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG …

Chronic Viral Mimicry Induction Following P53 Loss Promotes Immune Evasion, Charles A Ishak, Sajid A Marhon, Naïri Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M Gonzaga, Melanie Peralta, Ilinca M Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago Da Silva Medina, Felipe Campos De Almeida, Jane Bayani, Jason Li, Spencer Macdonald, Yadong Wang, Sarah S Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran Austin, Peter J B Sabatini, Benjamin D Greenbaum, Catherine A O'Brien, Trevor G Shepherd, Ming Sound Tsao, Katherine B Chiappinelli, Amit M Oza, Blaise A Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D De Carvalho

Faculty, Staff and Student Publications

Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation …

The Microbiome-Restorative Potential Of Ibezapolstat For The Treatment Of Clostridioides Difficile Infection Is Predicted Through Variant Polc-Type Dna Polymerase Iii In Lachnospiraceae And Oscillospiraceae, Jacob K Mcpherson, Julian G Hurdle, Matthew L Baker, Tahir Hussain, Ashok Kumar, Kevin W Garey

Faculty, Staff and Student Publications

Ibezapolstat (IBZ), a first-in-class antibiotic targeting the PolC-type DNA polymerase III alpha-subunit (PolC) in low G + C bacteria, is in clinical development for the treatment of Clostridioides difficile infection (CDI). In the phase 2 trials, IBZ had potent activity against C. difficile while sparing or causing regrowth of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales, common commensal low G + C bacteria. The purpose of this study was to utilize in silico approaches to better interpret the narrower than expected IBZ spectrum of activity. IBZ susceptibility to human commensal microbiota was predicted using genomic analysis and PolC phylogenetic tree construction in relation …

An Examination Of Ambulatory Care Code Specificity Utilization In Icd-10-Cm Compared To Icd-9-Cm: Implications For Icd-11 Implementation, Susan H Fenton, Cassandra Ciminello, Vickie M Mays, Mary H Stanfill, Valerie Watzlaf

Faculty, Staff and Student Publications

Objective: The ICD-10-CM classification system contains more specificity than its predecessor ICD-9-CM. A stated reason for transitioning to ICD-10-CM was to increase the availability of detailed data. This study aims to determine whether the increased specificity contained in ICD-10-CM is utilized in the ambulatory care setting and inform an evidence-based approach to evaluate ICD-11 content for implementation planning in the United States.

Materials and methods: Diagnosis codes and text descriptions were extracted from a 25% random sample of the IQVIA Ambulatory EMR-US database for 2014 (ICD-9-CM, n = 14 327 155) and 2019 (ICD-10-CM, n = 13 062 900). Code …

Adoptively Transferred Tumor-Specific Il-9-Producing Cytotoxic Cd8+ T Cells Activate Host Cd4+ T Cells To Control Tumors With Antigen Loss, Liuling Xiao, Rui Duan, Wendao Liu, Chuanchao Zhang, Xingzhe Ma, Miao Xian, Qiang Wang, Qi Guo, Wei Xiong, Pan Su, Lingqun Ye, Yabo Li, Ling Zhong, Jianfei Qian, Yong Lu, Zhongming Zhao, Qing Yi

Faculty, Staff and Student Publications

Host effector CD4+ T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8+ T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8+ T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4+ T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4+ T cells against relapsed tumors. Host CD4+ …

Llm-Ie: A Python Package For Biomedical Generative Information Extraction With Large Language Models, Enshuo Hsu, Kirk Roberts

Faculty, Staff and Student Publications

Objectives: Despite the recent adoption of large language models (LLMs) for biomedical information extraction (IE), challenges in prompt engineering and algorithms persist, with no dedicated software available. To address this, we developed LLM-IE: a Python package for building complete IE pipelines.

Materials and methods: The LLM-IE supports named entity recognition, entity attribute extraction, and relation extraction tasks. We benchmarked it on the i2b2 clinical datasets.

Results: The sentence-based prompting algorithm resulted in the best 8-shot performance of over 70% strict F1 for entity extraction and about 60% F1 for entity attribute extraction.

Discussion: We developed a Python package, LLM-IE, …

The Relationship Between Physical Activity And Telomere Length In Women: A Systematic Review, Jeni Page, Catherine Stephens, Melissa Richard, Elizabeth Lyons, Elizabeth Baumler, M Terese Verklan, Elizabeth Lorenzo

Faculty, Staff and Student Publications

Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A …

Revisions To The Safety Assurance Factors For Electronic Health Record Resilience (Safer) Guides To Update National Recommendations For Safe Use Of Electronic Health Records, Dean F Sittig, Trisha Flanagan, Patricia Sengstack, Rosann T Cholankeril, Sara Ehsan, Amanda Heidemann, Daniel R Murphy, Hojjat Salmasian, Jason S Adelman, Hardeep Singh

Faculty, Staff and Student Publications

The Safety Assurance Factors for Electronic Health Record (EHR) Resilience (SAFER) Guides provide recommendations to healthcare organizations for conducting proactive self-assessments of the safety and effectiveness of their EHR implementation and use. Originally released in 2014, they were last updated in 2016. In 2022, the Centers for Medicare and Medicaid Services required their annual attestation by US hospitals.

Objectives: This case study describes how SAFER Guide recommendations were updated to align with current evidence and clinical practice.

Materials and methods: Over nine months, a multidisciplinary team updated SAFER Guides through literature reviews, iterative feedback, and online meetings.

Results: We reduced …

Frequency Of Variants In Mendelian Alzheimer’S Disease Genes Within The Alzheimer’S Disease Sequencing Project, Dongyu Wang, Alexandra Scalici, Yanbing Wang, Honghuang Lin, Achilleas Pitsillides, Nancy Heard-Costa, Carlos Cruchaga, Ellen Ziegemeier, Joshua C Bis, Myriam Fornage, Eric Boerwinkle, Philip L De Jager, Ellen Wijsman, Josée Dupuis, Alan E Renton, Sudha Seshadri, Alison M Goate, Alzheimer's Disease Neuroimaging Initiative (Adni), The Alzheimer's Disease Sequencing Project, Anita L Destefano, Gina M Peloso

Faculty, Staff and Student Publications

Background:

Prior studies examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer’s Disease Sequencing Project (ADSP).

Objective:

To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP.

Methods:

We identified rare variants (MAF< 1%) in PSEN2, PSEN1, and APP in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (Ntotal = 31,490). We additionally curated …

Learning Tracheal Intubation With A Hyperangulated Videolaryngoscopy Blade: Sub-Analysis Of A Randomised Controlled Trial, Sascha Ott, Lukas M Müller-Wirtz, Sergio Bustamante, Julian Rössler, Nikolaos J Skubas, Karan Shah, Daniel I Sessler, Alparslan Turan, Kurt Ruetzler

Faculty, Staff and Student Publications

Introduction: The number of tracheal intubation attempts required to reach proficiency in videolaryngoscopy with hyperangulated blades is unknown. Understanding this training requirement might guide training for clinicians who perform laryngoscopy. We therefore performed a planned sub-analysis of a randomised controlled trial comparing tracheal intubation success with videolaryngoscopy vs. direct laryngoscopy to determine the number of tracheal intubations with a hyperangulated videolaryngoscope blade needed to provide an acceptable first-attempt success rate.

Methods: We included clinicians from a randomised controlled trial who were familiar with direct laryngoscopy and Macintosh-blade videolaryngoscopy but inexperienced with hyperangulated videolaryngoscopy. Cumulative sum statistics were used to generate …

"When The Bills Keep On Coming:" The Experiences Of Seafood Processors During The Covid-19 Pandemic, Shannon Guillot-Wright, Laura Porterfield, Brenda Wilson, Lacy Davis

Faculty, Staff and Student Publications

Essential workers were at increased risk during the COVID-19 pandemic, including seafood processors who are often rendered invisible within the public sphere. To examine the health and safety concerns of seafood processors, many who are low income or im/migrant workers on H-2B visas, our team conducted qualitative research with 44 participants. We found that in addition to high occupational health hazards that existed before the pandemic, COVID-19 increased workers' financial risks, which put them in more dangerous health and safety positions, since they needed to work through physical and mental health illness. These financial risks can be seen through the …