Digital Commons Network^™

Cross-Tissue Coordination Between Slc Nucleoside Transporters Regulates Reproduction In Caenorhabditis Elegans, Youchen Guan, Yong Yu, Shihong M Gao, Lang Ding, Qian Zhao, Meng C Wang

Faculty, Staff and Students Publications

Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter …

Changes In Adequacy Of Splanchnic Oxygen Delivery And Splanchnic Artery Doppler After Bolus Feedings In Infants: A Systematic Review And Meta-Analysis, Rohit S Loomba, Saloni P Sheth, Joshua Wong, Megan Davis, Juan S Farias, Enrique G Villarreal, Saul Flores

Faculty, Staff and Students Publications

Background: Current practice regarding timing of feed initiation and feed tolerance largely relies on anecdotal practice and protocols. This study aims to provide an objective measure to guide clinical practice by analyzing changes in splanchnic regional oxygen saturation and Doppler patterns with feeds.

Methods: A systematic review was performed. Inclusion criteria were: 1) patients under 1 year of age; 2) splanchnic regional oxygen saturation with near infrared spectroscopy before and after feeds or mesenteric Doppler findings before and after feeds; and 3) clinical parameters must have been presented as either mean and standard deviation or median and range. Endpoints of …

Digital Interventions For Suicide Prevention, Sean K Burr, Miao Yu, Danny Clark, Dana Alonzo, Robin E Gearing

Faculty, Staff and Students Publications

Background: Digital-based mobile interventions hold significant promise in preventing suicide. Although mixed, some evidence suggests these interventions are effective and capable of overcoming barriers such as cost and stigma. Aim(s): This review aimed to determine the effectiveness of digital interventions designed to address suicidal ideation and behaviors and the impacts of age, gender, and control group type on these outcomes.

Methods: Databases were searched for randomized controlled trials (RCTs) on digital suicide interventions (apps/online programs) published before January 1, 2022. Data were analyzed using a random-effects model in Stata 17.

Results: The search identified 4,317 articles, and 16 were included. …

Digital Twins, Synthetic Patient Data, And In-Silico Trials: Can They Empower Paediatric Clinical Trials?, Mohan Pammi, Prakesh S Shah, Liu K Yang, Joseph Hagan, Nima Aghaeepour, Josef Neu

Faculty, Staff and Students Publications

Randomised controlled trials are the gold standard to assess the effectiveness and safety of clinical interventions; however, many paediatric trials are discontinued early due to challenges in patient enrolment. Hence, most paediatric clinical trials suffer from lack of adequate power. Additionally, trials are expensive and might expose patients to unproven therapies. Alternatives to overcome these issues using virtual patient data—namely, digital twins, synthetic patient data, and in-silico trials—are now possible due to rapid advances in digital health-care tools and interventions. However, such digital innovations have been rarely used in paediatric trials. In this Viewpoint, we propose using virtual patient data …

Early Prediction Of Mortality And Morbidities In Vlbw Preterm Neonates Using Machine Learning, Chi-Hung Shu, Rema Zebda, Camilo Espinosa, Jonathan Reiss, Anne Debuyserie, Kristina Reber, Nima Aghaeepour, Mohan Pammi

Faculty, Staff and Students Publications

Background: Predicting mortality and specific morbidities before they occur may allow for interventions that may improve health trajectories.

Hypothesis: Integrating key maternal and postnatal infant variables in the first 2 weeks of age into machine learning (ML) algorithms will reliably predict survival and specific morbidities in VLBW preterm infants.

Methods: ML algorithms were developed to integrate 47 features for predicting mortality, bronchopulmonary dysplasia (BPD), neonatal sepsis, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), and retinopathy of prematurity (ROP). A retrospective cohort (n = 3341) was used to train and validate the models with a repeated 10-fold cross-validation …

The Contribution Of De Novo Coding Mutations To Meningomyelocele, Yoo-Jin Jiny Ha, Ashna Nisal, Isaac Tang, Chanjae Lee, Ishani Jhamb, Cassidy Wallace, Robyn Howarth, Sarah Schroeder, Keng Ioi Vong, Naomi Meave, Fiza Jiwani, Chelsea Barrows, Sangmoon Lee, Nan Jiang, Arzoo Patel, Krisha Bagga, Niyati Banka, Liana Friedman, Francisco A Blanco, Seyoung Yu, Soeun Rhee, Hui Su Jeong, Isaac Plutzer, Michael B Major, Béatrice Benoit, Christian Poüs, Caleb Heffner, Zoha Kibar, Gyang Markus Bot, Hope Northrup, Kit Sing Au, Madison Strain, Allison E Ashley-Koch, Richard H Finnell, Joan T Le, Hal S Meltzer, Camila Araujo, Helio R Machado, Roger E Stevenson, Anna Yurrita, Sara Mumtaz, Awais Ahmed, Mulazim Hussain Khara, Osvaldo M Mutchinick, José Ramón Medina-Bereciartu, Friedhelm Hildebrandt, Gia Melikishvili, Ahmed I Marwan, Valeria Capra, Mahmoud M Noureldeen, Aida M S Salem, Mahmoud Y Issa, Maha S Zaki, Libin Xu, Ji Eun Lee, Donghyuk Shin, Anna Alkelai, Alan R Shuldiner, Stephen F Kingsmore, Stephen A Murray, Heon Yung Gee, W Todd Miller, Kimberley F Tolias, John B Wallingford, Spina Bifida Sequencing Consortium, Sangwoo Kim, Joseph G Gleeson

Faculty, Staff and Students Publications

Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or …

Multi-Epitope Immunocapture Of Huntingtin Reveals Striatum-Selective Molecular Signatures, Joshua L Justice, Todd M Greco, Josiah E Hutton, Tavis J Reed, Megan L Mair, Juan Botas, Ileana M Cristea

Faculty, Staff and Students Publications

Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established …

Recommendations For Design, Execution, And Reporting Of Studies On Experimental Thoracic Aortopathy In Preclinical Models, Alan Daugherty, Dianna M Milewicz, David A Dichek, Ketan B Ghaghada, Jay D Humphrey, Scott A Lemaire, Yanming Li, Ziad Mallat, Yvan Saeys, Hisashi Sawada, Ying H Shen, Toru Suzuki, Zhen Zhou

Faculty, Staff and Students Publications

There is a recent dramatic increase in research on thoracic aortic diseases that includes aneurysms, dissections, and rupture. Experimental studies predominantly use mice in which aortopathy is induced by chemical interventions, genetic manipulations, or both. Many parameters should be deliberated in experimental design in concert with multiple considerations when providing dimensional data and characterization of aortic tissues. The purpose of this review is to provide recommendations on guidance in (1) the selection of a mouse model and experimental conditions for the study, (2) parameters for standardizing detection and measurements of aortic diseases, (3) meaningful interpretation of characteristics of diseased aortic …

Translational Genomics Of Osteoarthritis In 1,962,069 Individuals, Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefansdottir, Cindy G Boer, Merry-Lynn Mcdonald, J Patrick Pett, Young-Chan Park, Margo Tuerlings, Rick Mulders, Andrei Barysenka, Ana Luiza Arruda, Vinicius Tragante, Alison Rocco, Norbert Bittner, Shibo Chen, Susanne Horn, Vinodh Srinivasasainagendra, Ken To, Georgia Katsoula, Peter Kreitmaier, Amabel M M Tenghe, Arthur Gilly, Liubov Arbeeva, Lane G Chen, Agathe M De Pins, Daniel Dochtermann, Cecilie Henkel, Jonas Höijer, Shuji Ito, Penelope A Lind, Bitota Lukusa-Sawalena, Aye Ko Ko Minn, Marina Mola-Caminal, Akira Narita, Chelsea Nguyen, Ene Reimann, Micah D Silberstein, Anne-Heidi Skogholt, Hemant K Tiwari, Michelle S Yau, Ming Yue, Wei Zhao, Jin J Zhou, George Alexiadis, Karina Banasik, Søren Brunak, Archie Campbell, Jackson T S Cheung, Joseph Dowsett, Tariq Faquih, Jessica D Faul, Lijiang Fei, Anne Marie Fenstad, Takamitsu Funayama, Maiken E Gabrielsen, Chinatsu Gocho, Kirill Gromov, Thomas Hansen, Georgi Hudjashov, Thorvaldur Ingvarsson, Jessica S Johnson, Helgi Jonsson, Saori Kakehi, Juha Karjalainen, Elisa Kasbohm, Susanna Lemmelä, Kuang Lin, Xiaoxi Liu, Marieke Loef, Massimo Mangino, Daniel Mccartney, Iona Y Millwood, Joshua Richman, Mary B Roberts, Kathleen A Ryan, Dino Samartzis, Manu Shivakumar, Søren T Skou, Sachiyo Sugimoto, Ken Suzuki, Hiroshi Takuwa, Maris Teder-Laving, Laurent Thomas, Kohei Tomizuka, Constance Turman, Stefan Weiss, Tian T Wu, Eleni Zengini, Yanfei Zhang, Arcogen Consortium, Argo Consortium, Dbds Genomic Consortium, Estonian Biobank Research Team, Finngen, Genes & Health Research Team, Hunt All-In Pain, Million Veteran Program, Regeneron Genetics Center, Manuel Allen Revez Ferreira, George Babis, Aris Baras, Tyler Barker, David J Carey, Kathryn S E Cheah, Zhengming Chen, Jason Pui-Yin Cheung, Mark Daly, Renée De Mutsert, Charles B Eaton, Christian Erikstrup, Ove Nord Furnes, Yvonne M Golightly, Daniel F Gudbjartsson, Nils P Hailer, Caroline Hayward, Marc C Hochberg, Georg Homuth, Laura M Huckins, Kristian Hveem, Shiro Ikegawa, Muneaki Ishijima, Minoru Isomura, Marcus Jones, Jae H Kang, Sharon L R Kardia, Margreet Kloppenburg, Peter Kraft, Nobuyuki Kumahashi, Suguru Kuwata, Ming Ta Michael Lee, Phil H Lee, Robin Lerner, Liming Li, Steve A Lietman, Luca Lotta, Michelle K Lupton, Reedik Mägi, Nicholas G Martin, Timothy E Mcalindon, Sarah E Medland, Karl Michaëlsson, Braxton D Mitchell, Dennis O Mook-Kanamori, Andrew P Morris, Toru Nabika, Fuji Nagami, Amanda E Nelson, Sisse Rye Ostrowski, Aarno Palotie, Ole Birger Pedersen, Frits R Rosendaal, Mika Sakurai-Yageta, Carsten Oliver Schmidt, Pak Chung Sham, Jasvinder A Singh, Diane T Smelser, Jennifer A Smith, You-Qiang Song, Erik Sørensen, Gen Tamiya, Yoshifumi Tamura, Chikashi Terao, Gudmar Thorleifsson, Anders Troelsen, Aspasia Tsezou, Yuji Uchio, A G Uitterlinden, Henrik Ullum, Ana M Valdes, David A Van Heel, Robin G Walters, David R Weir, J Mark Wilkinson, Bendik S Winsvold, Masayuki Yamamoto, John-Anker Zwart, Kari Stefansson, Ingrid Meulenbelt, Sarah A Teichmann, Joyce B J Van Meurs, Unnur Styrkarsdottir, Eleftheria Zeggini

Faculty, Staff and Students Publications

Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including …

Psychiatric Genetics In The Diverse Landscape Of Latin American Populations, Estela M Bruxel, Diego L Rovaris, Sintia I Belangero, Gabriela Chavarría-Soley, Alfredo B Cuellar-Barboza, José J Martínez-Magaña, Sheila T Nagamatsu, Caroline M Nievergelt, Diana L Núñez-Ríos, Vanessa K Ota, Roseann E Peterson, Laura G Sloofman, Amy M Adams, Elinette Albino, Angel T Alvarado, Diego Andrade-Brito, Paola Y Arguello-Pascualli, Cibele E Bandeira, Claiton H D Bau, Cynthia M Bulik, Joseph D Buxbaum, Carolina Cappi, Nadia S Corral-Frias, Alejo Corrales, Fabiana Corsi-Zuelli, James J Crowley, Renata B Cupertino, Bruna S Da Silva, Suzannah S De Almeida, Juan F De La Hoz, Diego A Forero, Gabriel R Fries, Joel Gelernter, Yeimy González-Giraldo, Eugenio H Grevet, Dorothy E Grice, Adriana Hernández-Garayua, John M Hettema, Agustín Ibáñez, Iuliana Ionita-Laza, Maria Claudia Lattig, Yago C Lima, Yi-Sian Lin, Sandra López-León, Camila M Loureiro, Verónica Martínez-Cerdeño, Gabriela A Martínez-Levy, Kyle Melin, Daniel Moreno-De-Luca, Carolina Muniz Carvalho, Ana Maria Olivares, Victor F Oliveira, Rafaella Ormond, Abraham A Palmer, Alana C Panzenhagen, Maria Rita Passos-Bueno, Qian Peng, Eduardo Pérez-Palma, Miguel L Prieto, Panos Roussos, Sandra Sanchez-Roige, Hernando Santamaría-García, Flávio M Shansis, Rachel R Sharp, Eric A Storch, Maria Eduarda A Tavares, Grace E Tietz, Bianca A Torres-Hernández, Luciana Tovo-Rodrigues, Pilar Trelles, Eva M Trujillo-Chivacuan, Maria M Velásquez, Fernando Vera-Urbina, Georgios Voloudakis, Talia Wegman-Ostrosky, Jenny Zhen-Duan, Hang Zhou, Latin American Genomics Consortium, Marcos L Santoro, Humberto Nicolini, Elizabeth G Atkinson, Paola Giusti-Rodríguez, Janitza L Montalvo-Ortiz

Faculty, Staff and Students Publications

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and …

Computational And Functional Prioritization Identifies Genes That Rescue Behavior And Reduce Tau Protein In Fly And Human Cell Models Of Alzheimer Disease, Morgan C Stephens, Jiayang Li, Megan Mair, Justin Moore, Katy Zhu, Akash Tarkunde, Bismark Amoh, Alma M Perez, Arya Bhakare, Fangfei Guo, Joshua M Shulman, Ismael Al-Ramahi, Juan Botas

Faculty, Staff and Students Publications

Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available …

Functional Vision Assessment Over 4 Years In Ush2a Using The Veteran Affairs Low-Vision Visual Functioning Questionnaire, Bela Parekh, Nicholas Peck-Dimit, Jacque L Duncan, Lassana Samarakoon, Maria Fernanda Abalem, Chris A Andrews, Isabelle Audo, Allison R Ayala, Chris Bradley, Janet K Cheetham, Gislin Dagnelie, Todd A Durham, Rachel M Huckfeldt, Gabrielle D Lacy, Brett Malbin, Michel Michaelides, David C Musch, Katarina Stingl, Christina Y Weng, Alex Z Zmejkoski, Michele Melia, K Thiran Jayasundera, Foundation Fighting Blindness Clinical Consortium Investigator Group

Faculty, Staff and Students Publications

Purpose: The purpose of this study was to evaluate the validity of the Veterans Affairs Low Vision Visual Functioning Questionnaire (VALVVFQ-48) functional vision scores (FVS) in patients with USH2A-associated retinal degeneration. In addition, to correlate the change in the VALVVFQ-48 FVS with the change in visual function (VF) measurements.

Methods: The VALVVFQ-48 was administered verbally to participants ≥18 years of age at baseline, and after 2 and 4 years. Associations among changes in FVS and changes in VF measures were assessed using the Spearman correlation coefficients. Mixed effects regression models with a random intercept were used to estimate annual rates …

Antibiotic Prophylaxis With Urodynamic Studies In Spinal Cord Injury: Assessing Practice Patterns And Outcomes To Guide Future Practice In A Single Center, Du Pham, Bradley Chi, Felicia Skelton, Donna Huang

Faculty, Staff and Students Publications

Context/objective: Despite urinary tract infections (UTIs) being a common problem in patients with spinal cord injuries (SCIs), and a well-known complication of invasive urologic procedures, little consensus exists regarding the standard of care for peri-procedural antibiotic use for SCI patients undergoing urodynamics studies (UDS). Our research seeks to evaluate local antibiotic prophylaxis pattern in SCI patients undergoing UDS, assess incidence of post-procedural UTI, describe local antibiotic resistance trends, and provide antibiotic stewardship considerations to guide future practice.

Design/setting/participants: Retrospective cohort study of SCI patients undergoing UDS from January 2010 to January 2020 at a Veterans Affairs SCI Center. Data on …

Temi: Tissue-Expansion Mass-Spectrometry Imaging, Hua Zhang, Lang Ding, Amy Hu, Xudong Shi, Penghsuan Huang, Haiyan Lu, Paul W Tillberg, Meng C Wang, Lingjun Li

Faculty, Staff and Students Publications

The spatial distribution of diverse biomolecules in multicellular organisms is essential for their physiological functions. High-throughput in situ mapping of biomolecules is crucial for both basic and medical research, and requires high scanning speed, spatial resolution, and chemical sensitivity. Here we developed a tissue-expansion method compatible with matrix-assisted laser desorption/ionization mass-spectrometry imaging (TEMI). TEMI reaches single-cell spatial resolution without sacrificing voxel throughput and enables the profiling of hundreds of biomolecules, including lipids, metabolites, peptides (proteins), and N-glycans. Using TEMI, we mapped the spatial distribution of biomolecules across various mammalian tissues and uncovered metabolic heterogeneity in tumors. TEMI can be easily …

Priorities - Due Today, Joslyn W Fisher

Faculty, Staff and Students Publications

No abstract provided.

Bile Acid And Microbiome Interactions In The Developing Child, Mary Elizabeth M Tessier, Benjamin L Shneider, Joseph F Petrosino, Geoffrey A Preidis

Faculty, Staff and Students Publications

Interactions between the gut microbiome and bile acids are complex and are linked to outcomes in pediatric liver disease by mechanisms that are incompletely understood. In adults, primary bile acids are synthesized in the liver and secreted into the intestine, where complex communities of gut microbes deconjugate, oxidize, epimerize, and 7α-dehydroxylate bile acids into a diverse array of unconjugated, secondary, allo-, iso-, and oxo-bile acids. In contrast, the infant gut microbiota contains a simple, Bifidobacterium-dominant community that transitions to a more diverse, adult-like community as additional microbes colonize the gut. This microbial succession gradually confers deconjugation, oxidation, epimerization, and 7α-dehydroxylation …

Optimal Delay Time To Initiate Anticoagulation After Ischemic Stroke In Atrial Fibrillation: A Pragmatic, Response-Adaptive Randomized Clinical Trial, Steven J Warach, Lisa A Davis, Patrick Lawrence, Byron Gajewski, Jo Wick, Fred Shi, Ty T Shang, Daiwai M Olson, Sidarrth Prasad, Lee Birnbaum, Jody M Richardson, Sean I Savitz, Mark P Goldberg, Salvador Cruz-Flores, Israel Alba, Jane Anderson, Barbara Kimmel, Chethan P Venkatasubba Rao, Ben King, Adrienne N Dula, Truman J Milling

Faculty, Staff and Students Publications

Importance: Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke with atrial fibrillation. It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious hemorrhagic events.

Objective: To determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation-related stroke that minimizes the risk of a composite outcome of ischemic or hemorrhagic events.

Design, setting, and participants: This phase 2, pragmatic, response-adaptive randomized clinical trial was conducted between June 2017 and June 2023 at acute care …

Azetukalner, A Novel Kv7 Potassium Channel Opener, In Adults With Major Depressive Disorder: A Randomized Clinical Trial, Noam N Butterfield, Constanza Luzon Rosenblut, Maurizio Fava, Christoph U Correll, Anthony J Rothschild, James W Murrough, Sanjay J Mathew, Gregory N Beatch, Celene Grayson, Cynthia Harden, Jenny Qian, Joe Mcintosh, Rostam Namdari, Christopher Kenney

Staff and Researcher Publications

Importance: Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need.

Objective: To evaluate the efficacy and safety of azetukalner, a novel, potent KV7 potassium channel opener, in participants with MDD.

Design, setting, and participants: X-NOVA was a multicenter, proof-of-concept, phase 2, randomized, double-blind, parallel-group, placebo-controlled clinical trial that evaluated azetukalner in participants (adults aged ≥18 to ≤65 years) with moderate to severe MDD in a current depressive episode. Participants were enrolled between April 2022 and October 2023, and data analysis occurred from January 2023 to January 2024.

Intervention: Participants were …

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse, Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Center on Aging Staff Publications

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which …

Older Adults' Experiences Of Emergency Department Admission Decisions: A Qualitative Study In A Public Safety Net Hospital, Anita N Chary, Annika Bhananker, Beatrice Torres, Victoria Sofia Martell, Manish N Shah, Aanand D Naik

Faculty, Staff and Student Publications

Background: Hospital admission is a significant event in the healthcare trajectory of older adults (age 60 +). Numerous harms such as delirium, falls, and adverse medication events can arise that outweigh the benefits of admission. Little is known about how older adults feel about being hospitalized or what they think admission will achieve for them. These issues are particularly important to understand in socioeconomically disadvantaged patients, who have poor access to outpatient care and higher hospitalization rates.

Methods: We performed semi-structured interviews with emergency department (ED) patients aged 60 and older who were being admitted. The study site was a …

Interplay Between Skeletal Muscle Catabolism And Remodeling Of Arteriovenous Fistula By Yes-Associated Protein 1 (Yap1) Signaling, Yongdong Wu, Tae Hoon Lee, Owen H Cheng, Eric K Peden, Qingtian Li, Jun Wang, Fengzhang Huang, Marites P Melancon, David Sheikh-Hamad, Tao Wang, Luan Truong, William E Mitch, Ming Liang, Jizhong Cheng

Faculty, Staff and Student Publications

Key Points:

1. Atrophied muscle–derived myostatin stimulated mesenchymal stem cell differentiation and adverse arteriovenous (AV) fistula remodeling through yes-associated protein 1 (YAP1) activation.

2. Treatment with myostatin peptibody inhibited muscle wasting and blocked mesenchymal stem cell activation and AV fistula fibrosis.

3. A light-sensitive drug-release strategy was engineered for the periadventitial delivery of verteporfin to improve AV fistula patency.

Background: Arteriovenous (AV) fistulas are the preferred access for dialysis but have a high incidence of failure. The aim of this study was to understand the crosstalk between skeletal muscle catabolism and AV fistula maturation failure.

Methods: Skeletal muscle metabolism and AV fistula maturation …

Precision Proteogenomics Reveals Pan-Cancer Impact Of Germline Variants, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Kathleen J Imbach, Karl R Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M Yaron, Yize Li, Song Cao, Erik P Storrs, Olivia S Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A Kawaler, Matthew A Wyczalkowski, Robert J Klein, Berk Turhan, Karsten Krug, D R Mani, Felipe Da Veiga Leprevost, Alexey I Nesvizhskii, Steven A Carr, David Fenyö, Michael A Gillette, Antonio Colaprico, Antonio Iavarone, Ana I Robles, Kuan-Lin Huang, Chandan Kumar-Sinha, François Aguet, Alexander J Lazar, Lewis C Cantley, Urko M Marigorta, Zeynep H Gümüş, Matthew H Bailey, Gad Getz, Eduard Porta-Pardo, Li Ding

Faculty, Staff and Student Publications

We investigate the impact of germline variants on cancer patients' proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, "precision peptidomics," mapping 337,469 coding germline variants onto peptides from patients' mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial …

Identification Of Frailty Clusters Using Cross-Sectional Frailty And Frailty Trajectory: Cohort Of Heart Failure Veterans, Javad Razjouyan, Saeed Tofighi, Ariela R Orkaby, Biykem Bozkurt, Amir Sharafkhaneh, Molly J Horstman, Parag Goyal, Christopher I Amos, Orna Intrator, Aanand D Naik

Faculty, Staff and Student Publications

BACKGROUND: Frailty is a syndrome associated with increased vulnerability and diminished physiological reserves. Three-quarters (78%) of heart failure (HF) patients are frail. Traditional frailty indices (FIs) assess cross-sectional deficits, while frailty trajectories (FTs) measure changes over time.

OBJECTIVES: This study aims to examine the interaction between FI and FT to enhance risk stratification in hospitalized adults with HF.

METHODS: This retrospective cohort study utilized data from the Veterans Health Administration, including 143,687 veterans aged >50 admitted for HF from 2005 to 2019. FT measurements were derived from FI calculations for each of the 3 years before index hospitalization. Unsupervised clustering …

Maternal Dysbiosis Produces Long-Lasting Behavioral Changes In Offspring, Jacob Hudobenko, Claudia M Di Gesù, Patrick R Mooz, Joseph Petrosino, Nagireddy Putluri, Bhanu P Ganesh, Kristen Rebeles, Frank W Blixt, Venugopal R Venna, Louise D Mccullough

Faculty, Staff and Student Publications

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization …

Circulating Epstein-Barr Virus Antibody Levels As A Biomarker Of Socioecological Adversity In Amazonian Ecuador, Tyler M Barrett, Melissa A Liebert, Geeta N Eick, Julia G Ridgeway-Diaz, Felicia C Madimenos, Aaron D Blackwell, Tara J Cepon-Robins, Samuel S Urlacher, Lawrence S Sugiyama, J Josh Snodgrass

Faculty, Staff and Students Publications

Objectives: Circulating Epstein-Barr virus antibodies (EBV-Ab) are used as a biomarker of chronic stress in high-income settings, but their relevance in environments with a high burden of infectious disease, nutritional constraints, and limited resources is less clear. We investigated EBV-Ab as a biomarker of adversity in a setting where local ecology and economy may affect immune development differently than in wealthy countries.

Methods: We measured EBV-Ab in finger-prick dried blood spots collected from Indigenous Shuar (n = 433) and non-Indigenous Colonos (n = 84) ranging from < 1 to 87 years old in Amazonian Ecuador. For a subset of adults (≥ 15 years, n = 210), we collected socioeconomic information (income, education, and occupation) and assessed household-level market integration. We determined the most important predictors of EBV-Ab for adults and children using multi-model averaging of linear regression models.

Results: Male children (< 15 years) had lower EBV-Ab than female children (model averaged β [SE]: -0.238 [0.066]). For adults, Shuar had higher EBV-Ab than Colonos (model averaged β [SE]: 0.235 [0.113]), and high systolic blood pressure was an important predictor of elevated EBV-Ab (model averaged β [SE]: 0.088 [0.047]). Individuals who reported unpaid domestic work as their primary occupation had higher EBV-Ab than agricultural workers (model averaged β [SE]: 0.302 [0.113]). Individuals living in houses with more market-sourced infrastructure had lower EBV-Ab (model averaged β [SE]: -0.088 [0.068]).

Conclusions: Circulating EBV-Ab may capture context-specific aspects of socioecological adversity …

Discharge Practice Variability In Pediatric Chronic Home Invasive Ventilation, Guillermo Beltran-Ale, Ryne Simpson, Terri Magruder, Ajay S Kasi, Amit Agarwal, Jake A Kaslow

Faculty, Staff and Students Publications

Introduction: The Pediatric Mechanical Ventilation Society is a collaboration of pediatric pulmonologists with a focus on pediatric chronic home invasive ventilation (PCHIV). Since the initial discharge on PCHIV is not always directed by pediatric pulmonologists, we sought to understand how this variability between centers impact adherence to American Thoracic Society (ATS) guidelines for PCHIV.

Methods: A survey was distributed to pediatric pulmonologists across multiple platforms inquiring about discharging practices for PCHIV and adherence to six of the nine ATS recommendations for PCHIV. Two subgroups were created based on common practices - discharge by pediatric pulmonologists from a non-ICU unit (pulmonary …

Metastatic Medulloblastoma Remodels The Local Leptomeningeal Microenvironment To Promote Further Metastatic Colonization And Growth, Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino De Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G Lucas, Charles G Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N Rich, Xiaochong Wu, Xi Huang, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges …

Derisking Phase Ii Clinical Trials In Heart Failure: A Position Paper From Jacc: Basic To Translational Science And The Heart Failure Collaboratory, Douglas L Mann, G Michael Felker, Ellis F Unger, Janet T Wittes, Biykem Bozkurt, Fady I Malik, Norman Stockbridge, Benjamin R Saville, Mona Fiuzat, Christopher M O'Connor, Scott D Solomon

Faculty, Staff and Students Publications

Phase II clinical trials play an important role in drug development, providing key data that guide decision-making for promising therapeutic candidates. An important objective of phase II is to establish proof of concept by demonstrating that the drug produces its intended biological effects in the target population. Phase II trials also evaluate pharmacokinetics, pharmacodynamics, safety, and dose-response relationships. Ultimately, the goal is to generate the evidence needed to inform go/no-go decisions for further development. However, as we will discuss, phase II studies have inherent limitations and cannot fully predict phase III outcomes. In this JACC: Basic to Translational Science and …

New Performance Measurement Framework For Realizing Patient-Centered Clinical Decision Support: Qualitative Development Study, Prashila Dullabh, Courtney Zott, Nicole Gauthreaux, James Swiger, Edwin Lomotan, Dean F Sittig

Faculty, Staff and Student Publications

Background: Patient-centered clinical decision support (PC CDS) exists on a continuum that reflects the degree to which its knowledge base, data, delivery, and use focus on patient needs and experiences. A new focus on value-based, whole-person care has resulted in broader development of PC CDS technologies, yet there is limited information on how to measure their performance and effectiveness. To address these gaps, there is a need for more measurement guidance to assess PC CDS interventions.

Objective: This paper presents a new framework that incorporates patient-centered principles into traditional health IT and clinical decision support (CDS) evaluation frameworks to create …

Chemotherapy-Free Treatment With Radiotherapy And Immunotherapy For Locally Advanced Non-Small Cell Lung Cancer, M Zeeshan Ozair, Balazs Halmos, Angelica D'Aiello, Jaewon Yun, Andrea R Filippi, Andreas Rimner, Steven H Lin, Charles B Simone, Nitin Ohri

Faculty, Staff and Student Publications

Background: Concurrent chemoradiotherapy (CRT) followed by immunotherapy is a standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC), yet many patients are ineligible due to treatment-related toxicity or poor functional status. Chemotherapy-free approaches using radiotherapy (RT) and immunotherapy may offer a safer and equally effective alternative in select patient populations.

Methods: A comprehensive literature review was conducted using PubMed, Google Scholar, and relevant conference proceedings focusing on trials between 2000 and 2024. Studies investigating chemotherapy-free regimens combining RT and immunotherapy in LA-NSCLC were analyzed, with emphasis on clinical outcomes, biomarker use, treatment sequencing, radiation dose/fractionation, and safety.

Results: Multiple …