Digital Commons Network^™

Ethical Controversies In Organ Procurement: A National Survey On Public Perceptions Of Thoracoabdominal Normothermic Regional Perfusion, Trevor M Bibler, Jill Oliver Robinson, Adam Omelianchuk, Tariq Nisar, Savitri Fedson, Ariel N Levchenko, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Thoracoabdominal normothermic regional perfusion (TA-NRP) would likely expand the quantity and quality of organs procured after controlled circulatory death donation in the United States, yet its ethical permissibility remains contested. We surveyed a representative sample of US adults (n = 975) with the goal of assessing their perspectives on the ethical permissibility of TA-NRP. After reading a neutral description of TA-NRP, participants judged its permissibility, reviewed 5 critic and 5 supporter arguments (in random order), and chose which argument they found most convincing. Multivariable logistic regression examined predictors of agreeing with critics. Before exposure to the arguments, 51.5% stated that …

Ins-17 Acts As A Nutrient Deprivation Signal To Mediate Adult Iis-Regulated Associative Behaviors In C. Elegans, Emily J Leptich, Priyadharshini Vijayakumar, Edward W Pietryk, Meredith I Williams, Rachana Rajupalem, Rachel N Arey

Faculty, Staff and Students Publications

Insulin/Insulin-like growth factor 1 (IGF-1) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes. Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IIS transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, …

The Association Between Physical Activity, Sedentary Time, And Sleep With Risk Of Hepatocellular Carcinoma In Patients With Cirrhosis, Samuel Ma, Yossef Alsabawi, Fasiha Kanwal, Hao Duong, Laith Elserag, Amit G Singal, Nicole E Rich, Saira Khaderi, Sumeet K Asrani, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

Background: The majority of hepatocellular carcinoma (HCC) cases arise in patients with cirrhosis, with known major risk factors of hepatitis B (HBV) or C (HCV) infection, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). However, the impact of additional risk factors that act independently or jointly on the pathogenesis of HCC in cirrhosis patients is unknown. The aim of this study was to determine whether sleep, sedentariness, or physical activity levels play a role in the progression of cirrhosis to HCC.

Methods: We systematically collected data on sleep, sedentary time, and physical activity from the ongoing prospective …

Kidney Disease And Heart Failure: Recent Advances And Current Challenges: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference, Carolyn S P Lam, Biykem Bozkurt, David Z I Cherney, Justin A Ezekowitz, Meg J Jardine, Sadiya S Khan, Magdalena Madero, Mark J Sarnak, Jozine M Ter Maaten, Michael Cheung, Jennifer M King, Morgan E Grams, Michel Jadoul, Nisha Bansal

Faculty, Staff and Students Publications

Heart failure (HF) and chronic kidney disease (CKD) frequently coexist, which elevates the risks of hospitalization, disease progression, and death. Despite advances in treating each condition independently, many challenges remain in diagnosing and managing them in combination. In March 2024, Kidney Disease: Improving Global Outcomes (KDIGO) held the Controversies Conference on Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Discussions highlighted the complex, bidirectional relationship between HF and CKD, including shared risk factors and overlapping pathophysiology as well as nuances in interpreting biomarkers such as natriuretic peptides and serum creatinine. Sodium-glucose cotransporter-2 inhibitors, renin-angiotensin-aldosterone system inhibitors, and emerging …

Driveline Infections Among Patients Supported With Left Ventricular Assist Devices: A Single Center Sixteen-Year Longitudinal Profile, Anh Nguyen, Alexis Shafii, Gabriel Loor, Andrew Civitello, O Howard Frazier, Todd Rosengart, Kenneth Liao

Faculty, Staff and Students Publications

Background: Left ventricular assist device (LVAD) driveline infections significantly impact patient outcomes. This study aimed to identify their risk factors.

Methods: We analyzed LVAD data from our institutional Intermacs database (January 1, 2008-December 31, 2023), combining primary implants and pump exchanges. Patient characteristics were summarized as frequencies for categorical variables and median (IQR) for continuous variables. The nature of repeated infection events was handled by the Andersen-Gill method within a multivariable Cox proportional hazards model for cause-specific hazard of driveline infections, accounting for death and heart transplant as competing risks.

Results: Our cohort included 1026 LVAD implants. Median patient age …

Glp1-Ra And Sglt2-I: Implementation And Insulin Deescalation Strategies, Arthi Palani, Sagar Patel, Shriya Patel, Shivani Srivastava, Jay Patel, Salman Salehin, Yochai Birnbaum, Joseph Allencherril

Faculty, Staff and Students Publications

Purpose of review: This review will summarize the most contemporary trials for glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and present guidance on management and recommendations on adjunctive tapering of insulin in patients with insulin-dependent diabetes mellitus, which we term "de-insulinization."

Recent findings: GLP1-RA and SGLT2-i are the principal classes of diabetes medications evidencing cardiovascular benefit. However, there is limited consensus on how to effectively prescribe and maintain these medications for patients on other glucose-lowering therapy, especially insulin. Patients with type 2 diabetes and cardiovascular disease should be started on either a GLP-1RA, SGLT-i, or …

Widespread Distribution Of Alu/Alu-Mediated Genomic Rearrangement Predisposing To A Broad Range Of Mendelian Disease And Cancer In Human Populations, Ruizhi Vince Duan, Haowei Du, Shruti Pande, Ahmed K Saad, Meryem M Atik, Minal Jamsandekar, Karen J Coveler, Zain Dardas, Shalini N Jhangiani, Jennifer E Posey, Richard A Gibbs, James R Lupski

Faculty, Staff and Students Publications

Background

Genome-wide distributions of Alu elements contribute to a broad range of structural variants (SVs) through Alu/Alu-mediated genomic rearrangement (AAMR). Yet, the prevalence and characteristics of AAMR on the human genome and its scale in generating pathogenic SVs remain poorly understood.

Methods

We established a disease-focused, AAMR-SV dataset and a control dataset to comprehensively delineate the genomic landscape of Alu mutagenesis. The disease-focused dataset included 407 published pathogenic AAMR-SV alleles in 115 known genes for Mendelian disorders or traits through a literature survey. A control dataset was collected from short-read genome sequencing analyses of 100 randomly selected, healthy individuals. …

Efficient In Vivo Pharmacological Inhibition Of Δfosb, An Ap-1 Transcription Factor, In The Brain, Sean Mcneme, Anil Kumar, Yun Young Yim, Brandon W Hughes, Corey St Romain, Yi Li, Ashwani Kumar, Qichao Bao, Molly Estill, Shanghua Fan, Nadeen Takatka, Earnest P Chen, Matthew Rivera, Haiying Chen, Alfred J Robison, Mischa Machius, Stephen J Haggarty, Jeannie Chin, Eric J Nestler, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a …

Dominant Clones Leverage Developmental Epigenomic States To Drive Ependymoma, Alisha S Kardian, Hua Sun, Siri Ippagunta, Nicholas Laboe, Srinidhi Varadharajan, Kwanha Yu, Hsiao-Chi Chen, Erik Emanus, Tuyu Zheng, Riley M Deneen, Jon P Connelly, Yong-Dong Wang, Jiangshan Zhan, Hengxi Liu, Kimberley Lowe, Taylor Bugbee, Rakesh Pathak, Amanda Bland, Sanya Mehta, Sophie Cochiolo, Amir Arabzade, Blake Holcomb, Kaitlin M Budd, Gabriele Kembuan, Tristen Wright, Emma Caesar, Maxwell Park, Amelia Hancock, David Gee, Joel Murdoch, Yi Xiao, Samuel K Mcbrayer, Thomas E Merchant, Jun Qi, Adam D Durbin, Lindsay A Schwarz, Li Wang, Andrew M Donson, Nicholas K Foreman, Sameer Agnihotri, Alfonso Lavado, Suzanne J Baker, David W Ellison, Hyun Kyoung Lee, Shondra M Pruett-Miller, Kelsey C Bertrand, Benjamin Deneen, Stephen C Mack

Faculty, Staff and Students Publications

ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse …

Variability In The Orthopaedic Residency Trainee Trauma Surgical Experience, Todd Phillips, Benjamin Fiedler, Joshua T Morrow, Zbigniew Gugala, Melvyn Harrington, Douglas R Dirschl

Faculty, Staff and Students Publications

Background: The aim of this study was to analyze fracture fixation case logs from residents training at a level 1 trauma center to assess variability across residents' surgical experiences within a single residency program. The authors hypothesize that notable variability exists between residents' surgical experiences in fracture care.

Methods: A retrospective case series was conducted at a single, urban residency program with a level 1 trauma center. Completed case logs were collected from program graduates from 2022 to 2024. All surgical cases involving fracture fixation at the level 1 trauma center were included for analysis. The anatomic region of the …

Feasibility Of A Large Language Model Chatbot To Support Parental Understanding In The Picu, R Brandon Hunter, Satid Thammasitboon, Sreya Rahman, Sriya Kakarla, Pamela Petersen, Shelley Kumar, Thomas Rappold, Sanjiv Mehta

Faculty, Staff and Students Publications

Objectives: To evaluate the feasibility of a large language model (LLM)-based chatbot for answering parental questions in the PICU and inform design of a randomized controlled trial (RCT).

Design: Prospective single-arm feasibility study conducted from August 2024 to December 2024.

Setting: Quaternary PICU.

Subjects: Fourteen parents of children admitted to the PICU.

Interventions: Parents engaged in 10-minute sessions with a HIPAA-compliant GPT-4o- (Generative Pretrained Transformer 4o, OpenAI, San Francisco, CA) based chatbot prompted with patient-specific electronic health record (EHR) data.

Measurements and main results: Feasibility was assessed through four criteria: parental engagement and satisfaction, provider perceptions, accuracy and safety, and …

Development And Internal Validation Of A Pretransplant Biomarker Panel For Mortality Prediction Following Liver Transplant, Guergana G Panayotova, Sopio Simonishvili, Lianhua Jin, Duc T Nguyen, Edward A Graviss, Yong Qin, Anastasia Xynogala, Tumininu Ayorinde, Laurie J Minze, Alexander Lemenze, Krupa R Mysore, Julie M Corkrean, Linda W Moore, Flavio Paterno, Ashish Saharia, Constance M Mobley, Arpit Amin, Mark J Hobeika, Xian C Li, Paul J Gaglio, R Mark Ghobrial, James V Guarrera, Keri E Lunsford

Faculty, Staff and Students Publications

Importance: Current pretransplant clinical scoring systems fail to accurately estimate post-liver transplant (LT) survival, making recipient selection challenging. Persistent immune dysfunction contributes to early LT recipient mortality but is not captured by existing models.

Objective: To identify plasma biomarkers of pretransplant immune dysfunction and to develop a biomarker-based pre-LT risk stratification tool to predict post-LT mortality.

Design, setting, and participants: Prospective biomarker analysis of consecutively enrolled adult LT recipients was conducted. Healthy controls were included for baseline comparison. Patients undergoing LT at Houston Methodist Hospital (October 1, 2013, to December 31, 2017) and Rutgers/University Hospital (January 1, 2019, to March …

Long-Term Outcomes Of Left Bundle-Branch Pacing Vs Biventricular Pacing In Heart Failure: The Heartsync-Lbbp Randomized Clinical Trial, Xueying Chen, Xi Liu, Ruogu Li, Zhongkai Wang, Yixiu Liang, Lei Zhang, Wei Wang, Jin Bai, Jingfeng Wang, Shengmei Qin, Weiwei Zhang, Tianbao Yao, Dong Huang, Ting Chen, Xianxian Zhao, Dening Liao, Jingbo Li, Jialiang Mao, Mihail G Chelu, Yangang Su, Kenneth A Ellenbogen, Junbo Ge

Faculty, Staff and Students Publications

Importance: Left bundle-branch pacing (LBBP) has been proposed as an alternative to biventricular pacing (BiVP) for patients with heart failure with left bundle-branch block (LBBB). However, robust clinical evidence from randomized clinical trials is lacking.

Objective: To evaluate the long-term clinical outcomes of LBBP and BiVP.

Design, setting, and participants: This multicenter, prospective, randomized clinical trial enrolled 200 patients at 6 centers in China with a left ventricular ejection fraction (LVEF) of 35% or less and LBBB from October 2020 to March 2022. This study was took place from October 2020 to September 2024. These data were analyzed September 2024 …

Phenome-Wide Analysis Of Copy Number Variants In 470,727 Uk Biobank Genomes, Xueqing Zoe Zou, Fengyuan Hu, Haiyi Lou, Oliver S Burren, Xiaoyin Li, Karyn Megy, Eleanor Wheeler, Qiang Wu, Santosh S Atanur, Marcin Karpinski, Douglas Loesch, Zammy Fairhurst-Hunter, Sri V V Deevi, Erin Oerton, Sean Wen, Xiao Jiang, Cecilia Salvoro, Jonathan Mitchell, Abhishek Nag, Ben Hollis, Amanda O'Neill, Jen Harrow, Stewart Macarthur, Sebastian Wasilewski, Sean O'Dell, Lifeng Tian, Katherine R Smith, Guillermo Del Angel, Margarete Fabre, Ryan S Dhindsa, Quanli Wang, Slavé Petrovski, Keren Carss

Duncan NRI Faculty and Staff Publications

Copy number variants (CNVs) are key drivers of human diversity and disease risk1. Here we evaluate the role of CNVs across a broad range of human phenotypes and diseases by analysing CNVs from 470,727 UK Biobank whole-genome sequences and conducting a variant- and gene-level phenome-wide association study (PheWAS) with 2,941 plasma protein abundance measurements, 13,336 binary clinical phenotypes and 1,911 quantitative traits. Proteomic analyses validated functional associations of CNVs with nearby genes (cis-protein quantitative trait loci; cis-pQTLs)—with deletions and duplications typically associated with reduced and increased protein levels, respectively—and uncovered previously unknown protein–protein interactions …

Methodological Progress Note: Logic Models, Molly J Horstman, Kyler M Godwin

Faculty and Staff Publications

Logic models are an accessible tool to organize the planning, management, and evaluation of programs across healthcare disciplines. This methodological progress note describes the five standard components of a logic model (Inputs, Activities, Outputs, Outcomes, and Impact) and provides guidance for developing a logic model. Logic models offer a visual representation of the work and theory of a program and should be created with input from all interested parties. Logic models are living tools that need to be revised as programs evolve and new information becomes available.

Tfeb Degradation Is Regulated By An Ikk/Β-Trcp2 Phosphorylation-Ubiquitination Cascade, Yan Xiong, Jaiprakash Sharma, Meggie N Young, Wen Xiong, Ali Jazayeri, Karl F Poncha, Ma Xenia G Ilagan, Qing Wang, Bei Gao, Hui Zheng, Nicolas L Young, Marco Sardiello

2020-Current year OA Pubs

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues …

Neighborhood Physical Disinvestment And Incident Diabetes Between Visits 1 And 2 Of The Hispanic Community Health Study/Study Of Latinos (Hchs/Sol)., Cara M. Smith, Elizabeth W. Spalt, Linda C. Gallo, Jordan A. Carlson, Matthew Allison, Bharat Thyagarajan, Earle C. Chambers, Amber Pirzada, Martha Daviglus, Christina Cordero, Qibin Qi, Elena Austin, Amanda M. Fretts, India Ornelas, Robert Kaplan, Joel D. Kaufman, Stephen J. Mooney

Manuscripts, Articles, Book Chapters and Other Papers

Neighborhood-scale environmental factors, including disinvestment in infrastructure, may impact cardiometabolic disease risk. To our knowledge, no prior studies have investigated the association between neighborhood disinvestment and incident diabetes. We used a virtual street audit of Google Street View Imagery to generate a neighborhood disinvestment score for participants' residential addresses in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). An item response theory model was fit to indicators (litter, graffiti, under-maintained buildings, bars on windows, and abandoned buildings) to form a scale measuring a latent level of disinvestment. Ordinary kriging was used to estimate levels for each residential address within the …

Understanding Atomoxetine Exposure Variability In Children And Adolescents With Adhd Through Population Pharmacokinetics., Kevin V. Tobin, Addison M. Pritchett Ms, J Steven Leeder, Joga Gobburu, Allison Dunn

Manuscripts, Articles, Book Chapters and Other Papers

Atomoxetine, a selective norepinephrine reuptake inhibitor, is a nonstimulant alternative to treat attention-deficit/hyperactivity disorder in children and adolescents. Atomoxetine exposure is highly variable due to cytochrome P450 polymorphism; however, the impact of these genetic variations has not been adequately characterized in the pediatric population. A population pharmacokinetic (PK) model was developed to evaluate steady-state atomoxetine exposures after oral administration in a large, heterogeneous population of children and adolescents with different metabolic phenotypes. Due to the highly variable and complex absorption between subjects and occasions, a two-stage approach was implemented, treating each participant/occasion as a separate individual. First, the individual atomoxetine …

Cd8 Trm-Like T Cells Expressing Perforin And Ifn-Γ Define A Pediatric Activated T-Cell Acute Liver Failure Endotype., Tamir Diamond, Catherine A. Chapin, Caroline J. Diorio, Sarah Mccuaig, Michelle Lau, Niansheng Chu, Nora M. Gibson, Portia A. Kreiger, Simon Horslen, Kathleen M. Loomes, Anna M. Banc-Husu, Jaime Chu, M Kyle Jensen, Daniel H. Leung, Amrita Narang, Beth A. Carter, Scott Elisofon, Ryan T. Fischer, Steven J. Lobritto, Mike Leonis, Anna L. Peters, Norberto Rodriguez-Baez, Rene Romero, Philip Rosenthal, David Rudnick, James Squires, Shikha Sundaram, Kyla M. Tolliver, Pamela Valentino, Valerie Durkalski, Estella M. Alonso, Edward M. Behrens

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Activated T-cell pediatric acute liver failure (TC-PALF) is the most common cause of non-acetaminophen PALF, with poor transplant-free survival. Livers in TC-PALF are infiltrated by effector cytotoxic T lymphocytes with markers of tissue-resident memory function (CD8 Trm) and an interferon gamma (IFNγ) transcriptional signature. The PALF-Immune Response Network (PALF-IRN) and the prospective TReatment for ImmUne-Mediated PathopHysiology (TRIUMPH) clinical trial (NCT04862221) aim to characterize the TC-PALF immune pathology and utility of T-cell directed therapy to improve transplant-free survival.

METHODS: TRIUMPH patients with TC-PALF were compared with healthy children and disease controls utilizing multiparameter flow cytometry and 3' single-cell RNA sequencing …

Factors Associated With Child Protective Services Referrals In Young Children With Isolated Skull Fractures., Karli Breeden-Carino, Joanne N. Wood, Cindy W. Christian, Tagrid M. Ruiz-Maldonado, Daniel M. Lindberg, Angela Bachim, Lori Frasier, Terra N. Frazier, Nancy S. Harper, Sara E. Kruczek, Farah Brink, Jennifer E. Wolford, Jan Leonard, M Katherine Henry

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Many young children with isolated skull fractures are referred to child protective services (CPS) despite being assessed to have a low likelihood of abuse. We sought to identify factors associated with CPS referrals in this population and to quantify hospital-level variation.

METHODS: We performed a multicenter retrospective cross-sectional study of children < 2 years with skull fractures with or without a small underlying intracranial hemorrhage (ICH) and no additional injuries undergoing a child abuse pediatrics (CAP) subspecialty evaluation. We explored associations between demographic factors, clinical characteristics, psychosocial risk factors, and hospital site with CPS referral status. We performed multivariable logistic regression, adjusting for transfer status and all significant covariates from unadjusted analyses. We utilized marginal standardization to calculate the estimated probability of CPS referrals at each site, adjusting for all factors in the final model.

RESULTS: Of 528 children, 303 (57.4%) were referred to CPS, with 86.5% referred before CAP consultation. In multivariable logistic regression, presence of psychosocial risk factors (OR 4.00; 95% CI 2.25, 7.11), in-person CAP consult (OR 3.93; 1.61, 9.62), inflicted or no trauma history provided (OR 6.15; 3.30, 11.45), …

Confessions In Cases Of Child Physical Abuse-A Capnet Study., Margaret R. Russell, Antoinette L. Laskey, Henry T. Puls, Suzanne P. Starling, Joanne N. Wood, Daniel M. Lindberg, Nancy S. Harper, Caitlin R. Mcnamara, Angela W. Bachim, Farah W. Brink, Lori D. Frasier, James Anderst, Porcia Vaughn, Kristine A. Campbell

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Prior research on confessions of physical abuse (PA) has explored mechanisms of injury. Little is known about conditions supporting a confession of abuse or how confessions may influence case outcomes.

METHODS: This cross-sectional study of suspected PA in children aged < 10 years at 10 centers participating in CAPNET, a multicenter child PA research network, included children with in-person Child Abuse Pediatrics (CAP) consultations between February 2021 and December 2022 and excluded children without injury. Our focus was a confession of inflicted injury known to the CAP during clinical involvement. We compared child and clinical characteristics, out-of-home (OOH) placements, and arrests between cases with and without confessions. Multivariable models using generalized estimating equations (GEE) produced adjusted predicted probabilities (APP) clustering by CAPNET site.

RESULTS: Confessions were known to CAPs in 115/4297 (2.7%) cases, with significant site variability. In a multivariable GEE model, confessions were more likely in cases with injuries with high specificity for abuse (APP 6.0% vs 1.6%, P < .001), near-fatality (APP 5.6% vs 2.3%, P < .001), and older children (APP 4.8% vs 2.5%, P = .025). OOH placements and arrests were more common in cases with confessions. CAP awareness of confessions, OOH placements, and arrests did not follow racial or ethnic patterns seen in the US child welfare system. Lower socioeconomic status was associated with OOH placements and arrests but not with CAP awareness of confessions.

CONCLUSIONS: Our findings highlight differences in case characteristics and outcomes where a confession is known to the CAP and raise questions about …

Quality Of Antenatal And Delivery Care And Postnatal Care Use: A Multi-Country Observational Study Of 400,000 Births, Jan E. Cooper, Hwa-Young Lee, Katherine Wright, Prashant Jaryan, Margaret E. Kruk

2020-Current year OA Pubs

BACKGROUND: Postnatal care (PNC) plays a crucial role in averting newborn mortality, yet its use remains low, particularly in regions with the highest mortality. While demographic and social determinants of PNC use have been well studied and have informed current strategies focused on changing care-seeking behaviors, the stagnating decline in neonatal mortality highlights the need for upstream and system-wide approaches to increase PNC uptake. Limited evidence exists to guide system-level reforms; therefore, we investigated whether health systems that ensure high-quality perinatal care are associated with increased use of PNC.

METHODS AND FINDINGS: We performed a cross-sectional observational study using Demographic …

Detailed Single-Cell Mapping Of The Transcriptional Response To A Virus Infection Driven By Copy-Back Viral Genomes, Yanling Yang, Emna Achouri, Munyaradzi Tambo, Carolina B. López

2020-Current year OA Pubs

The antiviral response to several clinically significant viruses, including respiratory syncytial virus and parainfluenza virus, is driven by copy-back viral genomes (cbVGs) generated during virus replication. However, the broader impact of cbVGs on the functional states of host cells remains undefined. Here, we developed a single-cell RNA-sequencing and computational framework to map cbVG-driven host responses during Sendai virus infection. Unsupervised profiling identified distinct transcriptional states throughout the course of infection, highlighting a shift from early antiviral signaling to later inflammatory and remodeling programs. Stratifying infected cells by cbVG status demonstrated that cbVG-positive cells initiate interferon and chemokine programs, which later …

Developing A Novel Index For Neighborhood Social Determinants Of Cardiovascular Diseases In The Cardia Study, Tao Gao, Yinan Zheng, Brian T Joyce, Lei Liu, Lili Liu, Catarina Kiefe, Sarah Forrester, Penny Gordon-Larsen, Chunyu Liu, Donald Lloyd-Jones, Kai Zhang, Lifang Hou

2020-Current year OA Pubs

Neighborhood social determinants of health have been shown to influence cardiovascular risk and the development of cardiovascular disease, but few studies have been done about early-life exposure as well as the combined effect of multiple neighborhood social determinants of health measures. Each 1-standard-deviation increase in the neighborhood social determinants of health index is associated with increased risk of coronary artery calcification at the year 7, year 15, and year 20 visits (Odds Ratios range from 1.15 to 1.17). The area under the Receiver Operating Characteristics curve ranges between 0.718 (year 7) and 0.719 (year 20). Compared to White participants, Black …

A Pathogenic Tau Mutation Drives Autophagy-Lysosome Dysfunction That Limits Tau Degradation In A Model Of Frontotemporal Dementia, Farzaneh S Mirfakhar, Jacob A Marsh, Chihiro Sato, Kylie J Schache, Miguel A Minaya, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Shannon L Macauley, Celeste M Karch

2020-Current year OA Pubs

Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, …

Post-Hemorrhagic Hydrocephalus Of Prematurity Is Associated With Disruption Of Tight Junctions And Increased Macrophage Activity In The Choroid Plexus, Maria Garcia-Bonilla, Rajiv Swarup, Owen W Limbrick, Habeebah Z Vohra, Ayodamola Otun, Konrad Mckalip, William Bernhardt, Kirill Shumilov, Marie Michenkova, Jayne Crouthamel, Mackenzie Newman, Krikor Dikranian, James P Mcallister Ii, David D Limbrick

2020-Current year OA Pubs

BACKGROUND: Previous studies on intraventricular hemorrhage (IVH), a common and severe complication of preterm birth, and subsequent post-hemorrhagic hydrocephalus (PHH), have predominantly concentrated on the secretory function of the choroid plexus (ChP), with considerably less emphasis on its barrier function. We hypothesized that PHH is associated with immune-related alterations in the junction biology of ChP. METHODS: We examined differences in tight junctions and macrophages using a neonatal mouse model of PHH (n = 40) and in vitro ChP explants (n = 22), as well as human post-mortem samples (n = 6). To test our hypothesis, we employed histology, immunofluorescence, magnetic …

Provider And Caregiver Perspectives On Vision Services For Childhood Cancer Survivors: A Qualitative Study, Asha Parvathaneni, Luke Zabotka, Jacob Strelnikov, Allison J L'Hotta, Matthew J Ehrhardt, Maria Montoya, Kyathi Thallapureddy, Robert J Hayashi, Margaret Reynolds, Sara Malone

2020-Current year OA Pubs

PURPOSE: This study qualitatively explored barriers and facilitators to accessing supportive vision services for childhood cancer survivors with vision deficits and identified current service-delivery contexts from the perspectives of community professionals and caregivers. METHODS: Participants included caregivers and professionals who completed semi-structured interviews. Provider questions focused on patient identification and assessment, follow-up protocols, and available resources, while caregiver questions addressed navigating survivorship care, academic needs, and goals for their children. Transcripts were thematically analyzed following inductive and deductive coding. RESULTS: Six caregivers and 10 professionals completed interviews. Thematic analysis resulted in three contexts for barriers and facilitators: school settings, community …

Breast Cancer-Derived Extracellular Vesicle Mir-425-5p (Mir-425) Promotes Brain Metastasis Via Activating Astrocytes Through The Novel Mir-425-Znf24-Ccl8 Signaling Axis, Grace L Wong, Munazza S Khan, Sara Manore, Shivani Bindal, Ravi Singh, Hui-Wen Lo

Faculty, Staff and Student Publications

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; however, the inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. We further observed that EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. To elucidate how …

Helminth Coinfections Mitigate Clinical, Parasitological, And Immune Outcomes In Mozambican Children With Malaria, Inocência Cuamba, Rebeca Santano, Berta Grau-Pujol, Marta Vidal, Ruth Aguilar, Anélsio Cossa, Chenjerai Jairoce, Rojelio Mejia, Augusto Nhabomba, Jose Muñoz, Gemma Moncunill, Carlota Dobaño

Faculty, Staff and Students Publications

Background: Clearance of Plasmodium falciparum infection requires a TH1 immune response with production of pro-inflammatory cytokines, IgG1, and IgG3 responses. In contrast, infections with helminths are dominated by TH2/Treg immune responses characterized by production of anti-inflammatory cytokines, IgE, and IgG4, which could potentially interfere with malaria outcomes and immune responses.

Methods: We recruited 441 malaria-symptomatic children aged 2-10 years attending two hospitals in the Manhiça District (Mozambique) and assessed infection by rapid antigen diagnostic test, microscopy, and/or quantitative PCR. Using Luminex, we measured concentrations of 30 cytokines and IgA, IgM, IgE, IgG, and IgG1-4 levels against 12 P. falciparum antigens …

Free Versus In Situ Right Internal Mammary Artery As A Conduit In Coronary Artery Bypass Surgery: A Meta-Analysis, Yuta Kikuchi, Tomoki Sakata, Tomonari Shimoda, Shinichi Fukuhara, Junichi Shimamura, Makoto Hibino, Tsuyoshi Kaneko, Hiroo Takayama, Hisato Takagi, Michel Pompeu Sa, Toshiki Kuno

Department of Medicine Faculty Papers

OBJECTIVES: There is debate regarding the optimal choice for a second conduit in coronary artery bypass grafting. The right internal mammary artery (RIMA) is commonly employed as a second conduit; however, it is unclear whether the free (fRIMA) or in situ (isRIMA) configuration yields superior outcomes. We performed a systematic review and meta-analysis to compare clinical outcomes between fRIMA and isRIMA as the second conduit.

METHODS: A comprehensive search of PubMed (MEDLINE), EMBASE, and CENTRAL was performed through May 2025 to identify studies comparing outcomes in patients undergoing coronary artery bypass grafting with either fRIMA or isRIMA as a second …