Digital Commons Network^™

Early-Life Wnt4 Expressing Colon Stromal Cells Orchestrate Lifelong Mucosal Homeostasis Via Bmp-Driven Inkt Cell Imprinting, Xi Lin, Chloe Hyun-Jung Lee, Ting Zhang, Agne Antanaviciute, Thomas Hanley, Jonathan N Glickman, Nikhila S Bharadwaj, Vicki Rosen, Jenny E Gumperz, Matthew K Waldor, Alison Simmons, Thomas Gensollen, Richard S Blumberg

2020-Current year OA Pubs

The early-life intestinal microenvironment plays a pivotal role in shaping immune cell development. Here, we identify a colonic Wnt4-expressing stromal cell, enriched during early-life, that promotes iNKT cell proliferation via BMP-MAPK signaling. These stromal cells are spatially associated with iNKT cells and macrophages and exhibit high Bmp2 expression during the neonatal period. Depletion of BMP2 in Wnt4

Development Of Antagonist Peptides Of The Crk/Crkl Sh2 Domains By Modifying The Peripheral Amino Acid Residues Of The Yxxp Motif., Taeju P. Park, Anuradha Roy, Justin T. Douglas, Laurie Harned, Sarah A. Neuenswander, Neka Large, Giridhar Mudduluru, Melinda Broward, David K. Johnson

Manuscripts, Articles, Book Chapters and Other Papers

Protein-protein interactions (PPIs) through the phosphotyrosine-Src homology 2 (SH2) interaction play critical roles in many signal transduction pathways. CT10 regulator of kinase (Crk) and Crk-like (CrkL) are structurally and functionally similar adaptor proteins that mediate PPIs through their SH2 domains. Crk and CrkL are essential in tumor cell migration and invasion and have been proposed as therapeutic targets. However, there are no Crk and CrkL inhibitors available. Previously, we designed a conserved heptapeptide that binds to Crk by analyzing the 15 YXXP motifs in p130Cas. The peptide bound to the SH2 domain of Crk (CrkSH2) and inhibited the CrkSH2-p130Cas interaction. …

Large-Scale Genetic Characterization Of Parkinson’S Disease In The African And African Admixed Populations, Fulya Akçimen, Kimberly Paquette, Peter Wild Crea, Kathryn Step, Emily Waldo, Mathew J Koretsky, Paula Saffie-Awad, Charles Achoru, Funmilola Taiwo, Simon Ozomma, Gerald Onwuegbuzie, Marzieh Khani, Spencer Grant, Lukman Owolabi, Chiamaka Okereke, Olajumoke Oshinaike, Emmanuel Iwuozo, Suleyman Can Akerman, Paul Suhwan Lee, Shyngle Oyakhire, Nosakhare Osemwegie, Kensuke Daida, Sani Abubakar, Adedunni Olusanya, Mariam Isayan, Christiane Alvarez, Rami Traurig, Adebimpe Ogunmodede, Sarah Samuel, Mary B Makarious, Fadimatu Sa'ad, Rashidat Olanigan, Kristin Levine, Ewere Marie Ogbimi, Dan Vitale, Francis Odiase, Francis Ojini, Olanike Odeniyi, Zih-Hua Fang, Nkechi Obianozie, Deborah A Hall, Ernest Nwazor, Tao Xie, Francesca Nwaokorie, Mahesh Padmanaban, Paul Nwani, Ejaz A Shamim, Alero Nnama, David Standaert, Morenikeji Komolafe, Marissa Dean, Godwin Osaigbovo, Elizabeth Disbrow, Ismaila Ishola, Ashley Rawls, Frank Imarhiagbe, Shivika Chandra, Cyril Erameh, Vanessa Hinson, Naomi Louie, Ahmed Idowu, J Solle, Scott A Norris, Abdullahi Ibrahim, Camilla Kilbane, Gauthaman Sukumar, Lisa M Shulman, Daniel Ezuduemoih, Julia Staisch, Sarah Breaux, Clifton Dalgard, Erin R Foster, Abiodun Bello, Andrew Ameri, Raquel Real, Erica Ikwenu, Huw R Morris, Roosevelt Anyanwu, Erin Furr Stimming, Kimberley Billingsley, Wemimo Alaofin, Pilar Alvarez Jerez, Osigwe Agabi, Dena G Hernandez, Rufus Akinyemi, Sampath Arepalli, Laksh Malik, Raymond Owolabi, Yakub Nyandaiti, Hampton L Leonard, Kolawole Wahab, Oladunni Abiodun, Carlos F Hernandez, Fatima Abdulai, Hirotaka Iwaki, Soraya Bardien, Christine Klein, John Hardy, Henry Houlden, Kamalini Ghosh Galvelis, Mike A Nalls, Nabila Dahodwala, Whitley Aamodt, Emily Hill, Alberto Espay, Stewart Factor, Chantale Branson, Cornelis Blauwendraat, Andrew B Singleton, Oluwadamilola Ojo, Lana M Chahine, Njideka Okubadejo, Sara Bandres-Ciga

Faculty, Staff and Student Publications

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 …

Apathy, Effort-Based Decisions And Brain Integrity In Alzheimer’S And Parkinson’S Diseases, Lee-Anne Morris, Hideo Suzuki, Seonjoo Lee, Zekai Jin, Bryan B Chen, Ana Marin, Edward D Huey, Yunglin Gazes, Sarah R Heilbronner, Campbell J Le Heron, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy, or loss of motivation, is a prominent syndrome accompanying both Alzheimer's and Parkinson's diseases, in addition to other disorders. One approach to understanding motivational loss is to examine the processes underlying goal-directed behaviour. Weighing up rewarding outcomes against the effort costs required to obtain them (effort-based decision-making) is a core computation when deciding to act for outcomes. Although a growing body of evidence points to disruption of this computation in people with apathy, which underlying decision parameters drive this disruption, their neural associations and whether these would generalize or differ across brain disorders have not been examined. People with …

Mitochondrial Etf Insufficiency Drives Neoplastic Growth By Selectively Optimizing Cancer Bioenergetics, David Papadopoli, Sergej Djuranovic, Et Al.

2020-Current year OA Pubs

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH …

Large-Scale Genetic Characterization Of Parkinson's Disease In The African And African Admixed Populations, Fulya Akçimen, Scott A Norris, Erin R Foster, Et Al.

2020-Current year OA Pubs

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 …

Transcriptome Predictors Of Second Breast Events In Ductal Carcinoma In Situ: A Case‒Control Study Including Black And White Women, Aditi Hazra, Emma Berdan, Thomas Walsh, Sarah Humble, Jen Tappenden, Katherine Deschryver, Deborah Veis, Kiran Vij, Shannan Ho Sui, Graham A Colditz

2020-Current year OA Pubs

BACKGROUND: Black women diagnosed with ductal carcinoma in situ (DCIS) experience disproportionately higher risk of second breast cancer events (SBEs), including both ipsilateral and contralateral recurrences, yet remain underrepresented in molecular biomarker studies compared to non-Hispanic White women.

METHODS: We performed RNA sequencing on 200 archival DCIS samples from the Resource of Archival Breast Tissue cohort, including 33% self-reported Black women. We correlated transcriptomic and clinical data to identify predictors of SBEs. Cases (n = 100) who developed SBEs between 1999 and 2019 were matched 1:1 to controls (n = 100) on age, race, and margin status, who remained event-free …

Randomised Controlled Trial Comparing Antibiotic Cement Bead Pouch Versus Negative Pressure Wound Therapy For The Management Of Severe Open Tibia Fracture Wounds: Beads Versus Vac (Bvv) Protocol, Lucas S Marchand, Gerard Slobogean, Nathan N O'Hara, Anthony D Harris, David W Grainger, Lehana Thabane, Mohit Bhandari, Gregory J Della Rocca, Patrick J Kellam, Robert D Zura, Debra Marvel, Jeffrey L Wells, I Leah Gitajn, Kyle J Jeray, Robert V O'Toole, Zachary M Working, Roman M Natoli, Patrick F Bergin, Jennifer E Hagen, Ashley E Levack, Ernesto Guerra-Farfan, Gregory M Schrank, Joan N Hebden, Franca Mossuto, Cassandra Tsoutsounakis, David Pogorzelski, Hailey Pineda, Sofia Bzovsky, Sheila Sprague, Bvv Investigators

Faculty, Staff and Student Publications

Introduction: Early open fracture management aims to minimise the risk of complications. For the most severe open fracture wounds, multiple irrigation and debridement surgeries are required to overcome severe wound contamination, to reassess the evolving tissue injury or to temporise and plan further surgery. When multiple irrigation and debridement surgeries are needed, uncertainty remains about how the open fracture wound should be managed to best minimise complications. The primary aim of this trial is to compare the antibiotic cement bead pouch vs negative pressure wound therapy in the management of patients with severe open tibia fracture wounds.

Methods and analysis: …

Tractor Workflow: A Scalable Nextflow Framework For Local Ancestry-Aware Genome-Wide Association Studies, Nirav N Shah, Taotao Tan, Jessica Honorato-Mauer, Yi-Sian Lin, Adam X Maihofer, Clement C Zai, Pgc-Ptsd Ancestry Working Group, Marcos Santoro, Caroline M Nievergelt, Elizabeth G Atkinson

Faculty, Staff and Students Publications

Motivation: The routine exclusion of admixed individuals from traditional genome-wide association studies (GWAS) due to concerns about spurious associations has limited multi-ancestry genetic discovery. Tractor addresses this issue by incorporating local ancestry into association testing, enabling the identification of ancestry-enriched signals and generating ancestry-specific summary statistics. However, adoption has been constrained by the complexity of prerequisite steps, including phasing and local ancestry inference, which require substantial bioinformatics expertise and introduce key analytical decision points.

Results: We developed a scalable, automated Nextflow workflow that integrates phasing, local ancestry inference, and Tractor association testing into a reproducible end-to-end pipeline. To demonstrate its …

Antibody-Drug Conjugates Beyond Her2 In Non-Small Cell Lung Cancer (Nsclc): Mechanisms, Emerging Targets, And Future Directions., Ahmed Ismail, Aakash Desai, George R Simon, Yanis Boumber

Oncology Articles

Antibody-drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of …

Securepose: Automated Face Blurring And Human Movement Kinematics Extraction From Videos Recorded In Clinical Settings, Rishabh Bajpai, Bhooma Aravamuthan

2020-Current year OA Pubs

Movement disorder diagnosis often relies on expert evaluation of patient videos, but sharing these videos poses privacy risks. Current methods for de-identifying videos, such as blurring faces, are often manual, inconsistent, or inaccurate. Furthermore, these methods can compromise automated kinematics extraction-a valuable aid to movement analysis. To address these challenges, we developed SecurePose, open-source software that provides both reliable de-identification and automated body kinematic extraction from videos recorded in clinic settings using smartphones/tablets. We validated SecurePose on gait videos recorded in outpatient clinic visits of 116 children with cerebral palsy, assessing both the accuracy of its de-identification compared to the …

Plasma Constituents Promote Endothelial Thromboinflammatory Dysfunction After Hemorrhagic Shock, Kelly E Sanders, Marissa D Pokharel, Baron K Osborn, Yao-Wei Wang, Charles E Wade, Lucy Z Kornblith, Mitchell J Cohen, Jessica C Cardenas

Faculty, Staff and Student Publications

Background: Hemorrhagic shock (HS) following traumatic injury is hallmarked by innate immune activation, hypercoagulability, and thromboinflammatory complications. To date, the direct link between HS, injury severity, and endothelial cell (EC) contributions to thromboinflammation remains poorly understood. The goals of this study were to determine the impact of injury severity and HS on endothelial-mediated thromboinflammation and examine whether these changes increase the propensity for thrombosis.

Methods: Plasma from 89 male trauma patients, stratified by HS and injury severity, and 10 healthy subjects were assessed for inflammatory mediators by BioPlex. Human lung microvascular endothelial cells were exposed to patient plasma for 4 …

Clinical And Demographic Characteristics Of Hospitalized Patients With Xylazine-Related Wounds, Elizabeth Novick, Nikhil Seval, Dagan Coppock, Mollie Tucker, Daniel Taupin, John Zurlo, Carolyn Kramer

Department of Medicine Faculty Papers

OBJECTIVES: Little is known about the demographic and clinical features of patients with xylazine-related wounds. We sought to characterize hospitalized patients with substance use disorder (SUD) and xylazine-related wounds seen for infectious diseases consultation.

METHODS: We retrospectively reviewed the medical records of 193 patients diagnosed with SUD at 3 Philadelphia hospitals between October 2023 and January 2024. Patients were identified as either being diagnosed with (n=73) or without (n=120) xylazine-related wounds. We compared the demographic and clinical features between the 2 groups.

RESULTS: Patients diagnosed with wounds were younger ( P < 0.001), more likely to be White or Hispanic and less likely to be Black/AA ( P < 0.001), more likely to have tested positive for fentanyl ( P < 0.001), amphetamines ( P < 0.001), and cocaine ( P 0.001), more likely to acknowledge injection ( P < 0.001), and more likely to leave the hospital by patient-directed discharge (PDD) ( P < 0.001). Most patients had multiple wounds (75%), and more than half (53%) had at least one wound greater than 10 cm at its widest dimension. Although most patients diagnosed with wounds received antibiotics, many did not have symptoms or signs of infection.

CONCLUSIONS: Xylazine-related wounds are highly associated with illicitly manufactured …

Functional Heterogeneity In Trophoblast Stem Cells Derived From Recurrent Pregnancy Loss Products Of Conception., Qi Fu, Keisuke Kozai, Xingrao Ke, Joe Varberg, Sheng Xia, Ashley S. Howard, Michael Lydic, Kristin Holoch, Courtney Marsh, Elin Grundberg, Kaela Varberg

Manuscripts, Articles, Book Chapters and Other Papers

Recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages, affects 1-5% of couples attempting to conceive and most frequently occurs between 6 and 8 weeks of gestation, coinciding with critical stages of placental development. Despite this temporal association, placental contributions to RPL pathogenesis remain poorly understood. We hypothesized that trophoblast lineage development, including extravillous trophoblast (EVT) and syncytiotrophoblast (STB) differentiation, are disrupted in RPL. To test this hypothesis, we established and functionally characterized human trophoblast stem (TS) cell lines derived from products of conception (POC) obtained from consenting idiopathic RPL cases. Four TS cell lines were successfully derived …

Ai-Powered Insights In Pediatric Nephrology: Current Applications And Future Opportunities., Arwa Nada, Yamen Ahmed, Jieji Hu, Darcy K. Weidemann, Gregory H. Gorman, Eva Glenn Lecea, Ibrahim A. Sandokji, Stephen Cha, Stella Shin, Salar Bani-Hani, Sai Sudha Mannemuddhu, Rebecca L. Ruebner, Aadil Kakajiwala, Rupesh Raina, Roshan George, Rim Elchaki, Michael L. Moritz, The American Society Of Pediatric Nephrology Quality Improvement And Artificial Intelligence (Aspn Qi/Ai) Interest Group

Manuscripts, Articles, Book Chapters and Other Papers

Artificial intelligence (AI) is rapidly emerging as a transformative force in pediatric nephrology, enabling improvements in diagnostic accuracy, therapeutic precision, and operational workflows. By integrating diverse datasets-including patient histories, genomics, imaging, and longitudinal clinical records-AI-driven tools can detect subtle kidney anomalies, predict acute kidney injury, and forecast disease progression. Deep learning models, for instance, have demonstrated the potential to enhance ultrasound interpretations, refine kidney biopsy assessments, and streamline pathology evaluations. Coupled with robust decision support systems, these innovations also optimize medication dosing and dialysis regimens, ultimately improving patient outcomes. AI-powered chatbots hold promise for improving patient engagement and adherence, while …

Regional Variation Of Underlying Kidney Diseases In Children Undergoing Chronic Kidney Replacement Therapy Around The Globe., Dagmara Borzych-Dużałka, Marjolein Bonthuis, Uma Ali, Yok-Chin Yap, Michael Manno, Yihui Zhai, Reyner Loza, Seema Hashmi, Naye Choi, Kenza Soulami, Judith Exantus, Mohamed S. Al Riyami, Sameh Mabrouk, Marbella Ma Angeles, Cristina Zelaya-Camacho, Henny Adriani Puspitasari, Syed Saimul Huque, Francisco Cano, Kar Hui Ng, Sevcan A. Bakkaloğlu, Jerome Harambat, Kitty J. Jager, Bradley A. Warady, Franz Schaefer

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is a scarcity of information regarding the distribution of the diseases leading to kidney failure (KF) in children living in the emerging world. We used registry data to provide a global overview of the underlying disease spectrum in children commencing kidney replacement therapy (KRT).

METHODS: We analyzed KF causes among 23,620 children and adolescents commencing maintenance KRT in 80 countries, using data from the IPNA Global KRT Registry (including ESPN/ERA Registry), the International Pediatric Dialysis Network (IPDN), the United States Renal Data System (USRDS), and the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). The analysis considered …

The Resilient Study: A Retrospective, Descriptive, Correlational Investigation Of Correlates Of Oral Endocrine Therapy Adherence In Older Women With Breast Cancer., Sunny Y. Ruggeri, Cynthia L. Russell Lippincott, Gregory L. Alexander, Rebecca J. Bartlett Ellis, Steven R. Chesnut, Lori A. Erickson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Breast cancer is the most prevalent and costly cancer. Oral endocrine therapy (OET) improves survival rates and quality of life while reducing recurrence, mortality, morbidity, and medical costs. However, adherence to OET is challenging because OET is prescribed for 5-10 years. Determinants of OET nonadherence (NA) among women aged 65 and older remain poorly characterized. Existing studies are limited, often focusing on small, single-site samples and focusing on patient-level rather than multi-level determinants. Despite the unique needs of older women, research on OET-NA remains scarce.

OBJECTIVE: This study identified multi-level determinants of OET-NA in older women using ecological systems …

Targeted Epigenome Sequencing Of Eosinophils Reveals Cpg Sites And Regulatory Variants Associated With Asthma., Rébecca Dionne-Gagné, Anne-Marie Madore, Anne-Marie Boucher-Lafleur, Tomi Pastinen, Catherine Laprise

Manuscripts, Articles, Book Chapters and Other Papers

Eosinophils are pro-inflammatory cells that play a central role in asthmatic inflammation. However, few studies have examined their methylation profiles in asthma, all relying on microarray-based approaches. Here, an epigenome-wide association study in 183 purified eosinophil samples from the Saguenay-Lac-Saint-Jean asthma family cohort was performed using a custom sequencing panel targeting 4,609,564 CpGs in immune regulatory regions. Two CpG sites in MAEA and SLC9A2 genes, known to be involved in immune function, were significantly associated with asthma, while five additional sites showed suggestive associations. Integration with genotype data (7,829,429 variants) and expression counts (17,513 genes) identified significant quantitative trait loci-mediated …

Leading With Hope: A Clinical Communication Campaign To Promote Partner Hiv Testing In Assisted Partner Notification And Antenatal Care Programs In Uganda., Emily A. Hurley, Violet Gwokyala, Linda Kisaakye Nabitaka, Jolly Beyeza Kashesya, Mercylynn Agasha, Florence Namaganda, Nikolaus Schuetz, J Nalubega Ross, Joseph K B Matovu, Rhoda Wanyenze, Glenn Wagner, Kathy Goggin

Manuscripts, Articles, Book Chapters and Other Papers

Among heterosexual couples in sub-Saharan Africa, fears of relationship dissolution and inability to bear healthy children following an HIV-positive result remain barriers to HIV testing. Recently expanded availability of pre-exposure prophylaxis (PrEP) affords a critical opportunity to promote HIV testing with reassuring communication that highlights use for relationship preservation and healthy childbearing. We aimed to develop a theoretically-grounded communication intervention to promote partner HIV testing within assisted partner notification (APN) and antenatal care (ANC) programs in Uganda. Through an 18-month iterative co-creation process, we developed the HOPE Clinical Communication Campaign (HOPE-CCC) in collaboration with a project advisory board (PAB) of …

Promises, Pitfalls, And Paths Forward For The Pediatric Research Equity Act., Alexa L. Pagano, Danielle J. Green, Jennifer Goldman, Anjali Deshmukh

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Since its enactment in 2003, the Pediatric Research Equity Act (PREA) has significantly increased the number of pediatric drug studies performed and expanded pediatric drug labeling. Despite these advancements, many drugs used in children still lack pediatric-specific US Food and Drug Administration (FDA) labeling, even when pediatric studies are required by law. Recent legislative changes strengthened the FDA's enforcement authority over PREA. As these changes are implemented, persistent gaps in pediatric drug development warrant examination. Addressing these gaps may help ensure that children are systematically included in clinical research and that medications used in children are supported by rigorous …

Accelerated Weaning Of Opioids To Reduce Pharmacologic Exposure For Neonatal Opioid Withdrawal Syndrome: A Randomized Clinical Trial., Abbot R. Laptook, Adam Czynski, Rouba Chahine, Rachel G. Greenberg, P Brian Smith, Erica Oliveira, Jenna Gabrio, Barry Eggleston, Abhik Das, Jeannette Lee, Barry Lester, Dave Clark, Michele Walsh, Helen Ko, Clare Campbell Asher, Hayley Friedman, Samuel Gentle, Karishma Rao, Anup Katheria, Kristen Benninger, Sanket Jani, Mark Cody Smith, Akram Khan, Ajay Talati, Shaina Lodhi, Fernando Mena, Amanda England, Prabhu Parimi, Ranjit Kylat, Heidi Harmon, Javed Mannan, Meghan P. Howell, Tanner Wright, Jessica Snowden, Act Now Collaborative

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To determine if newborns receiving morphine or methadone as the primary pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS) tolerate and receive fewer days of opioid using an accelerated wean protocol (15% decrements) compared with using a slower wean protocol (10% decrements).

STUDY DESIGN: Newborns ≥36 weeks of gestation receiving morphine or methadone for NOWS were enrolled in a pragmatic blinded, randomized multicenter trial. Newborns underwent protocol-driven weaning with decreasing opioid doses of either 15% or 10% decrements. Weaning was encouraged every 24 hours, and if signs of NOWS worsened, the preceding dose was resumed. To maintain blinding, the …

Exploring The Alignment Between Medical School Outcomes With Residency Competencies: A Modified Delphi Study, Sally A. Santen, Luan Lawson, Jose A. Negrete Manriquez, Marjorie Westerveld, Laurah Turner, Anita Wilson, Phd, Yoon Soo Park, Eric S. Holmboe, Michael S. Ryan, Medical School Outcomes Milestone Study Group

JeffMD Academic Affairs

PURPOSE: Facilitation of competency-based medical education adoption would benefit from alignment between medical school (undergraduate medical education [UME]) and residency (graduate medical education [GME]) assessments. This study explores the strength of an a priori alignment of medical school assessments with residency competency domains to guide programmatic assessment and research.

METHOD: In fall 2023, the authors (US faculty with UME and GME expertise) used a 2-phase Delphi consensus approach (9 participants in phase 1 and 16 in phase 2) to independently map medical school assessments to the Accreditation Council for Graduate Medical Education competency domains (0, no association; 1, some or …

Population Pharmacokinetics And Dosing Simulations Of Pentobarbital In The Pediatric Population, Victoria Etges Helfer, Lorena Medina-Aymerich, William J. Muller, Marisa Meyer, Amira Al-Uzri, Russell Mcculloh, Chi D. Hornik, Stephen J. Balevic, Rachel G. Greenberg, Daniel K. Benjamin, Sarah G. Anderson, Daniel Gonzalez

Department of Pediatrics Faculty Papers

Pentobarbital is a barbiturate with sedative and anticonvulsant properties, occasionally used in pediatric patients for preoperative sedation, deep sedation during mechanical ventilation, and seizure control. Despite its long-standing clinical use, age-appropriate dosing remains challenging due to variability across studies and limited pediatric pharmacokinetic (PK) data. This study (NCT01431326) aimed to characterize the population pharmacokinetics of pentobarbital in pediatric patients (birth to 21 years) and evaluate dosing strategies using model-based simulations. A two-compartment population PK model, allometrically scaled to total body weight, adequately described pentobarbital plasma concentrations, with no additional covariates identified as significant. Simulations were conducted across four age groups: …

Diacylglycerol Kinase Eta As A Novel Target In Nras Mutant Melanoma, Haley P. Wilson, Casey D. Stefanski, Signe Caksa, Glenn L. Mersky, Scott D. Varney, Jelan I. Haj, Dan A. Erkes, Timothy J. Purwin, Vivian Chua, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

NRAS mutations occur in 10%-30% of cutaneous melanomas and are associated with high tumor mutational burden. Mutant NRAS signaling drives aberrant cell growth and proliferation, in part, through activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have limited effectiveness in patients with NRAS mutant melanoma. The role of other targetable signaling pathways in NRAS mutant melanoma is poorly characterized. Here, we demonstrated that one isoform of diacylglycerol kinase, diacylglycerol kinase eta (DGKη), a lipid signaling regulator, was highly expressed in NRAS mutant melanoma patient samples. Knockdown of DGKH in NRAS mutant melanoma cell lines resulted in …

The Dietary Management Of Sodium In Children With Kidney Diseases-Clinical Practice Recommendations From The Pediatric Renal Nutrition Taskforce., José Renken-Terhaerdt, An Desloovere, Michiel Js Oosterveld, Nonnie Polderman, Evelien Snauwaert, Stella Stabouli, Johan Vande Walle, Caroline Anderson, Sheridan Collins, Larry A. Greenbaum, Matthew Harmer, Lyndsay Harshman, Christina L. Nelms, Pearl Pugh, Vanessa Shaw, Jetta Tuokkola, Molly R Wong Vega, Bradley A. Warady, Rukshana Shroff, Fabio Paglialonga

Manuscripts, Articles, Book Chapters and Other Papers

Sodium imbalance is a common concern in children with kidney diseases, presenting as either sodium excess or sodium deficit, each with significant clinical implications. Sodium excess contributes to fluid overload and hypertension, while increased sodium losses, particularly via urine or peritoneal fluid, can predispose patients to hypotension and growth failure. Effective sodium management is thus a critical component of care in pediatric kidney diseases, with dietary sodium intake playing a pivotal role in maintaining homeostasis. The Pediatric Renal Nutrition Taskforce (PRNT) has developed clinical practice recommendations (CPRs) for dietary sodium management in children with kidney diseases, addressing key aspects of …

Screening For Hypertension And Diabetes In Laundromats In The Largest Hispanic-Majority City In The U.S, Nicholas A Mccann, Vanessa Schick, Jack Tsai

Faculty, Staff and Student Publications

Purpose: This study aimed to assess the prevalence of hypertension and diabetes among laundromat users in San Antonio, Texas, and explore laundromats as a novel setting for health interventions regarding these 2 conditions.

Design: This descriptive, cross-sectional study involved demographic, blood pressure and HbA1c screenings to assess the health status of laundromat users.

Setting: The study took place in 7 laundromats in low-income areas of San Antonio.

Subjects: A total of 150 adults aged 18 and older who regularly used the laundromats and spoke either English or Spanish were eligible to participate.

>Measures: Hypertension was defined as a systolic BP …

An Integrated Framework For Early Detection And Transmissibility Assessment Of Emerging Variants In Wastewater, Xingwen Chen, Tin Phan, Wei Lin Lee, Katie Clark, Steven F Rhode, Samantha Brozak, Bruce Pell, Tsultrim Palden, Mats Leifels, Anna Gitter, Yang Kuang, Stefan Wuertz, Janelle Thompson, Kristina D Mena, Eric J Alm, Fuqing Wu

Faculty, Staff and Student Publications

Tracking the emergence of new viral variants is critical for epidemic preparedness, but remains challenging because variants typically circulate at low prevalence during the early phase of outbreaks. Here, we present an integrated framework that combines sensitive variant detection in wastewater with quantitative assessment of transmissibility through dynamic epidemic modeling. Using the SARS-CoV-2 Omicron variant as a proof of concept, we developed a novel nested allele-specific RT-qPCR assay (NAS-PCR) that achieved a thousand-fold increase in sensitivity compared with allele-specific RT-qPCR (limit of detection: 0.5 copies/μl). NAS-PCR detected Omicron in wastewater samples from the Greater Boston area starting in September 2021, …

Associations Of Blood Biomarkers Of Glial Cell Dysfunction And Neuronal Injury With Future Cognitive Decline And Incident Dementia, Srishti Shrestha, Xiaoqian Zhu, B Gwen Windham, Kevin J Sullivan, Priya Palta, Rebecca F Gottesman, Russell P Tracy, Clifford R Jack, Petrice M Cogswell, Prashanthi Vemuri, Sudha Seshadri, Thomas H Mosley, Michael E Griswold, Myriam Fornage

Faculty, Staff and Student Publications

Introduction: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking.

Methods: We jointly fitted linear mixed-effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble cluster of differentiation-14 (sCD14), neurofilament light chain (NfL), total tau (t-tau), and ubiquitin C-terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community-based Atherosclerosis Risk in Communities Study. sCD14 and YKL-40 were measured in 3082 …

Perceived Neighborhood Environment And Objectively Assessed, Habitual Physical Activity Among Us Adults: An All Of Us Research Program Study, Natalia I Heredia, Michael C Robertson, Christopher D Pfledderer, Ethan T Hunt, Timothy J Walker, Deborah Salvo

Faculty, Staff and Student Publications

Introduction: The purpose of this study was to assess the associations between perceived socioenvironmental neighborhood attributes and objectively assessed habitual physical activity among US adults as well as whether associations vary by sociodemographic characteristics.

Methods: We used data from the All of Us research program, a longitudinal cohort study of a diverse sample of Americans. Perceived neighborhood social cohesion, physical and social disorder, walkability, and sociodemographic characteristics were self-reported. Habitual physical activity was ascertained using Fitbit-derived step counts over ≥24 weeks. Generalized additive mixed-effects models were used to test the associations between perceived socioenvironmental neighborhood attributes and daily step counts. …

Addressing Nonignorable Missing Data And Heterogeneity In Prognostic Biomarker Assessment, Xinran Huang, Ruosha Li, Jing Ning, For The Alzheimer's Disease Neuroimaging Initiative

Faculty, Staff and Student Publications

Covariate-specific and time-dependent area-under-curve (AUC) is often used to evaluate the discriminative performance of biomarkers with time-to-event outcomes, particularly when certain covariates influence biomarkers' accuracy. In biomarker research, despite extensive efforts, missing data remain unavoidable, with nonignorable missingness posing significant challenges. This article focuses on estimating the impact of covariates on time-dependent AUC in the presence of nonignorable missing biomarkers. Assuming a parametric model on the missing probability, we leverage instrumental variables to address the identifiable issue and estimate the unknown parameters. We integrate the inverse probability weighting approach into the score equation of a pseudo partial likelihood for estimation …