Medical Sciences Commons^™

Upholding Our Promise: Negotiating Belonging And Professional Identity Formation In Underrepresented In Medicine Pediatric Residents, Oriaku A Kas-Osoka, Courtney A Gilliam, Lahia Yemane, Candice Taylor Lucas, Rebecca Blankenburg, H Mollie Grow, Laura Kester-Prakash, Jyothi Marbin, Patricia Poitevien, Audrea M Burns

Faculty, Staff and Students Publications

Objective: To explore UIM pediatric residents' perspectives on how belonging impacts PIF and Well-BP.

Methods: We conducted a national qualitative study grounded in a critical interpretivist paradigm using virtual focus groups with UIM pediatric residents between June 2022 and April 2023. Data were analyzed by 4 authors using reflexive thematic analysis until theoretical sufficiency was reached. Member-checking was conducted to ensure the trustworthiness of the themes.

Results: Twenty-four UIM pediatric residents across 20 programs participated. Five themes emerged as follows: 1) Belonging is a dynamic process shaped by daily affirmations and invalidations; 2) Clinical learning environments often erode belonging through …

Cytokine-Based Strategies To Improve Prognostic Enrichment Of Pediatric Ards, E Scott Halstead, Todd M Umstead, Zissis C Chroneos, Cainan Riccio-Baum, S Rameeza Allie, Daniel J Mckeone, Debbie Spear, Ryan A Nofziger, Ronald C Sanders, Danielle Ahn, Jasmine C Dowell, Asdis F Wagner, Neal J Thomas, Prithvi Sendi, W Joshua Frazier, Courtney M Rowan, Parag N Jain, Dalia A Bashir, Stuart H Friess, Brian M Varisco, Jocelyn Grunwell, Aline B Maddux, Stephen T Famularo, Nadir Yehya

Faculty, Staff and Students Publications

Background: Hyper-inflammation is common to multiple critical care syndromes, including acute respiratory distress syndrome (ARDS) and sepsis, and is associated with worse outcomes. A signature of hyper-inflammatory ARDS has been described in adults using IL-6, TNFR1, and bicarbonate, and has prognostic utility. We investigated the application of this traditional parsimonious signature to pediatric ARDS patients and tested whether we could improve prognostic enrichment using other cytokines.

Methods: We leveraged a prospective multicenter cohort study of 500 children with ARDS (Linking Endotypes and Outcomes in Pediatric Acute Respiratory Distress Syndrome [LEOPARDS]; NCT04113434) study. Plasma samples were obtained within 24 h …

Reclassifying Pediatric Nafld Using The Steatotic Liver Disease Framework: A Multicenter Retrospective Study From The Nash Crn, Tin Bo Nicholas Lam, Katherine P Yates, Sheila L Noon, Kimberly P Newton, Mark H Fishbein, Jean P Molleston, Stavra A Xanthakos, Ajay K Jain, Miriam B Vos, Niviann M Blondet, Krupa R Mysore, Cynthia A Behling, Laura A Wilson, Jeffrey B Schwimmer

Faculty, Staff and Students Publications

Background and aims: The terminology for hepatic steatosis and NAFLD was revised under the umbrella of steatotic liver disease, with metabolic dysfunction-associated steatotic liver disease (MASLD) as the primary subtype. MASLD is defined by hepatic steatosis plus at least 1 cardiometabolic risk factor. A new category, Met-ALD, describes MASLD with alcohol consumption below the defined thresholds for alcohol-associated liver disease (ALD). While adult studies have demonstrated strong concordance between NAFLD and MASLD, the applicability of this framework in children remains unclear.

Approach and results: We assessed children clinically diagnosed with NAFLD and enrolled in the NASH CRN who had available …

Quality Domains In Home-Based Pediatric Hospice And Palliative Care: Adolescent And Young Adult Perspectives, Daniel H Grossoehme, Claire A Crawford, Jhansi Chandra Ellakula, Toluwalase Ajayi, Justin N Baker, Sarah Friebert, Lisa Humphrey, Jillann Jarrell, Rachel Thienprayoon, Pamela S Hinds

Faculty, Staff and Students Publications

Background: Current United States palliative care practice guidelines are intended to cover care across all age groups. Previous research with pediatric providers and caregivers concluded that pediatric hospice and palliative care have unique attributes. Not known is how adolescent hospice and palliative care patients understand quality palliative care. The purpose of this study was to characterize and define quality of care domains as described by adolescent and young adult patients receiving home-based hospice and palliative care.

Methods: Semi-structured interviews with 10-26 year-olds who received home-based hospice and/or palliative care visits in the prior three years at six diverse sites in …

Author Correction: Plasticity And Language In The Anaesthetized Human Hippocampus, Kalman A Katlowitz, Eric R Cole, Elizabeth A Mickiewicz, Shraddha Shah, Melissa Franch, Joshua A Adkinson, James L Belanger, Raissa K Mathura, Domokos Meszéna, Matthew Mcginley, William Muñoz, Garrett P Banks, Sydney S Cash, Chih-Wei Hsu, Angelique C Paulk, Nicole R Provenza, Andrew J Watrous, Ziv Williams, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Sarah R Heilbronner, Robert Kim, Nuttida Rungratsameetaweemana, Benjamin Y Hayden, Sameer A Sheth

Faculty, Staff and Students Publications

This corrects the article "Plasticity and language in the anaesthetized human hippocampus" in volume 654 on page 714.

Biphasic Sleep Is A Feature Of Sleep Disturbance In Syngap1-Rd, Aida Doucoure, Het Patel, Mark A Abboud, Alice Sperry, Sarah K Wanigatunga, Deana Crocetti, Heather Volk, Adam P Spira, Stewart H Mostofsky, Vaishnav Krishnan, Constance Smith-Hicks

Faculty, Staff and Students Publications

Study objectives: Sleep problems are common in children with SYNGAP1-Related Disorder (SYNGAP1-RD). The use of devices that objectively estimate sleep are complicated by co-occurring sensory disorders in this population. We examined the feasibility and validity of wrist actigraphy to examine sleep and rest-activity rhythms (RAR).

Methods: Data from five children with SYNGAP1-RD and 42 typically developing children were analyzed. All children were asked to wear the Actiwatch-2 for 14 continuous days and caregivers were asked to complete a sleep diary and the Children Sleep Health Questionnaire (CSHQ). Parametric (alpha, beta, acrophase, amplitude, up/down mesor, mesor), nonparametric (intradaily variability, interdaily stability, …

Statistics Of Natural Scenes Shape Contextual Modulation In The Visual Cortex, Jiakun Fu, Suhas Shrinivasan, Luca Baroni, Zhuokun Ding, Paul G Fahey, Paweł A Pierzchlewicz, Nikos Karantzas, Kayla Ponder, Rachel Froebe, Lydia Ntanavara, Taliah Muhammad, Konstantin F Willeke, Eric Wang, Zhiwei Ding, Dat Tran, Stelios Papadopoulos, Saumil Patel, Jacob Reimer, Alexander S Ecker, Xaq Pitkow, Jan Antolik, Fabian H Sinz, Ralf M Haefner, Andreas S Tolias, Katrin Franke

Faculty, Staff and Students Publications

Vision is context dependent, with neuronal responses shaped not only by local features but also by surrounding visual input. While classical studies, using grating stimuli, show that iso-oriented surrounds suppress responses more than orthogonal surrounds, the role of contextual modulation under natural stimulus conditions remains less clear. Using recordings from mouse primary visual cortex (V1), we trained convolutional neural network models to predict neuronal responses to natural images and synthesized surround stimuli that selectively suppressed or facilitated responses to optimal center inputs. In vivo experiments confirmed these predictions. Facilitatory surrounds resembled naturalistic continuations of the optimal center stimulus, consistent with …

Development Of An Educational Curriculum For The Surgical Implantation Of Dbs Systems, David Bieber, Rany T Abdallah, Alaa Ab-Elsayed, Adam R Burkey, Dario J Englot, Kunal Gupta, Charles N Munyon, Casey H Halpern, Kai J Miller, Joshua M Rosenow, Ahmed M Raslan, Konstantin V Slavin, Jennifer A Sweet, Sameer Sheth, Nestor Tomycz, Ashwin Viswanathan, Chengyuan Wu, Jeffrey S Raskin

Faculty, Staff and Students Publications

Background: Deep-brain stimulation (DBS) systems are implanted for movement disorders, epilepsy, and psychiatric conditions. Neurologic surgery remains the only discipline credentialed to implant DBS devices, although significant practice variation exists, partly due to heterogeneous training. The North American Neuromodulation Society (NANS) education committee offers a granular recommendation for the progression of an early learner through the practitioner level. It is contextualized within the six-core competency rubric for the surgical implantation of DBS devices.

Materials and methods: Guided by the Accreditation Council for Graduate Medical Education (ACGME) core competencies, a subcommittee of the NANS education committee met virtually and in-person over …

A Nationwide Central Diagnosis For Pediatric Cns Tumors In Japan: The Jccg Brain Tumor And Pathology Committees, Yoshiko Nakano, Junko Hirato, Takako Yoshioka, Tetsuya Takimoto, Sumihito Nobusawa, Kaishi Satomi, Ran Tomomasa, Seiji Yamada, Taku Homma, Shoh Sasaki, Ayako Yamazaki, Maki Sakaguchi, Yasuhide Takeuchi, Nei Fukazawa, Kai Yamasaki, Kohei Fukuoka, Yui Shinohara Kimura, Yuki Nagayama, Yohei Inoue, Akira Miyahira, Ema Yoshioka, Asako Katsuma, Hayato Fukusumi, Tomoko Shofuda, Yuko Hibiya, Yuko Matsushita, Mai Honda Kitahara, Yuki Yomoda, Miho Kato, Michael D Taylor, Yasuhito Arai, Tatsuhiro Shibata, Hiroaki Sakamoto, Keita Terashima, Yoshiki Arakawa, Toshihiro Kumabe, Ryo Nishikawa, Junichi Hara, Yonehiro Kanemura, Koichi Ichimura

Faculty, Staff and Students Publications

In 2016, the Japan Children's Cancer Group launched a nationwide research initiative to provide central diagnosis incorporating pathology review and molecular profiling for pediatric central nervous system (CNS) tumors. Over the first eight years, 2224 cases were registered. Non-next-generation sequencing analyzes, such as pyrosequencing and NanoString, were routinely performed, mainly for glioma, medulloblastoma, and ependymoma. Additional analyzes, including methylation profiling and RNA sequencing, were conducted for selected diagnostically challenging cases. The most common diagnoses were low-grade glioma (26%), medulloblastoma (18%), germ cell tumor (16%), high-grade glioma (12%), and ependymoma (11%). Diagnostic or targetable alterations were detected in nearly half of …

Asynchronous Transitions From High-Risk Hepatoblastoma To Carcinoma, Xinjian Yu, Stephen Sarabia, Martin Urbicain, Sonal Somvanshi, Roma Patel, Priyanka Rao, Tuan M Tran, Yen-Ping Yeh, Keng-Shih Chang, Yi-Tzu Lo, Jessica Epps, Kathleen A Scorsone, Hua-Sheng Chiu, Emporia Faith Hollingsworth, Cintia R Perez, Mohammad Javad Najaf Panah, Barry Zorman, Jordan Muscal, Milton J Finegold, John A Goss, Rita Alaggio, Angshumoy Roy, Kevin E Fisher, Andras Heczey, Sarah Woodfield, Sanjeev Vasudevan, Kalyani Patel, Ting-Wen Chen, Dolores Lopez-Terrada, Pavel Sumazin

Faculty, Staff and Students Publications

Background & aims: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs.

Methods: We performed multi-omics profiling - including single-nucleus RNA …

Blinded, Bias-Controlled Multi-Rater Evaluation Of Human-Versus-Ai Brain Metastasis Segmentation Using A Hybrid Foundation-Model Framework, Yiding Han, Enze Zhu, Mhd Hasan Ai Mekdash, Omar Awad, Piyush Pathak, Shixiao Liang, Daniel Allan Hamstra, Xizhe Zhang, Zaid Ali Siddiqui, Baozhou Sun

Faculty, Staff and Students Publications

Background: Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance.

Purpose: To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment.

Methods: TUM-SAM integrates nnU-Net-based lesion detection with a …

Mechanisms Coordinating Exit From The Stem Cell State In Mammals, Emily J Park, Florencia Levin-Ferreyra, Bruno Di Stefano

Faculty, Staff and Students Publications

Differentiation requires coordinated exit from the stem cell state, during which gene regulatory networks sustaining self-renewal are dismantled, while lineage-specific programs are activated. This transition is governed by chromatin modifications, transcriptional networks, RNA processing, translational control, and metabolic rewiring that must operate with temporal precision. Despite significant progress in identifying individual regulatory components, understanding how these layers integrate to orchestrate irreversible cell fate commitment remains a fundamental challenge. This review examines common and unique regulatory principles governing stem cell exit, from totipotency during early embryogenesis to tissue-specific stem cell differentiation in adults. We synthesize recent findings on regulatory mechanisms across …

Leading Healthcare Improvement: An Implementation Strategy, Kelley Arredondo, Anthony Ecker, Lindsay Vaclavik, Jacquelene Shahin, Ashley Thompson, Molly Horstman, David Ramsey, Kyler M Godwin

Faculty, Staff and Students Publications

Introduction: Healthcare professionals often implement quality improvement (QI) initiatives but lack training to implement and sustain QI initiatives. Leading Healthcare Improvement (LHI) is a course that combines principles from change management, team science, and leadership effectiveness into an implementation strategy to enable clinicians to lead sustainable change.

Methods: LHI is a 6-session, 4-month interactive training. Learners work on an active QI project throughout the course. A Wilcoxon signed-rank test was conducted to evaluate pre- and post-course changes in learners' self-reported confidence across five QI competencies.

Results: Veterans Healthcare Administration clinicians and fellows completed the LHI pre- (n = 111) and …

Extended-Phase Anticoagulation For Pediatric Venous Thromboembolism After Einstein Jr, Nathan Wilken, Jun Teruya

Faculty, Staff and Students Publications

No abstract provided.

Fgfr3::Tacc3 Fusion And Notch1 Loss-Of-Function In A Case Of Hpv-Associated Sinonasal Squamous Cell Carcinoma: Diagnostic Challenge And Implications For Targeted Therapy, Xu Cao, Hong Yu, Reham Hamdy Abdulazim Soliman, Pei Ying, Songlin Zhang, Li Liang

Faculty, Staff and Students Publications

Sinonasal squamous cell carcinoma (SNSCC) comprises a heterogeneous group of tumors with emerging molecular subtypes. Human papillomavirus (HPV)-associated SNSCC is a distinct entity, although actionable genomic alterations beyond HPV-driven pathways remain underexplored. Distinguishing HPV-associated SNSCC from carcinoma ex inverted papilloma can be particularly challenging in limited biopsy specimens, as these lesions may appear morphologically similar. We report a case of HPV-associated SNSCC with concurrent FGFR3::TACC3 fusion and NOTCH1 p.C1416 stop-gain mutation.

Oncocytic Intraductal Carcinoma Of The Parotid Gland With Strn::Alk Fusion, Reham H Soliman, Chris Shi, Kevin E Fisher, Hong Yu, Fouad El-Dana, Xu Cao, Li Liang, Pei Ying, Songlin Zhang

Faculty, Staff and Students Publications

Intraductal carcinoma (IDC) of the salivary gland is an uncommon epithelial neoplasm characterized by a predominantly intraductal or intracystic proliferation rimmed by a myoepithelial cell layer. Advances in molecular profiling have revealed recurrent gene fusions in IDC, most frequently involving RET, although fusions implicating other kinase genes have also been described. Among these, ALK rearrangements are rare and remain poorly characterized. Herein, we report a case of oncocytic IDC of the parotid gland harboring a STRN::ALK fusion, further expanding the molecular landscape of this tumor. Although this fusion has been previously reported in intercalated duct IDC, to our knowledge, this …

Effect Of Androgen Receptor Polymorphism On Hypogonadism Severity And Efficacy Of Testosterone Replacement Therapy, Nelson W Mills, Beatriz S Hernandez, Peyton J Coady, Arnaav Walia, Gal Saffati, Daniela Orozco Rendon, Dalia Khera, Nadia Khera, Weitao Song, Mohit Khera

Faculty, Staff and Students Publications

Background: The preferred treatment for hypogonadism, testosterone replacement therapy (TRT), has a varying efficacy that is currently not fully understood. This observation may be explained by polymorphism of the androgen receptor (AR), a ligand-binding transcription factor whose polyglutamine tract length affects various health conditions and androgen sensitivity. It has been theorized that this polymorphism may also affect the severity of hypogonadism. This study sought to determine a correlation between hypogonadism severity, TRT efficacy, and number of CAG trinucleotide repeats in the AR gene.

Methods: One hundred sixty-two males presenting to a single institution with symptoms of hypogonadism were recruited for …

Tusc3 Serves As A Rate-Limiting Gatekeeper Of A Glycan-Mediated Er Triage Checkpoint For Bmp4/Dpp, Antonio Galeone, Emilio Solazzo, Francesco Lavezzari, Seung Yeop Han, Gaia Consonni, Bruna My, Riccardo Rizzo, Giuseppe Gigli, Hamed Jafar-Nejad, Thomas Vaccari

Faculty, Staff and Students Publications

Trimming of the three glucose residues decorating nascent N-glycoproteins is a critical step for their entry into the endoplasmic reticulum quality control (ERQC) and recognition by ER chaperones. However, the functional relevance of the second glucose (G2) and the regulatory step upstream of its removal by glucosidase II (GCS2) remain poorly understood. Here, we report that TUSC3, a component of the oligosaccharyltransferase (OST) complex, regulates G2 to G1 trimming on N-glycosylated bone morphogenetic protein 4 (BMP4) and its Drosophila homolog Dpp to promote their ERQC entry. Loss- and gain-of-function genetic experiments and biochemical assays in mammalian cells and flies indicate …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Yong Du, Li Yang, Hui Dai, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Reply To: A Lethal Progressive Neuroinflammation Disguised As Mogad Revealing A Final Diagnosis Of Griscelli Syndrome: Regarding: Mogad Is The Most Common Cause Of Isolated Optic Neuritis In Children, Chaitanya Aduru, Akansha Chandrasekar, Kyla Blasingame, Jonathan Rosen, Jesse M Levine, Karla Salazar, Madhuri Chilakapati, Rod Foroozan, Victoria Adeseye, Jonathan M Yarimi, Nikita Shukla, Timothy E Lotze, Kristen S Fisher, Alexander J Sandweiss

Faculty, Staff and Students Publications

No abstract provided.

Letter To The Editor: Hemodynamic Role In Hepatic Encephalopathy Pathogenesis Following Transjugular Intrahepatic Portosystemic Shunt Placement, John Halphen, Yash S Dayal, Cameron Laurie, Mohadese Ahmadzade, David Wynne, Mohammad Ghasemi-Rad

Faculty, Staff and Students Publications

Hepatic encephalopathy (HE) is a common complication following transjugular intrahepatic portosystemic shunt (TIPS) placement and is thought to result from reduced hepatic detoxification of neurotoxins. However, Zhuang et al in the World Journal of Radiology demonstrate that this understanding may be incomplete through exploration of the pathophysiology from a hemodynamic perspective. They found significant changes in cerebral blood flow (CBF) and spontaneous brain activity following TIPS. Initially, CBF increased in specific areas within the first month, followed by a return to baseline at three months. These CBF changes coincided with increased spontaneous brain activity that persisted in some areas, suggesting …

Long-Term Functional Synaptic Integration Of Genome-Edited Retinal Organoids In A Primate Model Of Macular Degeneration, Atsuta Ozaki, Akihiro Kawai, Ryutaro Akiba, Satoko Okayama, Nobuhiko Ohno, Keisuke Kajita, Tomohiro Masuda, Satoshi Yokota, Shin-Ichiro Ito, Du Peiyan, Kenta Onoue, Shigenobu Yonemura, Mineo Kondo, Yasuo Kurimoto, Yingbin Fu, Michiko Mandai

Faculty, Staff and Students Publications

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation non-human primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography, we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses …

Human Milk Small Extracellular Vesicles Elicit Changes In Inflammatory Response In Infant Human Intestinal Enteroids, Kacie D Waiters, Anthony S Peidl, Hailey A Mcandrew, Ashfia F Khan, Grace Adeniyi-Ipadeola, Hephzibah Nwanosike, Sana Sharif, M Funmi Babajide, Micah Castillo, Preethi H Gunaratne, Samaneh Karami, Hoa Nguyen-Phuc, Xinli Liu, Sasirekha Ramani, Tasneem Bawa-Khalfe

Faculty, Staff and Students Publications

Human milk (HM) is the key nutritional source for infants and the most effective preventative approach against serious gastrointestinal inflammatory diseases like necrotizing enterocolitis (NEC) in preterm infants. Numerous studies in animal models indicate HM-derived small extracellular vesicles (HMEV) reduce severity of inflammation; however, data on human-specific models are limited. Isolated HMEV were characterized from early-HM (colostrum and transitional), mature-HM, and a combined, pasteurized donor bank-like HM sample (pool-); pool-HMEV retains a profile aligned with HMEV from both early- and mature-HM samples. Exposure to pool-HMEV initiates unique gene signatures associated with reduction of inflammation including NFkB-driven TNFα signaling in human …

Plasma Gdf15 Affects Long-Term Dementia Risk And Alters Neuroimmune Signaling, Cassandra O Blew, Michael R Duggan, Dimitrios Tsitsipatis, Gabriela T Gomez, Zulema Rodriguez-Hernandez, Luke C Pilling, Jingsha Chen, Eva Jacobsen, Heather E Dark, Yifei Lu, Shannon M Drouin, Cassandra M Joynes, Minhao Yao, Murat Bilgel, Abhay Moghekar, Qu Tian, Julián Candia, Mary Kaileh, Aditi Gupta, Krystyna Mazan-Mamczarz, Myriam Gorospe, Alexey Lyashkov, Yevgeniya Lukyanenko, Mika Kivimaki, Philipp Frank, Lori L Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Lenore J Launer, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishita, Rei Otsuka, James R Pike, Mary R Rooney, Pascal Schlosser, Yuhan Cui, Guray Erus, Christos Davatzikos, Rebecca F Gottesman, Iwao Waga, Priya Palta, Christie Ballantyne, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Allison B Herman, Keenan A Walker

Faculty, Staff and Students Publications

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. …

Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction In An Alzheimer's Disease Model, Yufei Huang, Xueyi Xie, Zhenbo Huang, Ruifeng Chen, Himanshu Gangal, Xuehua Wang, Karienn Souza, Julia Hunter, Xin Wu, Doodipala Samba Reddy, Jeannie Chin, Jun Wang

Faculty, Staff and Students Publications

Cognitive flexibility declines early in Alzheimer's disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased excitatory input. Furthermore, glutamatergic transmission from the medial prefrontal cortex to striatal direct-pathway medium spiny neurons is enhanced and coincides with strengthened inhibitory transmission onto striatal cholinergic interneurons, reduced spontaneous firing, and diminished striatal acetylcholine release. Critically, sustained …

Adaptation Of The Transition Readiness Assessment Questionnaire For Pediatric-Onset Multiple Sclerosis: Protocol For A User-Centered Design Approach, Claudia Gambrah-Lyles, Aaron W Abrams, Sara Loud, Hollie Schmidt, Emily Blosberg, Melissa Wright, Kelsey E Poisson, Kristen S Fisher, Kimberly A O'Neill, Akash Virupakshaiah, John W Rose

Faculty, Staff and Students Publications

Background: Pediatric-onset multiple sclerosis (POMS) is a chronic, progressive neurologic condition requiring lifelong management and coordinated transition from pediatric to adult care. Evidence-based guidelines identify transition readiness assessment as a core component of successful transition; however, most POMS clinics do not formally assess readiness, and existing tools do not address POMS-specific challenges, such as fluctuating disability, complex treatment regimens, and cognitive impairment. This gap underscores the need for a transition readiness measure tailored to POMS.

Objective: This paper aims to describe a stakeholder-engaged, implementation science-guided protocol for adapting the Transition Readiness Assessment Questionnaire (TRAQ) version 6.0 to reflect the unique …

Point-Of-Care Hrhpv Mrna Detection With Reverse Transcription Recombinase Polymerase Amplification On A Portable Fluorimeter From Provider-Collected Cervical Samples In Maputo, Mozambique, Emilie Newsham Novak, Cannon J Hansen, Zoha Wazir, Ariel Ma, Jennifer Carns, Hira Atif, Jane R Montealegre, Michael E Scheurer, Cesaltina Lorenzoni, Daniel G Rosen, Mila P Salcedo, Kathleen M Schmeler, Rebecca R Richards-Kortum

Faculty, Staff and Students Publications

Background: Cervical cancer is the most common cancer in women in Mozambique, where limited screening infrastructure contributes to high disease burden. While testing for high-risk human papillomavirus (hrHPV) DNA can identify women at risk for cervical cancer, its limited specificity may lead to overtreatment in screen-and-treat programs, straining resources. We performed a pilot study to evaluate preliminary feasibility of a novel, accessible test to detect hrHPV mRNA, a more specific biomarker for cervical cancer risk, from 22 women who previously screened positive for visual inspection with acetic acid at Maputo Central Hospital in Mozambique.

Methods: Cervicovaginal samples were analyzed for …

Evaluating The Reproducibility And Verifiability Of Nutrition Research: A Case Study Of Studies Assessing The Relationship Between Potatoes And Colorectal Cancer, Yasaman Jamshidi-Naeini, Colby J Vorland, Pranav Kapoor, Bailey Ortyl, Jocelyn Mineo, Luke Still, Korlu Sorsor, Shelby Rodney, Xander Tooze, Brent Flickinger, Beate Henschel, Stephanie L Dickinson, David B Allison

Faculty, Staff and Students Publications

The credibility of nutritional research is dependent on the rigor with which studies are conducted and the ability for independent assessment to be performed. Despite the importance of these, more work is needed in the field of nutrition to buttress the trustworthiness of nutrition research. To develop and apply a process for evaluating the rigor, reproducibility, and verifiability of nutritional research, using the relationship between potato consumption and Colorectal Cancer (CRC) as a case study. We updated existing systematic reviews to include studies on potatoes and CRC, assessing their design, execution, and reporting quality. We attempted to reproduce and verify …

A Multilevel Analysis Of Hiv Care Outcomes Across Age, Race, And Housing Among United States Women Veterans, Giselle Day, Amber B Amspoker, Alan Z Sheinfil, Liang Chen, Emmanuel Guajardo, Maria E Fernandez, Cici Bauer, Irene Tamí-Maury, Jan Lindsay

Faculty, Staff and Students Publications

Background: Women veterans with HIV represent a growing, diverse population within the Veterans Health Administration (VHA). This study examined HIV care continuum outcomes among women veterans using a multilevel intersectional approach.

Methods: We conducted a retrospective analysis of 1154 women veterans with HIV in VHA care in fiscal year 2022, with outcomes assessed in fiscal year 2023. We applied Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA) to evaluate how combinations of social positions (age, race/ethnicity, housing status) were associated with HIV outcomes.

Results: MAIHDA models showed that younger age (< 45 years) and being unhoused were consistently associated with lower odds of care engagement and viral suppression than midlife (45-64) and older (65+) housed women veterans. Additionally, predicted probability analyses revealed distinct clustering patterns. Younger non-Hispanic White women consistently ranked among the lowest performing strata across all outcomes, while midlife and older Hispanic and non-Hispanic Black women veterans clustered among the highest. Variance Partition Coefficients from null models were modest (1.8-3.0%). Fully adjusted models showed no remaining between-stratum variance, suggesting that the included social positions explained the observed differences in our dataset.

Conclusions: These findings highlight disparities in HIV care …

Conformational Cycling Of The Wntless Transporter Drives Trafficking And Secretion Of Wnt Morphogens, Yunhui Ge, Taciani De Almeida Magalhaes, Hongjiang Wu, Dick J H Van Den Boomen, Thu Uyen Nguyen, Tongyi Dou, Gaya P Yadav, Sukyeong Lee, Zhao Wang, Andrew Lemoff, Xuemei Luo, Sumitha S Menon, Min Zhang, Jin Wang, Zhicheng Jin, Jiansen Jiang, Adrian Salic, Pengxiang Huang

Faculty, Staff and Students Publications

Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts from the endoplasmic reticulum to the plasma membrane, then transfers them to extracellular carriers, forming active and soluble morphogen-carrier complexes. To dissect the mechanisms involved, we solve cryo-EM structures of Wnt-bound WLS and unliganded WLS, and perform structure-guided functional experiments. Wnts engage WLS via three conserved hairpins, which are all required for Wnt trafficking to the cell surface and carrier-mediated secretion. Wnt release from cells is driven by dramatic conformational changes in the WLS transmembrane domain, reminiscent …