Medicine and Health Sciences Commons^™

Anticipation Of A Therapeutic Odyssey Following Predictive Testing For Autism, Katherine E Macduffie, Aurora M Washington, Catherine A Burrows, Stephen R Dager, Jed T Elison, Annette M Estes, Rebecca Grzadzinski, Chimei M Lee, Joseph Piven, Mark D Shen, Benjamin S Wilfond, Jason Wolff, Lonnie Zwaigenbaum, John R Pruett Jr

2020-Current year OA Pubs

Brain-based tools are being developed to identify infants at ultra-high likelihood for developing autism and enable presymptomatic intervention, though such interventions are not yet clinically available. Given persistent challenges in accessing autism services, we sought to understand how families might use early predictive results to seek support. We analyzed 55 interviews with parents of infants aged 6-13 months; one group had experience parenting an older autistic child (n = 30), the other had no prior autism parenting experience (n = 25). All parents were asked what steps they would take if told their infant was likely to develop autism. Both …

Metabolic Dysfunction-Associated Steatotic Liver Disease And Colorectal Neoplasms Risk: A Global Propensity Score-Matched Retrospective Cohort Study, Mohammad Aldiabat, Ali Osman, Malek Ayoub, Mahmoud Y Madi, Kamran Qureshi, Wing-Kin Syn

2020-Current year OA Pubs

OBJECTIVES: To evaluate the association between metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic-associated steatohepatitis (MASH), and the risk of colorectal cancer (CRC) and benign colorectal neoplasms (BCN), and to explore whether liver fibrosis/cirrhosis modifies these associations.

DESIGN: Retrospective cohort study with 1:1 propensity score matching.

SETTING: Global, multicentre real-world analysis using deidentified electronic health records from over 130 healthcare organisations in the TriNetX Global Collaborative Network.

PARTICIPANTS: Hospitalised adults aged 45-75 years between October 2019 and October 2024. Patients with prior diagnoses of colorectal neoplasia or other chronic liver diseases were excluded. Final matched cohorts included 138 902 MASLD and …

The Mediating Role Of Social Connectedness Between Inflexibility, The Suppression Of Emotional Expression, And Symptoms Of Eating Disorders And Depression In Adolescents With Restrictive Eating Disorders Referred For Radically Open Dialectical Behaviour Therapy (Ro Dbt), Julian Baudinet, Lucinda J Gledhill, Molly Fennig Steinhoff, Kirsten Gilbert, Mima Simic

2020-Current year OA Pubs

BACKGROUND: Overcontrol is a transdiagnostic phenotype which has been associated with restrictive eating disorders and depression. It is characterised by traits such as cognitive and behavioural inflexibility, risk aversion, suppression of emotional expression, reduced reward sensitivity and higher temperamental anxiety. Two aspects of the overcontrol phenotype (inflexibility and the suppression of emotional expression) have been particularly linked with poorer mental health. Additionally, social connectedness has been shown to protect against mental health symptom severity. The current study aimed to test whether the relationship between these factors and mental health symptom severity, namely, eating disorder and depression, is mediated by social …

Cardiac Sr-Mitochondria Contacts-Impact On Cardiac Physiology And Mitochondrial Fitness, Celia Fernandez-Sanz, Shey-Shing Sheu, Sergio De La Fuente

Center for Translational Medicine Faculty Papers

In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca²⁺) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca²⁺ uniporter, while others …

Epigenetic Landscape In Lysosomal Storage Disorders: Mechanisms And Modulation, Andrés Felipe Leal, Harry Pachajoa, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Lysosomal storage disorders (LSDs) are rare substrate-accumulating diseases primarily characterized by mutations in genes encoding proteins involved in lysosomal function, most of which have enzymatic activity. Resulting lysosomal dysfunction leads to the overaccumulation of non- or partially degraded substrates. While it is true that enzyme deficiency is the primary cause of LSDs, the epigenetic alterations in DNA methylation, miRNA expression, and histone modifications appear to be critical mechanisms involved in the pathogenesis of LSDs. As epigenetic marks are, in most cases, reversible, their study becomes vital to developing strategies aimed at reversing epigenome alterations. Although classical therapeutic alternatives aim to …

Posterior Fossa Decompression In Syndromic Children With Chiari-Like Posterior Fossa Crowding: A Nationwide Us-Based Study, Victor Gabriel El-Hajj, Josué Aganze Mwambali, Ihab Ahmad Al-Rikabi, Erik Öhlen, Maria Gharios, Victor E. Staartjes, Joanna M. Roy, Basel Musmar, Pascal Jabbour, Erik Edström, Adrian Elmi-Terander

Department of Neurosurgery Faculty Papers

INTRODUCTION: Posterior fossa crowding, due to cerebellar tonsil herniation, often requires surgery with posterior fossa decompression (PFD). Although most cases are due to a Chiari-1 malformation (CM1), some are due to concomitant congenital conditions, mimicking a radiological CM1. The aim of this study was to compare PFD outcomes between CM1 and the syndromic Chiari-like crowding of the posterior fossa. A national pediatric surgical database was used to compare baseline characteristics and short-term postoperative outcomes.

METHODS: Pediatric patients undergoing PFD (2012-2021) were identified in the ACS NSQIP-P database. Baseline characteristics and 30-day outcomes were compared between syndromic and non-syndromic cases. Multivariate …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Reducing Moral Distress Through Interdisciplinary Collaboration: The Impact Of A Weekly Palliative Care And Neonatology Conference, Kirthi Devireddy, Riddhi Shukla, Rachel Boren, James E Slaven, Rebecca A Baker, Jayme D Allen, Karen M Moody

Faculty, Staff and Student Publications

Background: Moral distress is the experience of knowing what ethically right action to take, but being unable to act accordingly, due to external factors. It is an experience common to providers working in the neonatal intensive care unit (NICU) where care for infants, often born at the edges of viability or with other life-limiting diagnoses, includes life and death medical decision-making in the context of uncertain prognoses. Palliative care, which aims to reduce suffering, can assist with staff moral distress by providing space for conversations regarding goals-of-care and end-of-life decision making.

Methods: The palliative care and NICU teams co-developed a …

Expression Of Dementia Biomarkers In Appalachian And Non-Appalachian Elvo Patients During Thrombectomy, Neha Anil, Christopher J. Mclouth, Hunter S. Hazelwood, Elise Dahlke, Jacqueline A. Frank, Nathan Millson, Mais Al-Kawaz, Jordan P. Harp, Will Cranford, Shivani Pahwa, David Dornbos Iii, Justin F. Fraser, Keith R. Pennypacker

University Faculty Publications and Creative Works

Vascular Cognitive Impairment and Dementia (VCID) affects 25-30% of stroke patients and includes cognitive impairments caused by vascular injury, such as post-stroke dementia. Rehabilitation has the potential to improve the quality of life for patients at risk of developing dementia. However, there is currently no reliable method to identify those at risk of dementia after a stroke. Several biomarkers, including ADRD (Alzheimer’s disease and related dementias) biomarkers (Ab, tau, NfL, and GFAP) and angiogenic factors (VEGF, Flt-1, Tie-2, PIGF, and FGF) have been associated with the development of dementia. Populations in Appalachia experience a higher incidence of stroke and related …

Hepatic Ischemia-Reperfusion Injury: Underlying Mechanisms And Concepts In Liver Surgery And Liver Transplantation, Jie Zhao, Lidan Hou, Kenneth J Dery, Xiaoyi Yuan, Kang Ho Kim, Jerzy W Kupiec-Weglinski, David R Hall, Caitlin J Thornley, Mark J Hobeika, Holger K Eltzschig, Cynthia Ju

Faculty, Staff and Student Publications

Hepatic ischemia-reperfusion injury (H-IRI) is a critical complication in liver surgery and liver transplantation, contributing to graft dysfunction and poor clinical outcomes. When hepatocyte protective mechanisms are insufficient to counteract energy depletion and oxidative stress during ischemia, cell death occurs. Tissue damage during H-IRI leads to the release of damage-associated molecular patterns (DAMPs), which recruit and activate immune cells such as neutrophils and monocytes, orchestrating the initiation, progression, and eventual resolution of sterile inflammation. Extended criteria donor (ECD) livers, particularly steatotic ones, are more vulnerable to H-IRI, leading to poorer outcomes and limiting expansion of the donor pool. However, the …

Fear Avoidance After Concussion Tool (Fact): Patient-Reported Outcome Measure Development And Content Validation, Liam J. Sherwood, Gill Cowen, Mandy Vidovich, Jeanette Hasleby, Jon Patricios, Myles C. Murphy

Research outputs 2022 to 2026

Objective No valid patient-reported outcome measures (PROMs) exist to evaluate fear avoidance behaviour following concussion. This study developed a new PROM to evaluate fear avoidance behaviour following concussion and assessed the PROM content validity. Design PROM development was performed using a qualitative study, and content validation was performed using a mixed-methods approach. Methods The development phase consisted of compiling potentially relevant items (eg, questions) from other PROMs proposed to measure fear avoidance before proceeding to a series of one-on-one semistructured interviews with patient and professional participants. The content validity (relevance, comprehensibility and comprehensiveness) of the PROM was first assessed by …

Concordance Of Cancer-Associated Cytokines And Mitochondrial Dna Deletions In Individuals With Hepatocellular Carcinoma And People Living With Hiv In Ghana, James Odame Aboagye, Ruth Ayanful-Torgby, Lei Zhou, Prince Peter Wormenor, Vincent Ganu, Kenneth Tachi, Bernard Nii Akrashie Attoh, Miriam Mensah, Timothy Kuuguu, Sedzro Kojo Mensah, George Boateng Kyei, Elijah Paintsil

2020-Current year OA Pubs

BACKGROUND: Hepatocellular carcinoma (HCC) is becoming increasingly prevalent as a non-AIDS-defining cancer closely tied to chronic HIV infection. It is associated with increased secretion of inflammatory cytokines, immune system dysfunction, and alterations in mitochondrial function. The objective of this study was to investigate the levels of cytokine secretion and mitochondrial DNA (mtDNA) deletion in people living with HIV (PLWH) compared with individuals diagnosed with HCC without HIV.

METHODS: A cross-sectional study was conducted with PLWH and HCC patients recruited from the Korle-Bu Teaching Hospital, Accra, Ghana. Participants donated whole blood for the isolation of plasma and peripheral blood mononuclear cells …

Real-World Outcomes Of Infections Following Tisagenlecleucel In Patients With B-Cell All: A Cibmtr Analysis, Hemalatha G Rangarajan, Prakash Satwani, Megan M Herr, Min Chen, Michael J Martens, Kitsada Wudhikarn, Samuel John, Vanessa A Fabrizio, Emily M Hsieh, Amar H Kelkar, Erin Doherty, David I Marks, Olle Ringden, Brian Friend, Matthew S Kelly, Nosha Farhadfar, Tim Prestidge, Nasheed M Hossain, Hongtao Liu, Shahrukh Hashmi, Dipenkumar Modi, Lena E Winestone, Zeinab El Boghdadly, Hemant S Murthy, Miguel-Angel Perales, Roy F Chemaly, Christopher E Dandoy, Joshua A Hill, Anna Huppler, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. …

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

Infection After Cd19 Chimeric Antigen Receptor T-Cell Therapy For Large B-Cell Lymphoma: Real-World Analysis From Cibmtr, Kitsada Wudhikarn, Megan M Herr, Min Chen, Michael J Martens, John H Baird, Lohith Gowda, Hemalatha G Rangarajan, Muhammad Bilal Abid, Mohamed A Kharfan-Dabaja, Kirsten M Williams, Siddhartha Ganguly, Jo-Anne H Young, Akshay Sharma, Giancarlo Fatobene, Tania Jain, Christopher G Kanakry, Dipenkumar Modi, Natalie S Grover, Baheyeldin Salem, Marjorie Vieira Batista, Paschalis Vergidis, Dwight E Yin, Amer M Beitinjaneh, Amar H Kelkar, Taiga Nishihori, Jennifer Holter Chakrabarty, Usama Gergis, Melody Smith, Zeinab El Boghdadly, Christopher E Dandoy, Hemant S Murthy, Anna R Huppler, Miguel-Angel Perales, Roy F Chemaly, Joshua A Hill, Marcie Riches, Jeffery J Auletta

Faculty, Staff and Students Publications

Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, …

‘In Texas, Everybody Wants Antibiotics’: Reducing Inappropriate Antibiotic Expectations And Use With A Provider-Patient Communication Tool In Primary Care, Ashley Collazo, Paige Wermuth, Johanan Luna Rodriguez, Kiara Olmeda, Azalia Mancera, Fabrizia Faustinella, Michael K Paasche-Orlow, Roger Zoorob, Barbara Wells Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Background/objective: Patients often expect antibiotics for self-limiting diseases, pressuring providers to prescribe antibiotics unnecessarily. These expectations also contribute to the unsafe practice of taking antibiotics without a prescription (non-prescription use), such as pills retained from prior prescriptions or antibiotics from non-medical sources. Previous work shows that non-prescription use is due to strong, widely held misconceptions regarding the curative power of antibiotics. To reduce unnecessary use of antibiotics, we developed and pilot-tested a patient-focused, bilingual (English and Spanish) educational tool with patient and provider stakeholder input. The tool, a trifold brochure, included information on safe antibiotic use, potential antibiotic harms and …

Cgas-Agonistic Spherical Nucleic Acids Reprogram The Glioblastoma Immune Microenvironment And Promote Antitumor Immunity, Akanksha S Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M Forsyth, Bin Zhang, Jason Miska, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh

2020-Current year OA Pubs

The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell-enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the …

Impact Of Radiotherapy Site, Modality, And Dose On Subsequent Clonal Hematopoiesis, Alexander G Goglia, Griffen R Mustion, Leslie A Modlin, Ross L Levine, Kelly L Bolton, Lior Z Braunstein

2020-Current year OA Pubs

No abstract provided.

Protocol For A Multicenter, Cluster-Randomized, Stepped-Wedge, Implementation Trial Of A Prehospital Sepsis Protocol, Shamie Das, Stacey House, Melissa Kroll, Et Al.

2020-Current year OA Pubs

BACKGROUND: Sepsis is a common, life-threatening medical emergency in which early recognition and treatment are cornerstones of management. Best practice guidelines recommend standardized sepsis screening in hospitals to facilitate early recognition. In contrast, very little is known about the efficacy and safety of standardized sepsis screening in the prehospital Emergency Medical Services (EMS) environment. To help address this knowledge gap, this study protocol will evaluate the impact of implementing an evidence-based sepsis protocol in ambulances.

METHODS: We plan to conduct a multicenter, stepped-wedge, cluster-randomized trial at 3 sites and enroll 984 participants over 24 months. EMS personnel will be trained …

Editorial: Bridging Inflammation, Oxidative Stress, And Metabolic Dysfunction In Brain Disorders, Ansab Akhtar

School of Medicine Faculty Publications

We present this Special Issue of Brain Sciences, titled "Role of Inflammation, Oxidative Stress, and Metabolic Dysfunction in Neurodevelopmental and Neurodegenerative Diseases: Pharmacological Targets and Therapeutic Interventions", which brings together research and review articles that explore the molecular crosstalk between neuroinflammatory, oxidative stress, and metabolic pathways underlying both neurodegenerative and neurodevelopmental disorders [...].

Chronic Rhinosinusitis Is A Risk Factor For Interstitial Lung Disease In Sjogren’S Syndrome, Brian Schonewald, Christopher Xie, Andrew Engel, Ross Summer, Giorgos Loizidis

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND: Interstitial lung disease (ILD) is a leading cause of morbidity and mortality in Sjögren's syndrome (SS), but its risk factors remain unclear. Although SS affects both the upper and lower respiratory epithelium, it is unknown whether this occurs simultaneously or separately. In other autoimmune conditions-such as eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis-upper airway disease precedes lower lung involvement by months or even years. We hypothesized that chronic rhinosinusitis (CRS), as an upper airway disease, may be a risk factor for ILD in SS.

METHODS: We analyzed the TriNetX Research Network database to compare incident ILD in SS …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Whole-Exome Sequencing-Based Linkage Analysis Of Multiple Myeloma (Mm) And Monoclonal Gammopathy Of Undetermined Significance (Mgus) Pedigrees, Alyssa I Clay-Gilmour, Nicola J Camp, Xiaomu Wei, Angel Earle, Aaron Norman, Jason Sinnwell, Delphine Demangel, Rosalie Griffin, Charles Dumontet, James Mckay, Ken Offit, Vijai Joseph, Siwei Chen, Daniel O'Brien, Vincent Rajkumar, Robert Klein, Shaji Kumar, Steve Lipkin, Celine M Vachon

Faculty, Staff and Student Publications

Background/objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis.

Methods: Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander-Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, …

Investigating Prognostic Features In High-Grade Serous Ovarian Cancer Through Gene Regulatory Network Inference With Single-Cell Transcriptomic Profiles, Toshiyuki Itai, Yulin Dai, Wendao Liu, Dung-Fang Lee, Zhongming Zhao

Faculty, Staff and Student Publications

This study aimed to identify prognostic features in high-grade serous ovarian cancer (HGSOC) through the application of gene regulatory network (GRN) inference with single-cell RNA-sequencing (scRNA-seq) profiles. To achieve this goal, we developed a workflow comprising scRNA-seq analysis, metacell construction, GRN inference, and a binary classification task for prognosis prediction. We curated 118,173 cells from HGSOC patients in three conditions (Before-chemotherapy, After-chemotherapy, and control samples) from previous studies, and then constructed 1,211 metacells. GRN inference analysis revealed 312 regulons, each consisting of one transcription factor and its targeted features. For prognosis evaluation, we used bulk RNA-seq data covering 342 HGSOC …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Peripheral Microvascular And Cerebral White Matter Dysfunction In Schizophrenia: Implications Of A Body-Brain Endothelial Pathophysiology, Eric L Goldwaser, Alexa Yuen, Wyatt Marshall, Bhim M Adhikari, Joshua Chiappelli, Andrew Van Der Vaart, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Heather Bruce, Patrick Donnelly, Braxton Mitchell, Charles Hong, Danny J J Wang, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Background and hypothesis: Schizophrenia spectrum disorder (SSD) is a chronic neuropsychiatric illness accompanied by significant brain structural and functional abnormalities and higher rate of cardio- and cerebrovascular comorbidities. We hypothesized that genetic and environmental risk factors that led to SSD act throughout the body and demonstrated the association between lower integrity of peripheral vascular endothelium and white matter (WM) microstructure.

Study design: Microvascular endothelial function was evaluated using brachial artery post-occlusive reactive hyperemia (PORH), in which endothelial responses are measured under reduced blood flow and after blood flow is restored. White matter microstructure was assessed by multi-shell diffusion tensor imaging …

Comparison Of Bare Metal Vs Covered Proximal Stent Fixation During Fenestrated Endovascular Aortic Repair Of Complex Abdominal Aortic Aneurysms, Guilherme B Lima, Ying Huang, Lucas Ruiter Kanamori, Emanuel R Tenorio, Bruno P Schmid, Steven Maximus, Naveed Saqib, Thanila A Macedo, Bernardo C Mendes, Gustavo S Oderich

Faculty, Staff and Students Publications

Purpose: Fenestrated stent-grafts with proximal bare-metal fixation stent (BMFS) may provide better rotational movement to facilitate vessel catheterization, but novel designs with covered fixation stents (CFSs) have been increasingly utilized with lower profile fabric. This study aimed to evaluate procedural metrics and outcomes of fenestrated endovascular repair (FEVAR) using BMFS and CFS devices.

Methods: Clinical data of 502 consecutive patients enrolled in a prospective, non-randomized investigational device exemption (IDE) study were reviewed. Patients with 4-vessel fenestrated stent-grafts with BMFS or CFS for treatment of complex abdominal aortic aneurysms (CAAAs) and Extent IV thoracoabdominal aortic aneurysms (TAAAs) were included. Patients with …

Weight Loss And A Shunt On “Off”: An Odd Case Of Overshunting In An Idiopathic Intracranial Hypertension Patient Illustrative Case, Thomas Hamre, Ashley Ricciardelli, Alex Flores, Ashwin Viswanathan

Faculty, Staff and Students Publications

Background: CSF diversion with ventriculoperitoneal (VP) shunts is a common treatment for idiopathic intracranial hypertension (IIH). Rarely, overshunting can occur. Diagnosing and managing overshunting in an IIH patient with a shunt can be challenging. The authors present a unique etiology of overshunting successfully treated with shunt ligation.

Observations: A 48-year-old female with IIH who had undergone VP shunt placement with a programmable Certas valve presented with symptoms concerning for low-pressure headaches following a 25-kg weight loss. Intracranial pressure (ICP) monitoring along with an inpatient headache diary facilitated the diagnosis of intracranial hypotension secondary to CSF overdrainage through the shunt. Following …

Dissemination Of A Facilitation Strategy To De-Implement Unnecessary Post-Operative Antibiotics At Children's Hospitals: The Optimizing Perioperative Antibiotic In Children (Operatic) Trial 2.0, Emmanuel K Tetteh, Harry Obeng, Andrew Atkinson, Sara Malone, Matt Sattler, Tyler Walsh, Lauren Walsh, Jacqueline M Saito, Shawn J Rangel, Jason G Newland, Virginia R Mckay

2020-Current year OA Pubs

BACKGROUND: Excessive postoperative antibiotic use in pediatric surgical patients contributes to antibiotic resistance and increases the risk of Clostridioides difficile infection. Despite established guidelines recommending limited postoperative antibiotic duration, many hospitals struggle with de-implementation. This study aims to disseminate and evaluate the impact of a combined strategy to reduce unnecessary postoperative antibiotic use which combines enhanced antimicrobial stewardship program facilitation, defined as a set of actions to enable implementation, combined with order set review and modification. This multi-center study builds on an initial stepped wedge cluster randomized trial involving nine children's hospitals, where facilitation training improved implementation of surgical prophylaxis …

Use And Reporting Of Intervention Mapping For Adaptation: A Systematic Review Protocol, Eunyoung Kang, Hugo R Sánchez-Blas, Elizabeth O Obekpa, Maria E Fernandez

Faculty, Staff and Student Publications

Introduction: Intervention adaptation is likely to occur to some extent when implementing interventions in new implementation contexts. Using systematic frameworks can guide intentional and effective adaptation processes. Intervention Mapping for Adaptation (IM-ADAPT) is a framework that offers step-by-step guidance for systematic, theory-based intervention adaptation. Despite the increasing use of IM-ADAPT, there is limited understanding of the contexts in which it has been applied and how effectively it is used and reported. Addressing this knowledge gap can improve current adaptation practices and inform future enhancements of the IM-ADAPT framework and the broader science of intervention adaptation. This review aims to (1) …