Digital Commons Network^™

Decoding Cancer Etiology With Cellular Reprogramming, Mo-Fan Huang, Megan E Fisher, Trinh T T Phan, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

Cancer research remains clinically unmet in many areas due to limited access to patient samples and the lack of reliable model systems that truly reflect human cancer biology. The emergence of patient-derived induced pluripotent stem cells and engineered human pluripotent stem cells (hPSCs) has helped overcome these challenges, offering a versatile alternative platform for advancing cancer research. These hPSCs are already proving to be valuable models for studying specific cancer driver mutations, offering insights into cancer origins, pathogenesis, tumor heterogeneity, clonal evolution, and facilitating drug discovery and testing. This article reviews recent progress in utilizing hPSCs for clinically relevant cancer …

Chemoresistance-Motility Signature Of Molecular Evolution To Chemotherapy In Non-Muscle-Invasive Bladder Cancer And Its Clinical Implications, Mi-So Jeong, Seung-Woo Baek, Gi-Eun Yang, Jeong-Yeon Mun, Jeong Ah Kim, Tae-Nam Kim, Jong-Kil Nam, Yung-Hyun Choi, Ju-Seog Lee, In-Sun Chu, Sun-Hee Leem

Faculty, Staff and Student Publications

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature …

Imaging Lung Tumor Motion Using Integrated-Mode Proton Radiography-A Phantom Study Towards Tumor Tracking In Proton Radiotherapy, Ryan Fullarton, Mikaël Simard, Lennart Volz, Allison Toltz, Savanna Chung, Christoph Schuy, Daniel G Robertson, Gary Royle, Sam Beddar, Colin Baker, Christian Graeff, Charles-Antoine Collins-Fekete

Faculty, Staff and Student Publications

BACKGROUND: Motion of lung tumors during radiotherapy leads to decreased accuracy of the delivered dose distribution. This is especially true for proton radiotherapy due to the finite range of the proton beam. Methods for mitigating motion rely on knowing the position of the tumor during treatment.

PURPOSE: Proton radiography uses the treatment beam, at an energy high enough to traverse the patient, to produce a radiograph. This work shows the first results of using an integrated-mode proton radiography system to track the position of moving objects in an experimental phantom study; demonstrating the potential of using this method for measuring …

A Randomized, Double-Blind, Placebo-Controlled Trial Of Daxibotulinumtoxina For Injection For The Treatment Of Upper Limb Spasticity In Adults After Stroke Or Traumatic Brain Injury, Atul T Patel, Michael C Munin, Ziyad Ayyoub, Gerard E Francisco, Rashid Kazerooni, Todd M Gross

Faculty, Staff and Student Publications

Background: Intramuscular injection of botulinum toxin type A is a first-line pharmacotherapy for adults with upper limb spasticity (ULS). However, reemergence of symptoms within 12 weeks of treatment is common and longer-lasting treatments are needed.

Objective: To evaluate the efficacy and safety of three doses of DaxibotulinumtoxinA for Injection (DAXI) for treatment of ULS in adults with stroke or traumatic brain injury.

Intervention: Intramuscular injections of placebo (N = 24), DAXI 250 U (N = 22), DAXI 375 U (N = 19), or DAXI 500 U (N = 18) to the suprahypertonic muscle (SMG) and other muscle groups.

Design: Randomized, …

Comparing One Stage, Chromogenic Assay Results And Discrepancies With Bleeding Phenotype And Genetic Variants In Females With Hemophilia A, Lakshmi Srivaths, Joanna Larson, Sepideh Saroukhani, Mohammed Said, Deborah Brown, Nidra Rodriguez, Neethu Menon, Miguel Escobar

Faculty, Staff and Student Publications

Background: Increasing evidence in females with hemophilia A has shown significant bleeding symptoms. Accurate factor (F) VIII activity (FVIII:C) measurement is essential to assign correct diagnosis and severity. Assay discrepancies reported in male patients with hemophilia A are not well studied in females.

Objectives: Our research sought to assess the association of FVIII:C levels by one-stage versus chromogenic assays and the assay discrepancy with bleeding phenotype and genetic mutation in females with hemophilia A.

Methods: Data from 64 females with hemophilia A from our center were reviewed with center's institutional review board approval. Descriptive statistics, chi-squared, Fisher's exact, and Bland-Altman …

All Three Supersystems-Nervous, Vascular, And Immune-Contribute To The Cortical Infarcts After Subarachnoid Hemorrhage, Jens P Dreier, Alexander Joerk, Hiroki Uchikawa, Viktor Horst, Coline L Lemale, Helena Radbruch, Devin W Mcbride, Peter Vajkoczy, Ulf C Schneider, Ran Xu

Faculty, Staff and Student Publications

The recently published DISCHARGE-1 trial supports the observations of earlier autopsy and neuroimaging studies that almost 70% of all focal brain damage after aneurysmal subarachnoid hemorrhage are anemic infarcts of the cortex, often also affecting the white matter immediately below. The infarcts are not limited by the usual vascular territories. About two-fifths of the ischemic damage occurs within ~ 48 h; the remaining three-fifths are delayed (within ~ 3 weeks). Using neuromonitoring technology in combination with longitudinal neuroimaging, the entire sequence of both early and delayed cortical infarct development after subarachnoid hemorrhage has recently been recorded in patients. Characteristically, cortical …

Psychiatric Manifestations Of Encephalitis, Paris Bean, Ashley Heck, Ralph Habis, Swathi Sowmitran, Zoe Cartaina, Rajesh Gupta, John Probasco, Rodrigo Hasbun, Arun Venkatesan

Faculty, Staff and Student Publications

Objective: Encephalitis is a serious and potentially life-threatening condition of infectious or autoimmune cause. We aim to characterize the frequency and clinical spectrum of presenting psychiatric symptoms in encephalitis in order to inform earlier recognition and initiation of treatment.

Methods: This was a retrospective study of adult patients who met the 2013 International Encephalitis Consortium (IEC) and/or 2016 Graus criteria between February 2005 and February 2023. The study included two hospital systems in Houston, Texas, and Baltimore, Maryland and included a total of 642 patients. Psychiatric manifestations were grouped into five high-level categories: behavior, psychosis, mood, sleep disturbances, and catatonia. …

Protein Arginine Methyltransferases As Regulators Of Cellular Stress, Julia Zaccarelli-Magalhães, Cristiane Teresinha Citadin, Julia Langman, Drew James Smith, Luiz Henrique Matuguma, Hung Wen Lin, Mariana Sayuri Berto Udo

Faculty, Staff and Student Publications

Arginine modification can be a "switch" to regulate DNA transcription and a post-translational modification via methylation of a variety of cellular targets involved in signal transduction, gene transcription, DNA repair, and mRNA alterations. This consequently can turn downstream biological effectors "on" and "off". Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs 1-9) in both the nucleus and cytoplasm, and is thought to be involved in many disease processes. However, PRMTs have not been well-documented in the brain and their function as it relates to metabolism, circulation, functional learning and memory are understudied. In this review, we provide a comprehensive …

Deformity Considerations In Cervical Laminoplasty: A Narrative Review, Joseph P Drain, Paul Alvarez, William Ryan Spiker, Elizabeth Yu

Faculty, Staff and Student Publications

Objectives: We discuss the incidence of postoperative kyphosis following laminoplasty and its impact on outcomes, as well as critical radiographic parameters, intraoperative technical factors, and postoperative protocols that can be used to improve results.

Summary of background data: When appropriately selected, cervical laminoplasty is a motion-sparing treatment option for cervical myelopathy and is a valid alternative to laminectomy and fusion procedures. However, like other posterior-based cervical decompression techniques, laminoplasty can cause postoperative kyphosis.

Methods: A PubMed search was performed to gather articles that focus on cervical deformity in the context of cervical laminoplasty.

Results: The reported conversion rates of lordotic …

Non-Invasive Prenatal Screening: Testing Motivations And Decision Making In The Low-Risk Population, Jenna K Lea, Blair K Stevens, Shannon Mulligan, Syed S Hashmi, Rebecca Lunstroth, Meagan G Choates

Faculty, Staff and Student Publications

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) …

Respiratory Outcomes Of Infants Born Extremely Preterm In The Necrotizing Enterocolitis Surgery Trial, Sara B Demauro, Erik A Jensen, Scott A Mcdonald, Susan Hintz, Jon Tyson, David K Stevenson, Martin L Blakely

Faculty, Staff and Student Publications

The multicenter Necrotizing Enterocolitis Surgery Trial compared initial peritoneal drainage with laparotomy among infants with extremely low birth weight and surgical necrotizing enterocolitis or intestinal perforation. In this post hoc analysis of trial data, initial drainage was associated with adverse respiratory outcomes, both in hospital and through 2 years corrected age.

Refining Diagnostic Subtypes Of Peripheral T-Cell Lymphoma Using A Multiparameter Approach, Catalina Amador, Dennis D Weisenburger, Ana Gomez, Alyssa Bouska, Ahmad Alshomrani, Sunandini Sharma, Ab Rauf Shah, Timothy C Greiner, Francisco Vega, Andreas Rosenwald, German Ott, Andrew L Feldman, Elaine S Jaffe, Neval Ozkaya, Sarah L Ondrejka, James R Cook, Philipp W Raess, Kerry J Savage, Graham W Slack, Joo Y Song, David W Scott, Elias Campo, Lisa M Rimsza, Joseph D Khoury, Louis M Staudt, Wing C Chan, Javeed Iqbal

Faculty, Staff and Student Publications

Peripheral T-cell lymphoma (PTCL) is a heterogeneous category, and many cases are unclassifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated two prognostic subtypes within PTCL-NOS, PTCL-TBX21, and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including TFH biomarkers) and GEP analyses, separating them into PTCL-NOS (n=63) and PTCL-TFH (a.k.a. nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n=38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n=22; 34%) …

Testosterone Modulation Of Muscle Transcriptomic Profile During Lifestyle Therapy In Older Men With Obesity And Hypogonadism, Viola Viola, Tagari Samanta, Maria Liza Duremdes Nava, Alessandra Celli, Reina Armamento-Villareal, Ngoc Ho Lam Nguyen, Georgia Colleluori, Yoann Barnouin, Nicola Napoli, Clifford Qualls, Benny Abraham Kaipparettu, Dennis T Villareal

Faculty, Staff and Students Publications

Background: Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.

Objective: To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.

Methods: Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.

Results: Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (-2% vs. -4%, respectively; p = …

Five-Year Outcomes Of Lenadogene Nolparvovec Gene Therapy In Leber Hereditary Optic Neuropathy, Patrick Yu-Wai-Man, Nancy Newman, Valérie Biousse, Valerio Carelli, Mark Moster, Catherine Vignal-Clermont, Thomas Klopstock, Alfredo Sadun, Robert C Sergott, Rabih Hage, Simona Degli Esposti, Chiara La Morgia, Claudia Priglinger, Rustum Karanja, Magali Taiel, José-Alain Sahel

Department of Neurology Faculty Papers

IMPORTANCE: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).

OBJECTIVE: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.

DESIGN, SETTING, AND PARTICIPANTS: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE …

Structural Polymorphism And Diversity Of Human Segmental Duplications., Hyeonsoo Jeong, Philip C. Dishuck, Dongahn Yoo, William T. Harvey, Katherine M. Munson, Alexandra P. Lewis, Jennifer Kordosky, Gage H. Garcia, Human Genome Structural Variation Consortium (Hgsvc), Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

Segmental duplications (SDs) contribute significantly to human disease, evolution and diversity but have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies (from 85 samples representing 38 Africans and 47 non-Africans) in which the majority of autosomal SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms and sex chromosomes, we identify 173.2 Mb of duplicated sequence (47.4 Mb not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable, with rare events …

Exploring Individual Differences In Amygdala-Mediated Memory Modulation, Martina K Hollearn, Joseph R Manns, Lou T Blanpain, Stephan B Hamann, Kelly Bijanki, Robert E Gross, Daniel L Drane, Justin M Campbell, Krista L Wahlstrom, Griffin F Light, Aydin Tasevac, Phillip Demarest, Peter Brunner, Jon T Willie, Cory S Inman

Faculty, Staff and Students Publications

Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without …

Comprehensive Assessment Reveals Numerous Clinical And Neurophysiological Differences Between Mecp2-Allelic Disorders, Davut Pehlivan, Chengjun Huang, Holly K Harris, Christine Coquery, Aditya Mahat, Mirjana Maletic-Savatic, Laurence Mignon, Sukru Aras, Daniel G Glaze, Charles S Layne, Leonardo Sahelijo, Huda Y Zoghbi, Matthew J Mcginley, Bernhard Suter

Faculty, Staff and Students Publications

OBJECTIVE: Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) result from under- and overexpression of MECP2, respectively. Preclinical studies using genetic-based treatment showed robust phenotype recovery for both MDS and RTT. However, there is a risk of converting MDS to RTT, or vice versa, if accurate MeCP2 levels are not achieved. The aim of this study was to identify biomarkers distinguishing RTT from MDS.

MATERIALS AND METHODS: We prospectively enrolled 11 MDS and 6 male RTT like (MRL) individuals for a panel of clinical and neurophysiological assessments over two visits, 8-10 months apart.

RESULTS: We identified numerous clinical and physiological …

Disease Activity Of Rheumatoid Arthritis And Kidney Function Decline: A Large Prospective Registry Study, Sho Fukui, Wolfgang C Winkelmayer, Sara K Tedeschi, Javier Marrugo, Hongshu Guan, Leslie Harrold, Heather J Litman, Tomohiro Shinozaki, Daniel H Solomon

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain.

Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR< 60 mL/min/1.73 m2) and stage G3b (eGFR< 45 mL/min/1.73 m2). Results were adjusted for relevant time-fixed and time-varying covariates.

Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m2) contributed 234 973 visits and 146 778 person-years …

Implementation Of Electronic Triggers To Identify Diagnostic Errors In Emergency Departments, Viralkumar Vaghani, Ashish Gupta, Usman Mir, Li Wei, Daniel R Murphy, Umair Mushtaq, Dean F Sittig, Andrew J Zimolzak, Hardeep Singh

Faculty, Staff and Students Publications

Importance: Missed diagnosis can lead to preventable patient harm.

Objective: To develop and implement a portfolio of electronic triggers (e-triggers) and examine their performance for identifying missed opportunities in diagnosis (MODs) in emergency departments (EDs).

Design, setting, and participants: In this retrospective medical record review study of ED visits at 1321 Veterans Affairs health care sites, rules-based e-triggers were developed and implemented using a national electronic health record repository. These e-triggers targeted 6 high-risk presentations for MODs in treat-and-release ED visits. A high-risk stroke e-trigger was applied to treat-and-release ED visits from January 1, 2016, to December 31, 2020. A …

Hospital Commitments To Address Diagnostic Errors: An Assessment Of 95 Us Hospitals, Alexandra Campione Russo, Jean-Luc Tilly, Leah Kaufman, Melissa Danforth, Mark L Graber, J Matthew Austin, Hardeep Singh

Faculty, Staff and Students Publications

Background: Diagnostic errors are a leading cause of patient harm. In 2022, the Leapfrog Group published a report containing 29 evidence-based practices that hospitals can adopt to reduce diagnostic errors.

Objectives: To understand the extent to which US hospitals have already implemented these practices, we conducted a national pilot survey of Leapfrog-participating hospitals.

Methods: To reduce respondent burden, we divided the 29 practices across two surveys: one focused on organizational culture and structure (Domain 1), and the second focused on the diagnostic process itself (Domain 2).

Results: A total of 95 hospitals from 23 states responded to one or both …

Advance: A Biomedical Informatics Approach To Investigate Acute Kidney Injury In Infants, Jennifer A Rumpel, Sofia Perazzo, Jonathan Bona, Andrew M South, Matthew W Harer, Daniel Liu, Michelle C Starr, Mona Khattab, Rachel Han, Cara Slagle, Eileen Ciccia, Tasnim Najaf, Matthew Gillen, Mimily Harsono, Arwa Nada, Kiran Dwarakanath, Semsa Gogcu, Tahagod Mohamed, Christine Stoops, Elizabeth Bonachea, Mary Revenis, Jessica Roberts, Robert Michael Lenzini, Anne Debuyserie, Catherine Joseph, Karna Murthy, Patricio Ray, Mario Schootman, Corey Nagel

Faculty, Staff and Students Publications

Background: Acute kidney injury (AKI) occurs in up to half of infants admitted to the neonatal intensive care unit (NICU) and is associated with increased risks of death and more days of mechanical ventilation, hospitalization, and vasopressor drug support. Our objective was to build a granular relational database to study the impact that AKI has on infants admitted to Level-IV NICUs.

Methods: A relational database was created by linking data from the Children's Hospitals Neonatal Database with AKI-focused data from electronic health records from 9 centers.

Results: The current cohort consists of 24,870 infants with a median (IQR) gestational age …

Respiratory Syncytial Virus Disease Burden And Nirsevimab Effectiveness In Young Children From 2023-2024, Heidi L Moline, Ariana P Toepfer, Ayzsa Tannis, Geoffrey A Weinberg, Mary A Staat, Natasha B Halasa, Julie A Boom, Eileen J Klein, John V Williams, Jennifer E Schuster, Leah Goldstein, Erin R Mckeever, Casey Kalman, Clinton Paden, Lydia Atherton, Megha Aggarwal, Pavitra Roychoudhury, Pedro A Piedra, Leila C Sahni, Laura S Stewart, Rangaraj Selvarangan, Marian G Michaels, Elizabeth P Schlaudecker, Peter G Szilagyi, Janet A Englund, Benjamin R Clopper, Natalie J Thornburg, Gordana Derado, Meredith L Mcmorrow, Fatimah S Dawood, New Vaccine Surveillance Network Collaborators

Faculty, Staff and Students Publications

Importance: During the 2023-2024 respiratory syncytial virus (RSV) season in the United States, 2 new RSV prevention products were recommended to protect infants in their first RSV season: nirsevimab and Pfizer's maternal RSV vaccine. Postlicensure studies are needed to assess prevention product impact and effectiveness.

Objective: To compare the epidemiology and disease burden of medically attended RSV-associated acute respiratory illness (ARI) among children younger than 5 years during the 2023-2024 RSV season with 3 prepandemic RSV seasons (2017-2020), estimate nirsevimab effectiveness against medically attended RSV-associated ARI, and compare nirsevimab binding site mutations among circulating RSV in infants with and without …

Cross-Sectional Comparison Of Structural Mri Markers Of Impairment In A Diverse Cohort Of Older Adults, Julie K Wisch, Kalen Petersen, Peter R Millar, Omar Abdelmoity, Ganesh M Babulal, Karin L Meeker, Meredith N Braskie, Kristine Yaffe, Arthur W Toga, Sid O'Bryant, Beau M Ances, Habs‐Hd Study Team

2020-Current year OA Pubs

Neurodegeneration is presumed to be the pathological process measure most proximal to clinical symptom onset in Alzheimer Disease (AD). Structural MRI is routinely collected in research and clinical trial settings. Several quantitative MRI-based measures of atrophy have been proposed, but their low correspondence with each other has been previously documented. The purpose of this study was to identify which commonly used structural MRI measure (hippocampal volume, cortical thickness in AD signature regions, or brain age gap [BAG]) had the best correspondence with the Clinical Dementia Rating (CDR) in an ethno-racially diverse sample. 2870 individuals recruited by the Healthy and Aging …

Prospective Observational Study Of Fkrp-Related Limb-Girdle Muscular Dystrophy R9: A Grasp Consortium Study, Lindsay N Alfano, Stephanie Hunn, Conrad C Weihl, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Limb-girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin-related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb-girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross-sectional validity and reliability of clinical outcome assessments in patients with FKRP-related LGMDR9 participating in the Genetic Resolution and Assessments Solving …

Aperiodic (1/F) Neural Activity Robustly Tracks Symptom Severity Changes In Treatment-Resistant Depression, Carl Hacker, Madaline M Mocchi, Jiayang Xiao, Brian Metzger, Joshua Adkinson, Bailey Pascuzzi, Raissa Mathura, Denise Oswalt, Andrew Watrous, Eleonora Bartoli, Anusha Allawala, Victoria Pirtle, Xiaoxu Fan, Isabel Danstrom, Ben Shofty, Garrett Banks, Yue Zhang, Michelle Armenta-Salas, Koorosh Mirpour, Nicole Provenza, Sanjay Mathew, Jeffrey F Cohn, David Borton, Wayne Goodman, Nader Pouratian, Sameer Anil Sheth, Kelly R Bijanki

Faculty, Staff and Students Publications

Background: A reliable physiological biomarker for major depressive disorder is essential for developing and optimizing neuromodulatory treatment paradigms. In this study, we investigated a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours.

Methods: We analyzed brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human participants (nfemale = 3, nmale = 2). This surgical setting allowed for precise temporal and spatial sensitivity in the ventromedial prefrontal cortex, a challenging area to measure. We focused on the aperiodic …

A Statistical Framework For Multi-Trait Rare Variant Analysis In Large-Scale Whole-Genome Sequencing Studies, Xihao Li, Han Chen, Margaret Sunitha Selvaraj, Eric Van Buren, Hufeng Zhou, Yuxuan Wang, Ryan Sun, Zachary R Mccaw, Zhi Yu, Min-Zhi Jiang, Daniel Dicorpo, Sheila M Gaynor, Rounak Dey, Donna K Arnett, Emelia J Benjamin, Joshua C Bis, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, April P Carson, Jenna C Carlson, Nathalie Chami, Yii-Der Ida Chen, Joanne E Curran, Paul S De Vries, Myriam Fornage, Nora Franceschini, Barry I Freedman, Charles Gu, Nancy L Heard-Costa, Jiang He, Lifang Hou, Yi-Jen Hung, Marguerite R Irvin, Robert C Kaplan, Sharon L R Kardia, Tanika N Kelly, Iain Konigsberg, Charles Kooperberg, Brian G Kral, Changwei Li, Yun Li, Honghuang Lin, Ching-Ti Liu, Ruth J F Loos, Michael C Mahaney, Lisa W Martin, Rasika A Mathias, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Kari E North, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alexander P Reiner, Stephen S Rich, Colleen M Sitlani, Jennifer A Smith, Kent D Taylor, Hemant K Tiwari, Ramachandran S Vasan, Satupa'itea Viali, Zhe Wang, Jennifer Wessel, Lisa R Yanek, Bing Yu, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Josée Dupuis, James B Meigs, Paul L Auer, Laura M Raffield, Alisa K Manning, Kenneth M Rice, Jerome I Rotter, Gina M Peloso, Pradeep Natarajan, Zilin Li, Zhonghua Liu, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple …

Improving Individualized Rhabdomyosarcoma Prognosis Predictions Using Somatic Molecular Biomarkers, Mark Zobeck, Javed Khan, Rajkumar Venkatramani, M Fatih Okcu, Michael E Scheurer, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Molecular markers increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.

Methods: Clinical variables and somatic mutation data for 20 genes from 641 patients with RMS in the United Kingdom and the United States were used to develop three Cox proportional hazard models for predicting event-free survival (EFS). The Baseline Clinical (BC) model included treatment location, age, fusion status, and risk group. The Gene Enhanced 2 (GE2) model added TP53 and MYOD1 mutations to the BC predictors. The Gene …

Tuning A Secondary Dose Verification Software For A Ct-Guided Online Adaptive Delivery System, Xiaodong Zhao, Markus Baur, Phillip D H Wall, Eric Laugeman

2020-Current year OA Pubs

BACKGROUND: Quality assurance (QA) remains unstandardized for CT-guided online adaptive radiotherapy (CTgART) platforms (Ethos, Varian Medical Systems, Inc., Palo Alto, CA), as they become more clinically prevalent. A secondary dose calculation software (Mobius3D, Varian Medical Systems, Inc., Palo Alto, CA) is provided for this closed CTgART system. However, the clinical impact of tuning dosimetric leaf gap (DLG) correction values for specific delivery techniques for CTgART secondary dose calculations remains uninvestigated.

PURPOSE: Tuning the DLG correction value for different delivery techniques of the independent secondary dose verification software for adaptive online QA.

METHODS: A total of 31 volumetric arc therapy (VMAT) …

Mechanisms Of Uropathogenic E. Coli Mucosal Association In The Gastrointestinal Tract, Philippe N Azimzadeh, Nathaniel C Gualbuerto, Jerome S Pinkner, Kevin O Tamadonfar, Wandy Beatty, Thomas J Hannan, Karen W Dodson, Enid C Ibarra, Seonyoung Kim, Henry L Schreiber, James W Janetka, Andrew L Kau, Mark J Miller, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Urinary tract infections (UTIs) are highly recurrent and frequently caused by Uropathogenic

Ligand Distances As Key Predictors Of Pathogenicity And Function In Nmda Receptors, Ludovica Montanucci, Tobias Brünger, Nisha Bhattarai, Christian M Boßelmann, Sukhan Kim, James P Allen, Jing Zhang, Chiara Klöckner, Ilona Krey, Piero Fariselli, Patrick May, Johannes R Lemke, Scott J Myers, Hongjie Yuan, Stephen F Traynelis, Dennis Lal

Faculty, Staff and Student Publications

Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by …