Digital Commons Network^™

Genetics, Manifestations, And Management Of Catecholaminergic Polymorphic Ventricular Tachycardia, Shubh Desai, Oliver M Moore, Xander H T Wehrens

Faculty, Staff and Students Publications

Purpose of review: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating heritable channelopathy that can lead to sudden cardiac death in children and young adults. This review aims to explore genetics, the cardiac and extracardiac manifestations of mutations associated with CPVT, and the challenges involved with managing phenotypically variable variants.

Recent findings: The understanding of the genetics and mechanisms of CPVT continues to grow with recent discoveries including alternative splicing of cardiac TRDN and calmodulin gene variants. Additionally, there is an increasing recognition of the extra-cardiac manifestations such as epilepsy, neurodevelopmental delay, and glucose homeostasis abnormalities in RyR2 variant carriers. …

Spaceflight Associated Neuro-Ocular Syndrome (Sans) And Its Countermeasures, Tuan Nguyen, Joshua Ong, Tyson Brunstetter, C Robert Gibson, Brandon R Macias, Steven Laurie, Thomas Mader, Alan Hargens, Jay C Buckey, Mimi Lan, Peter Wostyn, Cihan Kadipasaoglu, Scott M Smith, Sara R Zwart, Benjamin J Frankfort, Sarah Aman, Jessica M Scott, Ethan Waisberg, Mouayad Masalkhi, Andrew G Lee

Faculty, Staff and Students Publications

Astronauts can develop a distinct collection of neuro-ophthalmic findings during long duration spaceflight, collectively known as Spaceflight Associated Neuro-ocular Syndrome (SANS). These clinical characteristics include optic disc edema, hyperopic refractive shifts, globe flattening, and chorioretinal folds, which may pose a health risk for future space exploration. Obtaining knowledge of SANS and countermeasures for its prevention is crucial for upcoming crewed space missions and warrants a multidisciplinary approach. This review examines the potential causes and countermeasures of SANS, including space anticipation glasses, lower body negative pressure, venoconstrictive thigh cuffs, impedance threshold devices, translaminar pressure gradient modulation, centrifugation, artificial gravity, pharmaceuticals, and …

Safety, Efficacy, And Pharmacokinetics Of Oral Testosterone Undecanoate In Males With Hypogonadism, Martin Miner, Christina Wang, Jed Kaminetsky, Mohit Khera, Irwin Goldstein, Culley Carson, Nachiappan Chidambaram, Shelby King, Adrian Dobs

Faculty, Staff and Students Publications

Background: Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations.

Objective: The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality-of-life assessments to 1.62% topical testosterone gel (AndroGel 1.62%; AbbVie).

Materials and methods: In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted …

Functional Genomics In Age-Related Macular Degeneration: From Genetic Associations To Understanding Disease Mechanisms, Rinki Ratnapriya, Felix Grassman, Rui Chen, Alex Hewitt, Jianhai Du, Daniel R Saban, Caroline C W Klaver, John Ash, Dwight Stambolian, Santa J Tumminia, Jiang Qian, Deeba Husain, Sudha K Iyengar, Anneke I Den Hollander

Faculty, Staff and Students Publications

Genome-wide association studies have been remarkably successful in identifying genetic variants associated with age-related macular degeneration (AMD), demonstrating a strong genetic component largely driven by common variants. However, progress in translating these genetic findings into a deeper understanding of disease mechanisms and new therapies has been slow. Slow progress in this area can be attributed to limited knowledge of the functional impact of AMD-associated non-coding variants on gene function, the molecular mechanisms and cell types underlying disease. This review offers a comprehensive overview of functional genomics approaches to uncover the genetic, epigenetic, cellular and molecular mechanisms underlying AMD and outlines …

Bi-Allelic Uggt1 Variants Cause A Congenital Disorder Of Glycosylation, Zain Dardas, Laura Harrold, Daniel G Calame, Claire G Salter, Takashi Kikuma, Kevin P Guay, Bobby G Ng, Kanae Sano, Ahmad K Saad, Haowei Du, Riccardo Sangermano, Sohil G Patankar, Shalini N Jhangiani, Semra Gürsoy, Mohamed S Abdel-Hamid, Mahmoud K H Ahmed, Reza Maroofian, Rauan Kaiyrzhanov, Kamran Salayev, Wendy D Jones, Ana Pérez Caballero, Lucy Mcgavin, Michael Spiller, Miranda Durkie, Nick Wood, Lauren O'Grady, Paula Goldenberg, Ann M Neumeyer, Amber Begtrup, Sherif F Abdel-Ghafar, Maha S Zaki, Hilde Van Esch, Jennifer E Posey, Olivia K Wenger, Ethan M Scott, Kinga M Bujakowska, Richard A Gibbs, Davut Pehlivan, Dana Marafi, Joseph S Leslie, Nishanka Ubeyratna, Jacob Day, Martina Owens, Jessica Settle, Soher Balkhy, Abdullah Tamim, Lama Alabdi, Fowzan S Alkuraya, Yoichi Takeda, Hudson H Freeze, Daniel N Hebert, James R Lupski, Andrew H Crosby, Emma L Baple

Faculty, Staff and Students Publications

Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including …

Psychiatric Genetics In The Diverse Landscape Of Latin American Populations, Estela M Bruxel, Diego L Rovaris, Sintia I Belangero, Gabriela Chavarría-Soley, Alfredo B Cuellar-Barboza, José J Martínez-Magaña, Sheila T Nagamatsu, Caroline M Nievergelt, Diana L Núñez-Ríos, Vanessa K Ota, Roseann E Peterson, Laura G Sloofman, Amy M Adams, Elinette Albino, Angel T Alvarado, Diego Andrade-Brito, Paola Y Arguello-Pascualli, Cibele E Bandeira, Claiton H D Bau, Cynthia M Bulik, Joseph D Buxbaum, Carolina Cappi, Nadia S Corral-Frias, Alejo Corrales, Fabiana Corsi-Zuelli, James J Crowley, Renata B Cupertino, Bruna S Da Silva, Suzannah S De Almeida, Juan F De La Hoz, Diego A Forero, Gabriel R Fries, Joel Gelernter, Yeimy González-Giraldo, Eugenio H Grevet, Dorothy E Grice, Adriana Hernández-Garayua, John M Hettema, Agustín Ibáñez, Iuliana Ionita-Laza, Maria Claudia Lattig, Yago C Lima, Yi-Sian Lin, Sandra López-León, Camila M Loureiro, Verónica Martínez-Cerdeño, Gabriela A Martínez-Levy, Kyle Melin, Daniel Moreno-De-Luca, Carolina Muniz Carvalho, Ana Maria Olivares, Victor F Oliveira, Rafaella Ormond, Abraham A Palmer, Alana C Panzenhagen, Maria Rita Passos-Bueno, Qian Peng, Eduardo Pérez-Palma, Miguel L Prieto, Panos Roussos, Sandra Sanchez-Roige, Hernando Santamaría-García, Flávio M Shansis, Rachel R Sharp, Eric A Storch, Maria Eduarda A Tavares, Grace E Tietz, Bianca A Torres-Hernández, Luciana Tovo-Rodrigues, Pilar Trelles, Eva M Trujillo-Chivacuan, Maria M Velásquez, Fernando Vera-Urbina, Georgios Voloudakis, Talia Wegman-Ostrosky, Jenny Zhen-Duan, Hang Zhou, Latin American Genomics Consortium, Marcos L Santoro, Humberto Nicolini, Elizabeth G Atkinson, Paola Giusti-Rodríguez, Janitza L Montalvo-Ortiz

Faculty, Staff and Students Publications

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and …

Multi-Epitope Immunocapture Of Huntingtin Reveals Striatum-Selective Molecular Signatures, Joshua L Justice, Todd M Greco, Josiah E Hutton, Tavis J Reed, Megan L Mair, Juan Botas, Ileana M Cristea

Faculty, Staff and Students Publications

Huntington's disease (HD) is a debilitating neurodegenerative disorder affecting an individual's cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established …

Computational And Functional Prioritization Identifies Genes That Rescue Behavior And Reduce Tau Protein In Fly And Human Cell Models Of Alzheimer Disease, Morgan C Stephens, Jiayang Li, Megan Mair, Justin Moore, Katy Zhu, Akash Tarkunde, Bismark Amoh, Alma M Perez, Arya Bhakare, Fangfei Guo, Joshua M Shulman, Ismael Al-Ramahi, Juan Botas

Faculty, Staff and Students Publications

Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available …

Expert Consensus For Key Components Of A High-Quality Ventral Hernia Repair Operative Note, Jonathan S Lall, Said Maldonado, Nicole B Lyons, Gina Adrales, Karla Bernardi, Anne P Ehlers, Hobart Harris, Julie Holihan, William Hope, Jeffrey E Janis, Michele Loor, Clayton Petro, Luke Putnam, Caroline E Reinke, John Scott Roth, Christopher Senkowski, Kendell Sowards, Shirin Towfigh, Daniel Dante Yeh, Zuhair Ali, Mike K Liang

Faculty, Staff and Students Publications

Background: Ventral hernia repair (VHR) is one of the most commonly performed procedures by surgeons; however, there remains a lack of consensus for key components of operative reporting. Prior literature has identified several key elements that are recommended for inclusion in ventral hernia repair operative notes, but it is unclear whether these details alone make for a high-quality operative note. This study sought to determine whether experts agree on what factors make a ventral hernia repair operative note high-quality.

Study design: A prospective exploratory sequential survey-based mixed-methods design was used for round 1. Conclusions via thematic analysis from survey responses …

Goal Attainment In Pmm2-Cdg: A New Approach Measuring Meaningful Clinical Outcomes, Sanne Verberkmoes, Gina L Mazza, Andrew C Edmondson, Fernando Scaglia, Seishu Horikoshi, Bryce Kuschel, Mirian C H Janssen, Jehan Mousa, Austin Larson, Rameen Shah, Georgia Mcdonald, Kyriaki Sarafoglou, Gerard Berry, Tamas Kozicz, Christina Lam, Eva Morava

Faculty, Staff and Students Publications

Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and research, though their use in rare diseases remains limited. In disorders with significant phenotypic variation, selecting appropriate outcome measures is crucial to ensuring the relevance of clinical trials for the patient population. Phosphomannomutase 2-CDG (PMM2-CDG) involves a complex genotype-phenotype relationship, making it challenging to predict clinical outcomes and select reliable measures for clinical trials. Caused by biallelic pathogenic variants in the PMM2, PMM2-CDG displays highly variable clinical severity, underscoring the need for personalized outcome measures. One such so far unexplored, individualized approach is Goal Attainment Scaling (GAS), which …

Uncovering Shared Genetic Features Between Inflammatory Bowel Disease And Systemic Lupus Erythematosus, Vikram R Shaw, Jinyoung Byun, Catherine Zhu, Rowland W Pettit, Jeffrey M Cohen, Younghun Han, Christopher I Amos

Faculty, Staff and Students Publications

Inflammatory bowel disease (IBD) is an autoimmune disease (AD) characterized by chronic, relapsing intestinal inflammation. Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multisystem involvement and overactivation of both innate and adaptive immunity. The extra intestinal manifestations (EIMs) that commonly occur in IBD include many of the organ sites that are affected by SLE. ADs are often comorbid with one another and may have shared underlying genetic features and architectures contributing to their pathogenesis and disease course. We performed both epidemiological and post-genome wide association study (GWAS) analyses to investigate the shared genetic features between IBD and systemic …

Antibiotic Prophylaxis With Urodynamic Studies In Spinal Cord Injury: Assessing Practice Patterns And Outcomes To Guide Future Practice In A Single Center, Du Pham, Bradley Chi, Felicia Skelton, Donna Huang

Faculty, Staff and Students Publications

Context/objective: Despite urinary tract infections (UTIs) being a common problem in patients with spinal cord injuries (SCIs), and a well-known complication of invasive urologic procedures, little consensus exists regarding the standard of care for peri-procedural antibiotic use for SCI patients undergoing urodynamics studies (UDS). Our research seeks to evaluate local antibiotic prophylaxis pattern in SCI patients undergoing UDS, assess incidence of post-procedural UTI, describe local antibiotic resistance trends, and provide antibiotic stewardship considerations to guide future practice.

Design/setting/participants: Retrospective cohort study of SCI patients undergoing UDS from January 2010 to January 2020 at a Veterans Affairs SCI Center. Data on …

Otolaryngology-Assisted Approach For Anterior Cervical Discectomy And Fusion, M Benjamin Larkin, Anthony K Allam, Cyrus B King, N Eddie Liou, Alexander E Ropper

Faculty, Staff and Students Publications

First introduced in 1955, anterior cervical discectomy and fusion (ACDF) surgery has seen minimal changes over the years. Its reproducibility, impressive long-term results, and minimal complication rates have established it as one of the most frequently performed cervical spinal fusion surgeries. Yet, postoperative dysphagia remains a concern with a 60% incidence rate. An otolaryngologist's expertise regarding cervical fascial anatomy can inform the spine surgeon's approach to an ACDF to potentially reduce postoperative dysphagia rates. We describe an illustrative case of a 35-year-old woman who presented with 8/10 neck and arm pain along with numbness in her fourth and fifth digits …

Misconceptions Among Mental Health Treatment Providers About Ocd And Ptsd, Caitlin M Pinciotti, Gabriella T Ponzini, Gianna M Colombo, Carmen P Mclean, Terri L Fletcher, Natalie E Hundt, Lauren P Wadsworth, Nathaniel Van Kirk, Stephanie Y Wells, Jonathan S Abramowitz, Wayne K Goodman, Eric A Storch

Faculty, Staff and Students Publications

Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) share overlapping features for which similar cognitive behavioral treatment (CBT) strategies can be employed. However, the comorbid presence of these conditions poses unique clinical considerations, and a nuanced approach to assessment, conceptualization, and treatment is needed when working with individuals with co-occurring OCD and PTSD. Treatment providers may not be aware of these nuances and may hold misconceptions about co-occurring OCD and PTSD, impacting their approach to assessment, conceptualization, and treatment. The current study sought to examine possible misconceptions among mental health treatment providers of differing specializations. Among 146 primarily CBT-oriented treatment …

Overlapping Clinical Phenotypes In Patients With Primary Ciliary Dyskinesia Or Activated Phosphoinositide 3-Kinase Delta Syndrome, Adam J Shapiro, Eveline Y Wu, Deborah J Morris-Rosendahl, Kenneth N Olivier, Sharon D Dell, Scott D Sagel, Cullen M Dutmer, Ricardo A Mosquera, Markus Rose, Michael G O'Connor, Chi A Ma, Gulbu Uzel, Timothy J Vece, Maimoona A Zariwala, Michael R Knowles, Margaret W Leigh, Stephanie D Davis, Thomas W Ferkol

Faculty, Staff and Student Publications

Primary ciliary dyskinesia and activated phosphoinositide 3-kinase delta syndrome type 1 present similarly, with recurrent respiratory infections and reduced nasal nitric oxide levels. When diagnostic confirmation of primary ciliary dyskinesia with genetic testing and/or ciliary electron microscopy is inconclusive, activated phosphoinositide 3-kinase delta syndrome type 1 and other inborn errors of immunity must be investigated.

Precision Proteogenomics Reveals Pan-Cancer Impact Of Germline Variants, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Kathleen J Imbach, Karl R Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M Yaron, Yize Li, Song Cao, Erik P Storrs, Olivia S Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A Kawaler, Matthew A Wyczalkowski, Robert J Klein, Berk Turhan, Karsten Krug, D R Mani, Felipe Da Veiga Leprevost, Alexey I Nesvizhskii, Steven A Carr, David Fenyö, Michael A Gillette, Antonio Colaprico, Antonio Iavarone, Ana I Robles, Kuan-Lin Huang, Chandan Kumar-Sinha, François Aguet, Alexander J Lazar, Lewis C Cantley, Urko M Marigorta, Zeynep H Gümüş, Matthew H Bailey, Gad Getz, Eduard Porta-Pardo, Li Ding

Faculty, Staff and Student Publications

We investigate the impact of germline variants on cancer patients' proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, "precision peptidomics," mapping 337,469 coding germline variants onto peptides from patients' mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial …

The Influence Of The American Association For Thoracic Surgery On Clinical Trial Development By Cardiothoracic Surgeons, Adishesh K Narahari, Taylor M Horgan, Anirudha S Chandrabhatla, Abhinav Kareddy, Ajami Gikandi, Marco A Zenati, David Harpole, David Jones, Leora T Yarboro, Bryan Burt, A Sasha Krupnick, J Hunter Mehaffey

Faculty, Staff and Students Publications

Objective: Clinical trials play a critical role in the rapidly evolving field of cardiothoracic surgery and the American Association for Thoracic Surgery Clinical Trials Methods Course has provided a biannual symposium led by preeminent surgeons with vast experience in planning, conducting, and analyzing surgical clinical trials. This study hypothesizes that participation in the course is associated with future success in clinical trial leadership.

Methods: A list of course attendees (2014-2022) was queried in ClinicalTrials.gov, a database of clinical trials funded by the US Department of Health and Human Services and the National Institutes of Health. The type of clinical trial …

A Standardized Nomenclature For The Rods And Cones Of The Vertebrate Retina, Tom Baden, Takeshi Yoshimatsu, Joseph C. Corbo, Et Al.

2020-Current year OA Pubs

Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably-and often confusingly-named according to morphology, presence/absence of 'rhodopsin', spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor type's putative evolutionary history. This classification is informed by the functional, anatomical, developmental, and molecular identities of the neuron …

Wb5, A Novel Biomarker For Monitoring Efficacy And Success Of Mass Drug Administration Programs For Wuchereria Bancrofti Elimination, Rachel E. Pietrow, Catherine Bjerum, Benjamin G. Koudou, Taniawati Supali, Philip J Budge, Peter U. Fischer, Thomas B. Nutman, Sasisekhar Bennuru

2020-Current year OA Pubs

The success of mass drug administration at reducing the prevalence of lymphatic filariasis in endemic areas has led to an increased need for highly sensitive and specific diagnostic assays. To be useful in post-elimination surveillance in areas with low to zero prevalence, high test performance characteristics are required to enable the early detection of infection recrudescence. As current testing suffers from either sensitivity or specificity levels that fail to meet adopted target product profiles, additional targets that could be used as confirmatory tests or in multiplexed assays could overcome these issues. To this end, bioinformatic analyses coupled with stage-specific expression …

The Multiverse Of Cd46 And Oncologic Interactions, M. Kathryn Liszewski, John P. Atkinson

2020-Current year OA Pubs

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a "pathogen" magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer …

Regulation Of Tfeb In Human Placental Cytotrophoblasts And Syncytiotrophoblasts, A Mathew, J S Trausch-Azar, C Azar, M Schuetz, M R Mahjoub, A L Schwartz

2020-Current year OA Pubs

While cellular proteins exist in a dynamic state maintained by the balance of synthesis and degradation, there is a paucity of information on these processes in placental trophoblasts, including within cytotrophoblasts which differentiate into multi-nucleate syncytiotrophoblasts. TFEB, a transcription factor with a myriad of cellular activities, is one of the most abundant genes expressed in syncytiotrophoblasts compared to cytotrophoblasts. TFEB is localized to the nucleus of human BeWo differentiated syncytiotrophoblasts and to the cytoplasm of the undifferentiated cytotrophoblasts. Within both the cytotrophoblasts and syncytiotrophoblasts, TFEB exists in subcellular compartments as both phosphorylated and unphosphorylated forms and translocates between cytoplasm and …

Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study Of Iluzanebart In Healthy Volunteers, Andreas Meier, Spyros Papapetropoulos, Andrew Marsh, Kelly Neelon, David Stiles, Ryan O'Mara, Evan A Thackaberry, Marco Colonna, Raj Rajagovindan

2020-Current year OA Pubs

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration.

METHODS: Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1-60 mg/kg (SAD) or 10-60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection …

Elevated P16ink4a Expression Enhances Tau Phosphorylation In Neurons Differentiated From Human-Induced Pluripotent Stem Cells, Kristopher Holloway, Kashfia Neherin, Yingduo Song, Kazuhito Sato, Andrew Houston, Feng Chen, Li Ding, Hong Zhang

2020-Current year OA Pubs

Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, …

Brain Morphometry In Infants Later Diagnosed With Autism Is Related To Later Language Skills, Luke E Moraglia, Kelly N Botteron, Natasha Marrus, Et Al.

2020-Current year OA Pubs

Autism spectrum disorder (ASD) presents early in life with distinct social and language differences. This study explores the association between infant brain morphometry and language abilities using an infant-sibling design. Participants included infants who had an older sibling with autism (high likelihood, HL) who were later diagnosed with autism (HL-ASD; n = 31) and two non-autistic control groups: HL-Neg (HL infants not diagnosed with autism; n = 126) and LL-Neg (typically developing infants who did not have an older sibling with autism; n = 77). Using a whole-brain approach, we measured cortical thickness and surface area at 6 and 12 …

Vascular Rings - What Has Changed, And What Do I Need To Know As A Practitioner?, Sarah Madira, William B Orr, Joshua M Rosenblum, Ryan Pitman, Quang-Tuyen Nguyen, David Molter, Ashley Lloyd, Julie Glickstein, Markus Renno, Pirooz Eghtesady, Jacob R Miller

2020-Current year OA Pubs

Vascular rings represent a heterogeneous set of aberrant great vessel anatomic configurations which can cause respiratory symptoms or dysphagia due to tracheal or oesophageal compression. These symptoms can be subtle and may present at varied ages. More recently, many have been identified in patients without symptoms, including fetal echocardiogram, resulting in a conundrum for practitioners when attempting to determine who will benefit from surgical correction. Here, we provide a review of vascular rings and a guide to the practitioner on when to consider additional imaging or referral. Additionally, we discuss the changing landscape regarding asymptomatic patients and fetal echocardiogram.

Plasma P-Tau217 And Tau-Pet Predict Future Cognitive Decline Among Cognitively Unimpaired Individuals: Implications For Clinical Trials, Rik Ossenkoppele, Tammie L S Benzinger, Suzanne E Schindler, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R

A Cerebrospinal Fluid Synaptic Protein Biomarker For Prediction Of Cognitive Resilience Versus Decline In Alzheimer's Disease, Hamilton Se-Hwee Oh, Yuanyuan Shen, Jigyasha Timsina, Chengran Yang, Daniel Western, Muhammad Ali, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau

Functions Of Communication During Emergency Care Of Children With Medical Complexity: Caregiver Perspectives, Julia A Ciurria, Jennifer Reyes Lin, Cassandra M Pruitt, Bryan A Sisk

2020-Current year OA Pubs

OBJECTIVE: We investigated communication experiences of caregivers of children with medical complexity (CMC) during emergency care.

METHODS: Fifteen caregivers of CMC participated in semi-structured interviews regarding communication while seeking care for their child in the emergency department (ED). Thematic analysis was applied using a previously established functional communication model as an a priori framework.

RESULTS: Each of the previously established 8 core functions of communication were identified in this population. "Building relationships" manifested as clinicians soliciting caregiver input and responding to the needs of the caregiver. "Exchanging information" included clearly explaining next steps to caregivers. "Responding to emotions" acknowledged the …

Differentiating Pathology Of Acute Disseminated Encephalomyelitis From Multiple Sclerosis In Children Using Diffusion Magnetic Resonance Biomarkers, Esra Pehlivan, Martin Kinuthia Mwangi, Vihas Abraham, Urmi Mange, Sheng-Kwei Song, Peng Sun, Soe Soe Mar

2020-Current year OA Pubs

BACKGROUND: To investigate the pathologic differences in patients with pediatric-onset multiple sclerosis (POMS) and acute disseminated encephalomyelitis (ADEM) using diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI).

METHODS: Fifteen children with POMS and eight children with ADEM underwent DTI and DBSI. The comparison of DTI and DBSI diffusivity measures of POMS (31 scans) and ADEM (17 scans) was performed as group comparison and association over time.

RESULTS: In univariate analysis of average measures of DBSI and DTI over time, DBSI fractional anisotropy is lower in POMS than ADEM (P = 0.002), indicative of axonal injury of POMS. Higher …

For Girls And Women (4gw) Hpv Rct Protocol: A Crowdsourced, Pragmatic Stepped-Wedge Cluster Randomized Trial To Improve Uptake Of Hpv Vaccination And Screening Among Mother-Daughter Dyads In Nigeria, Juliet Iwelunmor, Ekenechukwu Kokelu, Temitope Ojo, Olufunto Olusanya, Titilola Gbaja-Biamila, Peter Kalulu, Angel Obiorah, Maria Afadapa, Nkiruka Obodoechina, Onyeka Anikamadu, Et Al.

2020-Current year OA Pubs

BACKGROUND: Expanding human papillomavirus (HPV) vaccination for girls and HPV self-collection for women can reduce the global burden of cervical cancer. However, HPV vaccination and self-collection services are rarely implemented simultaneously in mother-daughter dyads, leaving a critical gap in cervical cancer prevention. From 2023 to 2024, a community-engaged model for combined HPV vaccination and screening was co-designed using crowdsourcing open calls and designathons with mother-daughter teams and pilot-tested by trained research facilitators. This study explores the impact of this crowdsourced, community-engaged mother-daughter campaign and implementation strategy bundle on HPV vaccination among girls and HPV screening among their mothers in Nigeria …