Medicine and Health Sciences Commons^™

Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes Of The Young (Mody), Mustafa Tosur, Louis H Philipson

Faculty, Staff and Students Publications

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require …

Extracellular Vesicles In Β Cell Biology: Role Of Lipids In Vesicle Biogenesis, Cargo, And Intercellular Signaling, Rebecca S Aguirre, Abhishek Kulkarni, Matthew W Becker, Xiaoyong Lei, Soumyadeep Sarkar, Sasanka Ramanadham, Edward A Phelps, Ernesto S Nakayasu, Emily K Sims, Raghavendra G Mirmira

Faculty, Staff and Students Publications

BACKGROUND: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between β cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been seen as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by β cells constitute an additional and biologically important mechanism for transmitting signals to within the islet.

SCOPE OF REVIEW: This review summarizes the general mechanisms of EV formation, with …

Dietary Fat Composition Shapes Bile Acid Metabolism And Severity Of Liver Injury In A Pig Model Of Pediatric Nafld, Rodrigo Manjarín, Kayla Dillard, Morgan Coffin, Gabriella V Hernandez, Victoria A Smith, Trista Noland-Lidell, Tanvi R Gehani, Hayden J Smart, Kevin Wheeler, Kimberly A Sprayberry, Mark S Edwards, Rob K Fanter, Hunter Glanz, Chad Immoos, Tasha M Santiago-Rodriguez, Jason M Blank, Douglas G Burrin, Brian D Piccolo, Mohammed Abo-Ismail, Michael R La Frano, Magdalena Maj

Faculty, Staff and Students Publications

The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-day-old Iberian pigs pair-housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 wk: 1) lard-enriched (LAR; n = 5 pens), 2) olive oil-enriched (OLI; n = 5), and 3) coconut oil-enriched (COC; n = 5). Animals were euthanized on week 10 after blood sampling, and liver, colon, and distal ileum (DI) were …

Transcatheter Aortic Valve Implantation For Severe Aortic Stenosis And Large Membranous Interventricular Septal Aneurysm, Maheedhar Gedela, Tomasz Stys, Terezia Petraskova, Adam Stys

The Texas Heart Institute Journal

No abstract provided.

Improved Right Ventricular Systolic Function After Cardiac Resynchronization Therapy In Patients With Heart Failure, Hakimeh Sadeghian, Ali Kazemisaied, Mehrnaz Rezvanfard, Arash Jalali, Afsaneh Sadeghian, Haleh Ashraf, Farbod Semnani, Amirhossein Ghaseminejad Raeini

The Texas Heart Institute Journal

Background

Since the introduction of cardiac resynchronization therapy (CRT) to improve left ventricular function, the effect of CRT on the right ventricle in patients with heart failure has not been well described.

Methods

We evaluated the effect of CRT on right ventricular systolic function in 20 patients (80% men; mean [SD] age, 58.5 [9.8] y) with cardiomyopathy and right ventricular systolic dysfunction (New York Heart Association class III or IV, left ventricular ejection fraction ≤35%, and QRS interval ≥120 ms). The median follow-up time was 15 months. Right ventricular systolic function, defined as a tricuspid annular plane systolic excursion (TAPSE) …

Combined Disease Of The Quadricuspid Aortic Valve, Robert Blazekovic, Jasmina Catic, Stjepan Barisin, Marko Kusurin, Savica Gjorgjievska, Stanislav Glumbic

The Texas Heart Institute Journal

No abstract provided.

Gene Expression Signatures Identify Biologically And Clinically Distinct Tuberculosis Endotypes, Andrew R Dinardo, Tanmay Gandhi, Jan Heyckendorf, Sandra L Grimm, Kimal Rajapakshe, Tomoki Nishiguchi, Maja Reimann, H Lester Kirchner, Jaqueline Kahari, Qiniso Dlamini, Christoph Lange, Torsten Goldmann, Sebastian Marwitz, Dzif-Tb Cohort Study Group, Abhimanyu, Jeffrey D Cirillo, Stefan H E Kaufmann, Mihai G Netea, Reinout Van Crevel, Anna M Mandalakas, Cristian Coarfa

Faculty, Staff and Students Publications

BACKGROUND:In vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.

METHODS: A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated …

‘Fly-Ing’ From Rare To Common Neurodegenerative Disease Mechanisms, Mengqi Ma, Matthew J Moulton, Shenzhao Lu, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Genome sequencing advances have enabled researchers and clinicians to probe vast numbers of human variants to distinguish pathogenic from benign variation. Model organisms have been critical in variant assessment and delineating molecular mechanisms of some of the diseases caused by these variants. The fruit fly, Drosophila melanogaster, has played a valuable role in this endeavor, taking advantage of its genetic technologies and established biological knowledge. In this review, we highlight the utility of the fly in studying the function of genes associated with rare neurological diseases that have led to a better understanding of common disease mechanisms. We emphasize …

Kctd7 Deficiency Induces Myoclonic Seizures Associated With Purkinje Cell Death And Microvascular Defects, Justine H Liang, Jonathan Alevy, Viktor Akhanov, Ryan Seo, Cory A Massey, Danye Jiang, Joy Zhou, Roy V Sillitoe, Jeffrey L Noebels, Melanie A Samuel

Duncan NRI Faculty and Staff Publications

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. KCTD7-driven disease is part of a large family of progressive myoclonic epilepsy syndromes displaying a broad spectrum of clinical severity. Animal models of KCTD7-related disease are lacking, and little is known regarding how KCTD7 protein defects lead to epilepsy and cognitive dysfunction. We characterized Kctd7 expression patterns in the mouse brain during development and show that it is selectively enriched in specific regions as the brain matures. We further …

Evidence For An Association Between Coffin-Siris Syndrome And Congenital Diaphragmatic Hernia, Yoel Gofin, Xiaonan Zhao, Amanda Gerard, Fernando Scaglia, Michael F Wangler, Samantha A Schrier Vergano, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and …

High Prevalence Of Osteopathy In Chronic Pancreatitis: A Cross-Sectional Analysis From The Proceed Study, Phil A Hart, Dhiraj Yadav, Liang Li, Savi Appana, William Fisher, Evan Fogel, Chris E Forsmark, Walter G Park, Stephen Pandol, Mark D Topazian, Stephen K Van Den Eden, Santhi Swaroop Vege, David Bradley, Jose Serrano, Darwin L Conwell

Center for Medical Ethics and Health Policy Staff Publications

Background & aims: Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP.

Methods: We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression …

Rates Of Laboratory Adverse Events By Course In Paediatric Leukaemia Ascertained With Automated Electronic Health Record Extraction: A Retrospective Cohort Study From The Children’S Oncology Group, Tamara P Miller, Kelly D Getz, Yimei Li, Biniyam G Demissei, Peter C Adamson, Todd A Alonzo, Evanette Burrows, Lusha Cao, Sharon M Castellino, Marla H Daves, Brian T Fisher, Robert Gerbing, Robert W Grundmeier, Edward M Krause, Judy Lee, Philip J Lupo, Karen R Rabin, Mark Ramos, Michael E Scheurer, Jennifer J Wilkes, Lena E Winestone, Douglas S Hawkins, M Monica Gramatges, Richard Aplenc

Center for Medical Ethics and Health Policy Staff Publications

Background: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia.

Methods: For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia …

Vaccine-Linked Chemotherapy With A Low Dose Of Benznidazole Plus A Bivalent Recombinant Protein Vaccine Prevents The Development Of Cardiac Fibrosis Caused By Trypanosoma Cruzi In Chronically-Infected Balb/C Mice, Victor Manuel Dzul-Huchim, Maria Jesus Ramirez-Sierra, Pedro Pablo Martinez-Vega, Miguel Enrique Rosado-Vallado, Victor Ermilo Arana-Argaez, Jaime Ortega-Lopez, Fabian Gusovsky, Eric Dumonteil, Julio Vladimir Cruz-Chan, Peter Hotez, María Elena Bottazzi, Liliana Estefania Villanueva-Lizama

Center for Medical Ethics and Health Policy Staff Publications

Background: Chagas disease (CD) is caused by Trypanosoma cruzi and affects 6-7 million people worldwide. Approximately 30% of chronic patients develop chronic chagasic cardiomyopathy (CCC) after decades. Benznidazole (BNZ), one of the first-line chemotherapy used for CD, induces toxicity and fails to halt the progression of CCC in chronic patients. The recombinant parasite-derived antigens, including Tc24, Tc24-C4, TSA-1, and TSA-1-C4 with Toll-like receptor 4 (TLR-4) agonist-adjuvants reduce cardiac parasite burdens, heart inflammation, and fibrosis, leading us to envision their use as immunotherapy together with BNZ. Given genetic immunization (DNA vaccines) encoding Tc24 and TSA-1 induce protective immunity in mice and …

Factors Associated With Severe Illness In Patients Aged <21 Years Hospitalized For Covid-19, Rewa Choudhary, Bryant J Webber, Lindsay S Womack, Hannah K Dupont, Sophia K Chiu, Valentine Wanga, Megan E Gerdes, Sophia Hsu, Dallas S Shi, Theresa M Dulski, Osatohamwen I Idubor, Arthur M Wendel, Nickolas T Agathis, Kristi Anderson, Tricia Boyles, Eleanor S Click, Juliana Da Silva, Mary E Evans, Jeremy A W Gold, Julia C Haston, Pamela Logan, Susan A Maloney, Marisol Martinez, Pavithra Natarajan, Kevin B Spicer, Mark Swancutt, Valerie A Stevens, Jessica Rogers-Brown, Gyan Chandra, Megan Light, Frederick E Barr, Jessica Snowden, Larry K Kociolek, Matthew Mchugh, David L Wessel, Joelle N Simpson, Kathleen C Gorman, Kristen A Breslin, Roberta L Debiasi, Aaron Thompson, Mark W Kline, Julie A Boom, Ila R Singh, Michael Dowlin, Mark Wietecha, Beth Schweitzer, Sapna Bamrah Morris, Emilia H Koumans, Jean Y Ko, David A Siegel, Anne A Kimball

Faculty, Staff and Students Publications

OBJECTIVES: To describe coronavirus disease 2019 (COVID-19)-related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness.

METHODS: We abstracted data from medical charts to conduct a cross-sectional study of patients agedchildren's hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation.

RESULTS: Of 947 hospitalized patients, 759 …

Quality Of Life, Illness Perceptions, And Parental Lived Experiences In Tango2-Related Metabolic Encephalopathy And Arrhythmias, Chaya N Murali, Seema R Lalani, Mahshid S Azamian, Christina Y Miyake, Hadley Stevens Smith

Faculty, Staff and Students Publications

TANGO2 disorder is a rare genetic disease with multi-system effects that causes episodic crises. Quality of life and psychosocial effects of this rare disease have not previously been studied. To examine health-related quality of life (HRQoL), illness perceptions, and lived experience, we surveyed 16 children and 31 parents of children with TANGO2 disorder identified via a disease-specific social media group and research foundation email distribution list. We assessed HRQoL by parent proxy-report and child self-report using the Pediatric Quality of Life Inventory (PedsQL™). Parental perceptions of their child's condition were assessed using the revised illness perceptions questionnaire adapted for TANGO2 …

Changes In Apparent Diffusion Coefficient (Adc) In Serial Weekly Mri During Radiotherapy In Patients With Head And Neck Cancer: Results From The Predict-Hn Study, Sweet Ping Ng, Carlos E Cardenas, Houda Bahig, Baher Elgohari, Jihong Wang, Jason M Johnson, Amy C Moreno, Shalin J Shah, Adam S Garden, Jack Phan, G Brandon Gunn, Steven J Frank, Yao Ding, Lumine Na, Ying Yuan, Diana Urbauer, Abdallah S R Mohamed, David I Rosenthal, William H Morrison, Michael P Macmanus, Clifton D Fuller

Faculty, Staff and Student Publications

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy.

Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman’s correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time.

Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that …

Short Signature Rpob Gene Sequence To Differentiate Species In Mycobacterium Abscessus Group, Jian R Bao, Kileen L Shier, Ronald N Master, Robert S Jones, Richard B Clark

Faculty, Staff and Student Publications

Mycobacterium abscessus group (MAG) are rapidly growing acid-fast bacteria that consist of three closely related species: M. abscessus (Ma), M. bolletii (Mb), and M. massiliense (Mm). Differentiation of these species can be difficult but is increasingly requested owing to recent infectious outbreaks and their differential drug resistance. We developed a novel and rapid pyrosequencing method using short signature sequences (35 to 45 bp) at a hypervariable site in the rpoB gene to differentiate the three MAG species, along with M. chelonae (Mc), and M. immunogenum (Mi). This method was evaluated …

Optimal Urine Culture Diagnostic Stewardship Practice- Results From An Expert Modified-Delphi Procedure, Kimberly C Claeys, Stephen Y Liang, Et Al.

2020-Current year OA Pubs

BACKGROUND: Urine cultures are nonspecific and often lead to misdiagnosis of urinary tract infection and unnecessary antibiotics. Diagnostic stewardship is a set of procedures that modifies test ordering, processing, and reporting in order to optimize diagnosis and downstream treatment. In this study, we aimed to develop expert guidance on best practices for urine culture diagnostic stewardship.

METHODS: A RAND-modified Delphi approach with a multidisciplinary expert panel was used to ascertain diagnostic stewardship best practices. Clinical questions to guide recommendations were grouped into three thematic areas (ordering, processing, reporting) in practice settings of emergency department, inpatient, ambulatory, and long-term care. Fifteen …

Proteomic Identification Of Potential Target Proteins Of Cathepsin W For Its Development As A Drug Target For Influenza, Sira C Günther, Carles Martínez-Romero, Milagros Sempere Borau, Christine T N Pham, Adolfo García-Sastre, Silke Stertz

2020-Current year OA Pubs

Influenza A virus (IAV) coopts numerous host factors for efficient replication. The cysteine protease cathepsin W (CTSW) has been identified as one host factor required for IAV entry, specifically for the escape of IAVs from late endosomes. However, the substrate specificity of CTSW and the proviral mechanism are thus far unknown. Here, we show that intracellular but not secreted CTSW promotes viral entry. We reveal 79 potential direct and 31 potential indirect cellular target proteins of CTSW using the high-throughput proteomic approach terminal amine isotopic labeling of substrates (TAILS) and determine the cleavage motif shared by the substrates of CTSW. …

Evolution Of Multiple Domains Of The Hiv-1 Envelope Glycoprotein During Coreceptor Switch With Ccr5 Antagonist Therapy, Yueqi Du, Ellen Wu, Xiang Gao, Jie Zhang, John C Martin, Bruce A Rosa, Makedonka Mitreva, Lee Ratner

2020-Current year OA Pubs

HIV-1 uses CD4 as a receptor and chemokine receptors CCR5 and/or CXCR4 as coreceptors. CCR5 antagonists are a class of antiretrovirals used to inhibit viral entry. Phenotypic prediction algorithms such as Geno2Pheno are used to assess CCR5 antagonist eligibility, for which the V3 region is screened. However, there exist scenarios where the algorithm cannot give an accurate prediction of tropism. The current study examined coreceptor shift of HIV-1 from CCR5-tropic strains to CXCR4-tropic or dual-tropic strains among five subjects in a clinical trial of the CCR5 antagonist vicriviroc. Envelope gene amplicon libraries were constructed and subjected to next-generation sequencing, as …

Virtual Global Health In Graduate Medical Education: A Systematic Review, Lisa Umphrey, Nora Lenhard, Suet Kam Lam, Nathaniel E Hayward, Shaina Hecht, Priya Agrawal, Amy Chambliss, Jessica Evert, Heather Haq, Stephanie M Lauden, George Paasi, Mary Schleicher, Megan Song Mchenry

Faculty, Staff and Students Publications

OBJECTIVES: To synthesize recent virtual global health education activities for graduate medical trainees, document gaps in the literature, suggest future study, and inform best practice recommendations for global health educators.

METHODS: We systematically reviewed articles published on virtual global health education activities from 2012-2021 by searching MEDLINE, EMBASE, Cochrane Library, ERIC, Scopus, Web of Science, and ProQuest Dissertations & Theses A&I. We performed bibliography review and search of conference and organization websites. We included articles about primarily virtual activities targeting for health professional trainees. We collected and qualitatively analyzed descriptive data about activity type, evaluation, audience, and drivers or barriers. …

Phage Resistance Accompanies Reduced Fitness Of Uropathogenic Escherichia Coli In The Urinary Environment, Jacob J Zulk, Justin R Clark, Samantha Ottinger, Mallory B Ballard, Marlyd E Mejia, Vicki Mercado-Evans, Emmaline R Heckmann, Belkys C Sanchez, Barbara W Trautner, Anthony W Maresso, Kathryn A Patras

Faculty, Staff and Students Publications

Urinary tract infection (UTI) is among the most common infections treated worldwide each year and is caused primarily by uropathogenic Escherichia coli (UPEC). Rising rates of antibiotic resistance among uropathogens have spurred a consideration of alternative treatment strategies, such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, namely, HP3 and ES17, against clinical UPEC isolates using in vitro and in vivo models of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6 to 8 h of coincubation. …

Is Cadaveric Dissection Essential In Medical Education? A Qualitative Survey Comparing Pre- And Post-Covid-19 Anatomy Courses, Smriti Kochhar, Tasfia Tasnim, Adarsh Gupta

Rowan-Virtua School of Osteopathic Medicine Departmental Research

CONTEXT: With the surge of the novel coronavirus (SARS-CoV-2 [COVID-19]), the modality of teaching anatomy has shifted from in-person cadaveric dissection to virtual lessons for incoming first-year medical students. As a result, we aim to assess the impact that this curriculum change has on student perspectives.

OBJECTIVES: This study aims to understand the relative effect of a virtual anatomy course implemented during the pandemic (2019-2020) on the confidence, skills, and perspectives of first-year medical students compared to medical students who had traditional in-person anatomy at Rowan University School of Osteopathic Medicine (Rowan SOM) in Stratford, New Jersey.

METHODS: The authors …

Endophenotype Effect Sizes Support Variant Pathogenicity In Monogenic Disease Susceptibility Genes, Jennifer L Halford, Valerie N Morrill, Seung Hoan Choi, Sean J Jurgens, Giorgio Melloni, Nicholas A Marston, Lu-Chen Weng, Victor Nauffal, Amelia W Hall, Sophia Gunn, Christina A Austin-Tse, James P Pirruccello, Shaan Khurshid, Heidi L Rehm, Emelia J Benjamin, Eric Boerwinkle, Jennifer A Brody, Adolfo Correa, Brandon K Fornwalt, Namrata Gupta, Christopher M Haggerty, Stephanie Harris, Susan R Heckbert, Charles C Hong, Charles Kooperberg, Henry J Lin, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Wendy Post, Bruce M Psaty, Susan Redline, Kenneth M Rice, Stephen S Rich, Jerome I Rotter, Peter F Schnatz, Elsayed Z Soliman, Nona Sotoodehnia, Eugene K Wong, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Marc S Sabatine, Christian T Ruff, Kathryn L Lunetta, Patrick T Ellinor, Steven A Lubitz

Faculty, Staff and Student Publications

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S. Regalado, Alan C. Braverman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

N1-Methylpseudouridine Found Within Covid-19 Mrna Vaccines Produces Faithful Protein Products, Kyusik Q Kim, Bhagyashri D Burgute, Shin-Cheng Tzeng, Crystal Jing, Courtney Jungers, Junya Zhang, Liewei L Yan, Richard D Vierstra, Sergej Djuranovic, Bradley S Evans, Hani S Zaher

2020-Current year OA Pubs

Synthetic mRNA technology is a promising avenue for treating and preventing disease. Key to the technology is the incorporation of modified nucleotides such as N1-methylpseudouridine (m1Ψ) to decrease immunogenicity of the RNA. However, relatively few studies have addressed the effects of modified nucleotides on the decoding process. Here, we investigate the effect of m1Ψ and the related modification pseudouridine (Ψ) on translation. In a reconstituted system, we find that m1Ψ does not significantly alter decoding accuracy. More importantly, we do not detect an increase in miscoded peptides when mRNA containing m1Ψ is translated in cell culture, compared with unmodified mRNA. …

A Multitrait Locus Regulates Sarbecovirus Pathogenesis, Alexandra Schäfer, Emma S Winkler, Michael S Diamond, Et Al

2020-Current year OA Pubs

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential …

Re-Examining Rotavirus Innate Immune Evasion: Potential Applications Of The Reverse Genetics System, Avan Antia, Amanda N Pinski, Siyuan Ding

2020-Current year OA Pubs

Rotaviruses represent one of the most successful pathogens in the world, with high infectivity and efficient transmission between the young of many animal species, including humans. To overcome host defenses, rotaviruses have evolved a plethora of strategies to effectively evade the innate immune response, establish initial infection in the small intestine, produce progeny, and shed into the environment. Previously, studying the roles and relative contributions of specific rotaviral factors in innate immune evasion had been challenging without a plasmid-only reverse genetics system. Although still in its infancy, current reverse genetics technology will help address important research questions regarding rotavirus innate …

Distinct Sensitivities To Sars-Cov-2 Variants In Vaccinated Humans And Mice, Alexandra C Walls, Laura A Vanblargan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited …