Medical Specialties Commons^™

Epidemiology Of Giardiasis And Assemblages A And B And Effects On Diarrhea And Growth Trajectories During The First 8 Years Of Life: Analysis Of A Birth Cohort In A Rural District In Tropical Ecuador, Tannya Sandoval-Ramírez, Victor Seco-Hidalgo, Evelyn Calderon-Espinosa, Diana Garcia-Ramon, Andrea Lopez, Manuel Calvopiña, Irene Guadalupe, Martha Chico, Rojelio Mejia, Irina Chis Ster, Philip J Cooper

Faculty, Staff and Students Publications

BACKGROUND: There are limited longitudinal data on the acquisition of Giardia lamblia infections in childhood using molecular assays to detect and type assemblages, and measure effects of infections on diarrhea risk and childhood growth.

METHODS: We analysed stool samples from a surveillance sample within a birth cohort in a rural district in tropical Ecuador. The cohort was followed to 8 years of age for the presence of G. lamblia in stools by quantitative PCR and A and B assemblages by Taqman assay or Sanger sequencing. We explored risk factors associated with infection using generalized estimating equations applied to longitudinal binary …

Does Chronic Obstructive Pulmonary Disease Originate From Different Cell Types?, Yohannes Tesfaigzi, Jeffrey L Curtis, Irina Petrache, Francesca Polverino, Farrah Kheradmand, Ian M Adcock, Stephen I Rennard

Faculty, Staff and Students Publications

The onset of chronic obstructive pulmonary disease (COPD) is heterogeneous, and current approaches to define distinct disease phenotypes are lacking. In addition to clinical methodologies, subtyping COPD has also been challenged by the reliance on human lung samples from late-stage diseases. Different COPD phenotypes may be initiated from the susceptibility of different cell types to cigarette smoke, environmental pollution, and infections at early stages that ultimately converge at later stages in airway remodeling and destruction of the alveoli when the disease is diagnosed. This perspective provides discussion points on how studies to date define different cell types of the lung …

Protein Advanced Glycation End Products And Their Implications In Pancreatic Cancer, Lakmini Senavirathna, Sheng Pan, Ru Chen

Faculty, Staff and Students Publications

Protein advanced glycation end products (AGE) formed by nonenzymatic glycation can disrupt the normal structure and function of proteins, and stimulate the receptor for AGEs (RAGE), triggering intricate mechanisms that are etiologically related to various chronic diseases, including pancreatic cancer. Many common risk factors of pancreatic cancer are the major sources for the formation of protein AGEs and glycative stress in the human body. Abnormal accumulation of protein AGEs can impair the cellular proteome and promote AGE-RAGE driven pro-inflammatory signaling cascades, leading to increased oxidative stress, protease resistance, protein dysregulation, transcription activity of STAT, NF-κB, and AP-1, aberrant status in …

Once-Weekly Transcon Cnp (Navepegritide) In Children With Achondroplasia (Accomplish): A Phase 2, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial, Ravi Savarirayan, Daniel G Hoernschemeyer, Merete Ljungberg, Yuri A Zarate, Carlos A Bacino, Michael B Bober, Janet M Legare, Wolfgang Högler, Teresa Quattrin, M Jennifer Abuzzahab, Paul L Hofman, Klane K White, Nina S Ma, Dirk Schnabel, Sérgio B Sousa, Meng Mao, Alden Smith, Mukta Chakraborty, Adebola Giwa, Bent Winding, Birgitte Volck, Aimee D Shu, Ciara Mcdonnell

Faculty, Staff and Students Publications

BACKGROUND: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.

METHODS: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety …

Overcoming Barriers To Drug Development And Enrollment In Clinical Trials For Adolescents And Young Adults With Lymphoma, Keri Toner, Carl E Allen, Shweta Jain, Brad Kahl, John Leonard, Heather Wasserstrom, Jonathan W Friedberg, Nita L Seibel, Kara Kelly

Faculty, Staff and Students Publications

Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward.

Mature B-Cell Lymphomas In Adolescents And Young Adults, Nader Kim El-Mallawany, Lisa Giulino-Roth, John M Burke, Michelle Hermiston, Carl E Allen

Faculty, Staff and Students Publications

Pediatric non-Hodgkin lymphoma includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the US, compared to >60,000 cases of adult NHL annually. Improvements in survival in pediatric and adolescent mature B cell NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes through dose escalation of chemotherapy and, more recently, targeted therapy with rituximab. Pediatric dose-intense strategies carry risks of long-term consequences, but treatment failure is nearly universally fatal. By comparison, adult mature B cell lymphoma is typically less aggressive and treated with less …

Baseline Leptin Predicts Response To Metformin In Adolescents With Type 1 Diabetes And Increased Body Mass Index, Heba M Ismail, Souptik Barua, Johnny Wang, Ashutosh Sabharwal, Ingrid Libman, Fida Bacha, Kristen J Nadeau, Mustafa Tosur, Maria J Redondo

Faculty, Staff and Students Publications

No abstract provided.

Untargeted Metabolomic Analysis Investigating Links Between Unprocessed Red Meat Intake And Markers Of Inflammation, Alexis C Wood, Goncalo Graca, Meghana Gadgil, Mackenzie K Senn, Matthew A Allison, Ioanna Tzoulaki, Philip Greenland, Timothy Ebbels, Paul Elliott, Mark O Goodarzi, Russell Tracy, Jerome I Rotter, David Herrington

Faculty, Staff and Students Publications

BACKGROUND: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships.

OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation.

METHODS: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, …

Feasibility Of A Dietary Intervention To Modify Gut Microbial Metabolism In Patients With Hematopoietic Stem Cell Transplantation, Mary M Riwes, Jonathan L Golob, John Magenau, Mengrou Shan, Gregory Dick, Thomas Braun, Thomas M Schmidt, Attaphol Pawarode, Sarah Anand, Monalisa Ghosh, John Maciejewski, Darren King, Sung Choi, Gregory Yanik, Marcus Geer, Ethan Hillman, Costas A Lyssiotis, Muneesh Tewari, Pavan Reddy

Faculty, Staff and Students Publications

Evaluation of the impact of dietary intervention on gastrointestinal microbiota and metabolites after allogeneic hematopoietic stem cell transplantation (HCT) is lacking. We conducted a feasibility study as the first of a two-phase trial. Ten adults received resistant potato starch (RPS) daily from day −7 to day 100. The primary objective was to test the feasibility of RPS and its effect on intestinal microbiome and metabolites, including the short-chain fatty acid butyrate. Feasibility met the preset goal of 60% or more, adhering to 70% or more doses; fecal butyrate levels were significantly higher when participants were on RPS than when they …

Breastfeeding And Risk Of Childhood Brain Tumors: A Report From The Childhood Cancer And Leukemia International Consortium, Jeremy M Schraw, Eleni Th Petridou, Audrey Bonaventure, John D Dockerty, Maria Karalexi, Evangelia Ntzani, Claire Infante-Rivard, Jacqueline Clavel, Paige M Bracci, Roberta Mckean-Cowdin, Eve Roman, Eleanor Kane, Friederike Erdmann, Joachim Schüz, Beth A Mueller, Michael E Scheurer

Faculty, Staff and Students Publications

Purpose: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence.

Methods: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, …

Intratumoral Nanofluidic System Enhanced Tumor Biodistribution Of Pd-L1 Antibody In Triple-Negative Breast Cancer, Hsuan-Chen Liu, Simone Capuani, Andrew A Badachhape, Nicola Di Trani, Daniel Davila Gonzalez, Robin S Vander Pol, Dixita I Viswanath, Shani Saunders, Nathanael Hernandez, Ketan B Ghaghada, Shu-Hsia Chen, Elizabeth Nance, Ananth V Annapragada, Corrine Ying Xuan Chua, Alessandro Grattoni

Faculty, Staff and Students Publications

Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off-target drug biodistribution, we developed the nanofluidic drug-eluting seed (NDES) platform for sustained intratumoral …

Pressure Injury Data Reconciliation In A Randomized Controlled Trial, Jeanine Blanchard, Cheryl Vigen, Trudy Mallinson, Mike Carlson, Susan L Garber, Barbara Bates-Jensen

Faculty, Staff and Students Publications

Objective: To advance pressure injury (PrI) research in individuals with spinal cord injury (SCI) by describing lessons learned and recommendations for future research, ultimately promoting PrI prevention and more effective wound care. This paper describes the detailed procedures undertaken to collect and reconcile PrI data and summarizes the types of discrepancies identified.

Design: Secondary analyses of PrI data collected between 2009 and 2014 in a randomized controlled trial (parent study).

Setting: Participants in the parent study were recruited from a large rehabilitation center in the Los Angeles area that serves primarily individuals with limited resources.

Participants: 232 participants with SCI …

Preface: Pediatric Plastic Surgery, Larry H Hollier

Faculty, Staff and Students Publications

No abstract provided.

Racial And Ethnic Variation In Ecmo Utilization And Outcomes In Pediatric Cardiac Icu Patients, Marissa A Brunetti, Heather M Griffis, Michael L O'Byrne, Andrew C Glatz, Jing Huang, Kurt R Schumacher, David K Bailly, Yuliya Domnina, Javier J Lasa, Michael Alice Moga, Hayden Zaccagni, Janet M Simsic, J William Gaynor

Faculty, Staff and Students Publications

Background: Previous studies have reported racial disparities in extracorporeal membrane oxygenation (ECMO) utilization in pediatric cardiac patients.

Objectives: The objective of this study was to determine if there was racial/ethnic variation in ECMO utilization and, if so, whether mortality was mediated by differences in ECMO utilization.

Methods: This is a multicenter, retrospective cohort study of the Pediatric Cardiac Critical Care Consortium clinical registry. Analyses were stratified by hospitalization type (medical vs surgical). Logistic regression models were adjusted for confounders and evaluated the association between race/ethnicity with ECMO utilization and mortality. Secondary analyses explored interactions between race/ethnicity, insurance, and socioeconomic status …

Commentary: A Different Animal But The Same Beast, Vicente Orozco-Sevilla, Joseph S Coselli

Faculty, Staff and Students Publications

No abstract provided.

Gastrointestinal Infections Modulate The Risk For Insulin Autoantibodies As The First-Appearing Autoantibody In The Teddy Study, Maria Lönnrot, Kristian F Lynch, Marian Rewers, Åke Lernmark, Kendra Vehik, Beena Akolkar, William Hagopian, Jeffrey Krischer, Rickhard A Mcindoe, Jorma Toppari, Anette-G Ziegler, Joseph F Petrosino, Richard Lloyd, Heikki Hyöty, Teddy Study Group

Faculty, Staff and Students Publications

OBJECTIVE: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort.

RESEARCH DESIGN AND METHODS: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study.

RESULTS: GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at(OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in …

Pax3 Lineage-Specific Deletion Of Gpr161 Is Associated With Spinal Neural Tube And Craniofacial Malformations During Embryonic Development, Sung-Eun Kim, Pooja J Chothani, Rehana Shaik, Westley Pollard, Richard H Finnell

Faculty, Staff and Students Publications

Sonic hedgehog (Shh) signaling is the morphogen signaling that regulates embryonic craniofacial and neural tube development. G protein-coupled receptor 161 (Gpr161) is a negative regulator of Shh signaling, and its inactivation in mice results in embryo lethality associated with craniofacial defects and neural tube defects. However, the structural defects of later embryonic stages and cell lineages underlying abnormalities have not been well characterized due to the limited lifespan of Gpr161 null mice. We found that embryos with Pax3 lineage-specific deletion of Gpr161 presented with tectal hypertrophy (anterior dorsal neuroepithelium), cranial vault and facial bone hypoplasia (cranial neural crest), vertebral abnormalities …

Sarcopenia Is Associated With Osteopenia And Impaired Quality Of Life In Children With Genetic Intrahepatic Cholestatic Liver Disease, Julia M Boster, Nathan P Goodrich, Cathie Spino, Kathleen M Loomes, Estella M Alonso, Binita M Kamath, Ronald J Sokol, Saul Karpen, Alexander Miethke, Benjamin L Shneider, Jean P Molleston, Rohit Kohli, Simon P Horslen, Philip Rosenthal, Pamela L Valentino, Jeffrey H Teckman, Thomas N Hangartner, Shikha S Sundaram

Faculty, Staff and Students Publications

BACKGROUND: Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes.

METHODS: Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed.

RESULTS: eSMM was …

Relationships Among Intragastric Meal Distribution During Gastric Emptying Scintigraphy, Water Consumption During Water Load Satiety Testing, And Symptoms Of Gastroparesis, Henry P Parkman, Laura A Wilson, Paul Silver, Alan H Maurer, Irene Sarosiek, Robert S Bulat, Braden Kuo, Madhusudan Grover, Gianrico Farrugia, Bruno P Chumpitazi, Robert J Shulman, Zubair Malik, Laura A Miriel, James Tonascia, Frank Hamilton, Thomas L Abell, Pankaj J Pasricha, Richard W Mccallum, Kenneth L Koch, Niddk Gastroparesis Clinical Research Consortium

Faculty, Staff and Students Publications

Gastric emptying scintigraphy (GES) measures total gastric retention after a solid meal and can assess intragastric meal distribution (IMD). Water load satiety test (WLST) measures gastric capacity. Both IMD immediately after meal ingestion [ratio of proximal gastric counts after meal ingestion to total gastric counts at time 0 (IMD⁰)] and WLST (volume of water ingested over 5 min) are indirect measures of gastric accommodation. In this study, IMD⁰ and WLST were compared with each other and to symptoms of gastroparesis to gauge their clinical utility for assessing patients with symptoms of gastroparesis. Patients with symptoms of gastroparesis …

Preterm Pigs Fed Donor Human Milk Have Greater Liver Β-Carotene Concentrations Than Pigs Fed Infant Formula, Nancy E Moran, Joshua Wade, Rachel Stroh, Barbara Stoll, Gregory Guthrie, Amy B Hair, Douglas G Burrin

Faculty, Staff and Students Publications

BACKGROUND: Milk carotenoids may support preterm infant health and neurodevelopment. Infants fed human milk often have higher blood and tissue carotenoid concentrations than infants fed carotenoid-containing infant formula (IF). Donor human milk (DHM) is a supplement to mother's own milk, used to support preterm infant nutrition.

OBJECTIVES: We tested whether tissue and plasma β-carotene concentrations would be higher in preterm pigs fed pasteurized DHM versus premature IF.

METHODS: This is a secondary analysis of samples collected from a study of the effects of enteral diet composition on necrotizing enterocolitis incidence. Preterm pigs received partial enteral feeding of either DHM (n …

Ewing's Sarcoma Of The Hand: An Unusual Presentation In A Young Hispanic Male, Dylan B Mcbee, Hope A Bentley, Giancarlo Toledanes

Faculty, Staff and Students Publications

Ewing's sarcoma is a neuroectodermal malignancy classically associated with innocuous and chronic symptomatology. Although tumors typically involve the axial skeleton, some malignancies may be confined to extraosseous tissue only. This report presents the case of a 15-year-old Hispanic male with a tender, slow-growing mass of seven months in the subcutaneous tissue of the right hand. Core needle biopsy and fine needle aspiration confirmed the diagnosis of high-grade extraosseous Ewing's sarcoma and the patient was treated via surgical resection and chemotherapy. Nonspecific findings of Ewing's sarcoma may mimic infection or trauma and contribute to a delay in diagnosis. However, social and …

The Development, Content And Response Process Validation Of A Caregiver-Reported Severity Measure For Cdkl5 Deficiency Disorder, Sonja I Ziniel, Alexandra Mackie, Jacinta Saldaris, Helen Leonard, Peter Jacoby, Eric D Marsh, Bernhard Suter, Elia Pestana-Knight, Heather E Olson, Dana Price, Judith Weisenberg, Rajsekar Rajaraman, Gina Vanderveen, Tim A Benke, Jenny Downs, Scott Demarest

Faculty, Staff and Students Publications

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity.

METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended.

RESULTS: The CCSA was refined during three rounds of cognitive interviews into …

Research Priorities For Pediatric Emergency Care To Address Disparities By Race, Ethnicity, And Language, Elyse N Portillo, Chris A Rees, Emily A Hartford, Zachary C Foughty, Michelle L Pickett, Colleen K Gutman, Bashar S Shihabuddin, Eric W Fleegler, Corrie E Chumpitazi, Tiffani J Johnson, David Schnadower, Kathy N Shaw

Faculty, Staff and Students Publications

IMPORTANCE: Health care disparities are well-documented among children based on race, ethnicity, and language for care. An agenda that outlines research priorities for disparities in pediatric emergency care (PEC) is lacking.

OBJECTIVE: To investigate research priorities for disparities in PEC among medical personnel, researchers, and health care-affiliated community organizations.

DESIGN, SETTING, AND PARTICIPANTS: In this survey study, a modified Delphi approach was used to investigate research priorities for disparities in PEC. An initial list of research priorities was developed by a group of experienced PEC investigators in 2021. Partners iteratively assessed the list through 2 rounds of electronic surveys using …

Camkk2 As An Emerging Treatment Target For Bipolar Disorder, Jacqueline Kaiser, Kevin Nay, Christopher R Horne, Luke M Mcaloon, Oliver K Fuller, Abbey G Muller, Douglas G Whyte, Anthony R Means, Ken Walder, Michael Berk, Anthony J Hannan, James M Murphy, Mark A Febbraio, Andrew L Gundlach, John W Scott

Faculty, Staff and Students Publications

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug …

Targeted Inhibition Of Lncrna Malat1 Alters The Tumor Immune Microenvironment In Preclinical Syngeneic Mouse Models Of Triple-Negative Breast Cancer, Oluwatoyosi Adewunmi, Yichao Shen, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Long noncoding RNAs (lncRNA) play an important role in gene regulation in both normal tissues and cancer. Targeting lncRNAs is a promising therapeutic approach that has become feasible through the development of gapmer antisense oligonucleotides (ASO). Metastasis-associated lung adenocarcinoma transcript (Malat1) is an abundant lncRNA whose expression is upregulated in several cancers. Although Malat1 increases the migratory and invasive properties of tumor cells, its role in the tumor microenvironment (TME) is still not well defined. We explored the connection between Malat1 and the tumor immune microenvironment (TIME) using several immune-competent preclinical syngeneic Tp53-null triple-negative breast cancer (TNBC) mouse models that …

Dominant Negative Variants In Kif5b Cause Osteogenesis Imperfecta Via Down Regulation Of Mtor Signaling, Ronit Marom, Bo Zhang, Megan E Washington, I-Wen Song, Lindsay C Burrage, Vittoria C Rossi, Ava S Berrier, Anika Lindsey, Jacob Lesinski, Michael L Nonet, Jian Chen, Dustin Baldridge, Gary A Silverman, V Reid Sutton, Jill A Rosenfeld, Alyssa A Tran, M John Hicks, David R Murdock, Hongzheng Dai, Maryann Weis, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, Richard Caswell, Carrie Pottinger, Deirdre Cilliers, Karen Stals, Undiagnosed Diseases Network, David Eyre, Deborah Krakow, Tim Schedl, Stephen C Pak, Brendan H Lee

Faculty, Staff and Students Publications

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.

METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, …

Biallelic Missense Variants In Cog3 Cause A Congenital Disorder Of Glycosylation With Impairment Of Retrograde Vesicular Trafficking, Ruizhi Duan, Dana Marafi, Zhi-Jie Xia, Bobby G Ng, Reza Maroofian, Farhana Taher Sumya, Ahmed K Saad, Haowei Du, Jawid M Fatih, Jill V Hunter, Hasnaa M Elbendary, Shahid M Baig, Uzma Abdullah, Zafar Ali, Stephanie Efthymiou, David Murphy, Tadahiro Mitani, Marjorie A Withers, Shalini N Jhangiani, Zeynep Coban-Akdemir, Daniel G Calame, Davut Pehlivan, Richard A Gibbs, Jennifer E Posey, Henry Houlden, Vladimir V Lupashin, Maha S Zaki, Hudson H Freeze, James R Lupski

Faculty, Staff and Students Publications

Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in humans. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3-CDG presentations. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed …

Aso Silencing Of A Glycosyltransferase, Poglut1, Improves The Liver Phenotypes In Mouse Models Of Alagille Syndrome, Nima Niknejad, Duncan Fox, Jennifer L Burwinkel, Neda Zarrin-Khameh, Soomin Cho, Armand Soriano, Ashley E Cast, Mario F Lopez, Kari A Huppert, Frank Rigo, Stacey S Huppert, Paymaan Jafar-Nejad, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in …

Oral Follicle-Stimulating Hormone Receptor Agonist Affects Granulosa Cells Differently Than Recombinant Human Fsh, Joie Z Guner, Diana Monsivais, Henry Yu, Fabio Stossi, Hannah L Johnson, William E Gibbons, Martin M Matzuk, Stephen Palmer

Faculty, Staff and Students Publications

Objective:

To determine whether TOP5300, a novel oral follicle stimulating hormone receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from in vitro fertilization patients.

Design:

Basic science research with a preclinical allosteric FSHR agonist.

Subjects:

Infertility patients at a single academic fertility clinic were recruited under an IRB-approved protocol. Primary granulosa cell cultures were established for 41 patients, of which 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovarian syndrome (PCOS), and 4 had a combination of diagnoses, such …

Relationship Between Age And Pathology With Treatment Of Pediatric And Adolescent Discoid Lateral Meniscus: A Report From The Score Multicenter Database, Rachel S Silverstein, Scott D Mckay, Pablo Coello, Lauren Pupa, Kevin Latz, W Craig Kemper, Elizabeth Adsit, Philip L Wilson, Members Of The Score Quality Improvement Registry, Jay Albright, Sheila Algan, Jennifer Beck, Richard E Bowen, Jennifer Brey, J Marc Cardelia, Christian Clark, Allison Crepeau, Eric Edmonds, Matthew Ellington, Peter D Fabricant, Jeremy S Frank, Theodore J Ganley, Daniel W Green, Andrew Gupta, Benton Heyworth, Alfred Mansour, Stephanie Mayer, Matthew D Milewski, Emily Niu, Donna M Pacicca, Shital N Parikh, Jason Rhodes, Michael Saper, Gregory A Schmale, Matthew Schmitz, Kevin Shea, Stephen Storer, Henry B. Ellis

Faculty, Staff and Students Publications

BACKGROUND: Surgical treatment options of discoid lateral meniscus in pediatric patients consist of saucerization with or without meniscal repair, meniscocapular stabilization, and, less often, subtotal meniscectomy.

PURPOSE: To describe a large, prospectively collected multicenter cohort of discoid menisci undergoing surgical intervention, and further investigate corresponding treatment of discoid menisci.

STUDY DESIGN: Cohort study; Level of evidence, 3.

METHODS: A multicenter quality improvement registry (16 institutions, 26 surgeons), Sports Cohort Outcomes Registry, was queried. Patient characteristics, discoid type, presence and type of intrasubstance meniscal tear, peripheral rim instability, repair technique, and partial meniscectomy/debridement beyond saucerization were reviewed. Discoid meniscus characteristics were …