Digital Commons Network^™

Epigenetic Developmental Mechanisms Underlying Sex Differences In Cancer, Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang

2020-Current year OA Pubs

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, …

Mhealth-Based Just-In-Time Adaptive Intervention To Improve The Physical Activity Levels Of Individuals With Spinal Cord Injury: Protocol For A Randomized Controlled Trial, Rachel Carey, Ha Le, Donna Coffman, Inbal Nahum-Shani, Mohanraj Thirumalai, Cole Hagen, Laura Baehr, M. Schmidt-Read, Marlyn Lamboy, Stephanie A Kolakowsky-Hayner, Ralph Marino, Stephen Intille, Shivayogi Hiremath

Moss-Magee Rehabilitation Papers

BACKGROUND: The lack of regular physical activity (PA) in individuals with spinal cord injury (SCI) in the United States is an ongoing health crisis. Regular PA and exercise-based interventions have been linked with improved outcomes and healthier lifestyles among those with SCI. Providing people with an accurate estimate of their everyday PA level can promote PA. Furthermore, PA tracking can be combined with mobile health technology such as smartphones and smartwatches to provide a just-in-time adaptive intervention (JITAI) for individuals with SCI as they go about everyday life. A JITAI can prompt an individual to set a PA goal or …

Randomized Controlled Trial Of Enteral Vitamin D Supplementation (Vides) In Infants <28 Weeks Gestational Age Or <1000 G Birth Weight: Study Protocol, Mar Romero-Lopez, Jon E Tyson, Mamta Naik, Claudia Pedroza, Lindsay F Holzapfel, Elenir Avritscher, Ricardo Mosquera, Amir Khan, Matthew Rysavy

Faculty, Staff and Student Publications

BACKGROUND: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear.

METHODS: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants(400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the …

Neural Circuits Expressing The Serotonin 2c Receptor Regulate Memory In Mice And Humans, Hesong Liu, Yang He, Hailan Liu, Bas Brouwers, Na Yin, Katherine Lawler, Julia M Keogh, Elana Henning, Dong-Kee Lee, Meng Yu, Longlong Tu, Nan Zhang, Kristine M Conde, Junying Han, Zili Yan, Nikolas A Scarcelli, Lan Liao, Jianming Xu, Qingchun Tong, Hui Zheng, Zheng Sun, Yongjie Yang, Chunmei Wang, Yanlin He, I Sadaf Farooqi, Yong Xu

Children’s Nutrition Research Center Staff Publications

Declined memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, …

Blood Phenylalanine Levels In Patients With Phenylketonuria From Europe Between 2012 And 2018: Is It A Changing Landscape?, Alex Pinto, Kirsten Ahring, Manuela Ferreira Almeida, Catherine Ashmore, Amaya Bélanger-Quintana, Alberto Burlina, Turgay Coşkun, Anne Daly, Esther Van Dam, Ali Dursun, Sharon Evans, François Feillet, Maria Giżewska, Hulya Gökmen-Özel, Mary Hickson, Yteke Hoekstra, Fatma Ilgaz, Richard Jackson, Alicja Leśniak, Christian Loro, Katarzyna Malicka, Michał Patalan, Júlio César Rocha, Serap Sivri, Iris Rodenburg, Francjan Van Spronsen, Kamilla Strączek, Ayşegül Tokatli, Anita Macdonald

School of Health Professions

Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, …

Cross-Sectional Analysis Of The Association Between Household Food Insecurity And Mental Health Conditions In Children Aged 5–11 Years In Canada, Justin Thielman, Sarah Orr, Saranya Naraentheraraja, Daniel Harrington, Sarah Carsley

Faculty, Staff and Student Publications

BACKGROUND: Children living in food insecure households have poorer mental health outcomes compared with their food-secure peers; however, the relationship between the severity of food insecurity and diagnosed mental health conditions in young children remains unknown. This study examined the association between household food insecurity and reported diagnosed mental health conditions among children aged 5-11 years in Canada.

METHODS: This study included 16 216 children aged 5-11 years living in Canada, from the 2019 Canadian Health Survey on Children and Youth. We measured household food insecurity using the Household Food Security Survey Module. We measured diagnosed mental health conditions by …

Electronic Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: Long-Term Results Of A Multicenter, Randomized, Controlled Trial, Wei Dai, Yaqin Wang, Jia Liao, Xing Wei, Zhen Dai, Wei Xu, Yangjun Liu, Xin Shelley Wang, Cecilia Pompili, Hongfan Yu, Yang Pu, Yuqian Zhao, Bangrong Cao, Qifeng Wang, Wenhong Feng, Yuanqiang Zhang, Fang Liu, Yuanle Deng, Jin Zhou, Juan Li, Shaohua Xie, Run Xiang, Xiang Wang, Bo Tian, Xiaozun Yang, Bin Hu, Xiaoqin Liu, Tianpeng Xie, Xiaojun Yang, Xiang Zhuang, Guibin Qiao, Qiang Li, Qiuling Shi

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported superior symptom control of electronic patient-reported outcome (ePRO)-based symptom management after lung cancer surgery for up to 1 month postdischarge. Here, we present the long-term results (1-12 months) of this multicenter, randomized trial, where …

Changes In Plasma Concentrations Of Per- And Polyfluoroalkyl Substances After Bariatric Surgery In Adolescents From The Teen-Longitudinal Assessment Of Bariatric Surgery (Teen-Labs) Study, Brittney O Baumert, Sandrah P Eckel, Jesse A Goodrich, Zhenjiang Li, Nikos Stratakis, Douglas I Walker, Yinqi Zhao, Fabian Christoph Fischer, Scott Bartell, Damaskini Valvi, Xiangping Lin, Zoe Coates Fuentes, Thomas Inge, Justin Ryder, Todd Jenkins, Rohit Kohli, Stephanie Sisley, Stavra Xanthakos, Sarah Rock, Michele A La Merrill, Rob Mcconnell, David V Conti, Lida Chatzi

Faculty, Staff and Students Publications

Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate …

Neuroecological Links Of The Exposome And One Health, Agustin Ibanez, Lucia Melloni, Paweł Świeboda, William Hynes, Burcin Ikiz, Rym Ayadi, Massamba Thioye, Consuelo Walss-Bass, Bahar Güntekin, Jyoti Mishra, Mohamed Salama, Sarah Dunlop, Claudia Duran-Aniotz, Harris A Eyre

Faculty, Staff and Student Publications

This NeuroView assesses the interplay among exposome, One Health, and brain capital in health and disease. Physical and social exposomes affect brain health, and green brain skills are required for environmental health strategies. Ibanez et al. address current gaps and strategies needed in research, policy, and technology, offering a road map for stakeholders.

Supporting Ontario Public Health Units To Address Adverse Childhood Experiences In Pandemic Recovery Planning: A Priority-Setting Exercise, Kimberly B Harding, Erica Di Ruggiero, Erick Gonzalez, Amanda Hicks, Daniel W Harrington, Sarah Carsley

Faculty, Staff and Student Publications

BACKGROUND: Adverse childhood experiences (ACEs) are potentially traumatic exposures experienced during childhood, for example, neglect. There is growing evidence that the coronavirus disease 2019 (COVID-19) pandemic and related socioeconomic conditions contributed to an increased risk of ACEs. As public health programs/services are re-evaluated and restored following the state of emergency, it is important to plan using an ACEs-informed lens. The aim of this study was to identify and prioritize initiatives or activities that Public Health Ontario (PHO) could undertake to support Ontario public health units' work towards ACEs-informed pandemic recovery plans.

METHODS: The Child Health and Nutrition Research Initiative method …

Associations Between Circadian Alignment And Cognitive Functioning In A Nationally Representative Sample Of Older Adults, Sophie Leahy, Qian Xiao, Chris Ho Ching Yeung, Mariana G Figueiro

Faculty, Staff and Student Publications

Proper alignment of activity-rest and light-dark patterns allows for healthy bodily functions to occur at optimal times of the day. Disruptions to this alignment may cause poor sleep as well as physical, mental, and cognitive problems. The purpose of this cross-sectional study was to determine if poorer circadian alignment was associated with decreased cognitive functioning among older (> 60 years) participants in the National Health and Nutrition Examination Survey. We utilized actigraphy-based rest-activity and dark-light measurements to calculate phasor magnitude (strength of circadian alignment coupling) and phasor angle (phase difference between activity-rest and light-dark cycles). Multiple linear regression models were …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Role Of Ethanolamine Utilization And Bacterial Microcompartment Formation In Listeria Monocytogenes Intracellular Infection, Ayan Chatterjee, Karan Gautam Kaval, Danielle A Garsin

Faculty, Staff and Student Publications

Ethanolamine (EA) affects the colonization and pathogenicity of certain human bacterial pathogens in the gastrointestinal tract. However, EA can also affect the intracellular survival and replication of host cell invasive bacteria such as Listeria monocytogenes (LMO) and Salmonella enterica serovar Typhimurium (S. Typhimurium). The EA utilization (eut) genes can be categorized as regulatory, enzymatic, or structural, and previous work in LMO showed that loss of genes encoding functions for the enzymatic breakdown of EA inhibited LMO intracellular replication. In this work, we sought to further characterize the role of EA utilization during LMO infection of host …

Folate As A Potential Treatment For Lethal Ventricular Arrhythmias In Tango2-Deficiency Disorder, Weiyi Xu, Yingqiong Cao, Sara B Stephens, Maria Jose Arredondo, Yifan Chen, William Perez, Liang Sun, Andy C Yu, Jean J Kim, Seema R Lalani, Na Li, Frank T Horrigan, Francisco Altamirano, Xander Ht Wehrens, Christina Y Miyake, Lilei Zhang

Faculty, Staff and Students Publications

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs …

Investigating The Association Between Metabolic Syndrome Conditions And Perinatal Mental Illness: A National Administrative Claims Study, Karishma Chhabria, Sudhakar Selvaraj, Jerrie Refuerzo, Chau Truong, Cecilia Ganduglia Cazaban

Faculty, Staff and Student Publications

BACKGROUND: Although the association between mental disorder and metabolic syndrome as a bidirectional relationship has been demonstrated, there is little knowledge of the cumulative and individual effect of these conditions on peripartum mental health. This study aims to investigate the association between metabolic syndrome conditions (MetS-C) and maternal mental illness in the perinatal period, while exploring time to incident mental disorder diagnosis in postpartum women.

METHODS: This observational study identified perinatal women continuously enrolled 1 year prior to and 1 year post-delivery using Optum's de-identified Clinformatics® Data Mart Database (CDM) from 2014 to 2019 with MetS-C i.e. obesity, diabetes, high …

Relationship Between Youth Cardiometabolic Health And Physical Activity In Medical Records., Bethany Forseth, Janelle R. Noel-Macdonnell Phd, Sarah Hampl, Jordan A. Carlson, Kelsee Halpin, Ann M. Davis, Tarin Phillips, Robin P. Shook

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Thers is limited research examining modifiable cardiometabolic risk factors with a single-item health behavior question obtained during a clinic visit. Such information could support clinicians in identifying patients at risk for adverse cardiometabolic health. We investigated if children meeting physical activity or screen time recommendations, collected during clinic visits, have better cardiometabolic health than children not meeting recommendations. We hypothesized that children meeting either recommendation would have fewer cardiometabolic risk factors.

METHODS AND FINDINGS: This cross-sectional study used data from electronic medical records (EMRs) between January 1, 2013 through December 30, 2017 from children (2-18 years) with a well …

Nurturing Care Assets For Food Security: A Community Asset Mapping Approach, Gabriela Buccini, Kaelia Lynn Saniatan, Ana Poblacion, Ana Bauman, Cristina Hernandez, Cali Larrison, Dodds P Simangan, Jyoti Desai, Yvonne Owens Ferguson, Alisa Howard, Melva Thompson-Robinson

2020-Current year OA Pubs

BACKGROUND: Zip codes classified by the Food Insecurity Index with moderate and high food insecurity (FI) risk can be a threat to the health and well-being of children during the first 1,000 days (from pregnancy to 2 years). The presence of nurturing care assets (i.e., stable environments that promote health and nutrition, learning opportunities, security and safety, and responsive relationships) can contribute to supporting families and their communities, and ultimately reduce systemic barriers to food security. We aimed to identify and characterize nurturing care assets in under-resourced communities with moderate and high FI risk.

METHODS: Four steps were used to …

Effects Of Protein-Enriched Nutritional Support On Skeletal Muscle Mass And Rehabilitative Outcomes In Brain Tumor Patients: A Randomized Controlled Trial, Kye Hee Cho, Eun Young Han, Min Kyu Jung, Chang Moo Kang, Ji Cheol Shin, Sang Hee Im

Faculty, Staff and Student Publications

Patients with brain tumors require extensive and prolonged rehabilitation efforts as they suffer from lesion-induced motor weakness as well as treatment-related side effects, often leading to a significant decline in function. Protein supplements have shown positive effects on promoting muscle strength and physical performance in various tumor etiologies. However, reports on their effects specifically in brain tumor patients remain scarce. This study aims to investigate the feasibility and efficacy of protein supplements in enhancing rehabilitative outcomes via muscle strengthening and functional gain in brain tumor patients with neurological demise. Sixty brain tumor patients were randomly assigned to either a protein …

Clinical Practice Guidelines For The Care Of Girls And Women With Turner Syndrome, Claus H Gravholt, Niels H Andersen, Sophie Christin-Maitre, Shanlee M Davis, Anthonie Duijnhouwer, Aneta Gawlik, Andrea T Maciel-Guerra, Iris Gutmark-Little, Kathrin Fleischer, David Hong, Karen O Klein, Siddharth K Prakash, Roopa Kanakatti Shankar, David E Sandberg, Theo C J Sas, Anne Skakkebæk, Kirstine Stochholm, Janielle A Van Der Velden, International Turner Syndrome Consensus Group, Philippe F Backeljauw

Faculty, Staff and Student Publications

Turner syndrome (TS) affects 50 per 100 000 females. TS affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and United States culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: (1) diagnosis and genetics, (2) growth, (3) puberty and estrogen treatment, (4) cardiovascular health, (5) transition, (6) fertility assessment, monitoring, and counselling, (7) health …

Barriers To And Facilitators Of Paediatric Medical Device Innovation: A Scoping Review Protocol, Lynn Kysh, Grzegorz Zapotoczny, Lisa Manzanete, Megan Carey, Payal Shah, Francesca Joseph, Haley Kempf, Abu Taher Sikder, Julia Finkel, Usha Thekkedath, Kara Toman, Chester J Koh, Kolaleh Eskandanian, Juan Espinoza

Faculty, Staff and Students Publications

INTRODUCTION: The development of paediatric medical devices continues to lag adult medical devices and contributes to issues of inequity, safety, quality and patient outcomes. New legislation and funding mechanisms have been introduced over the past two decades, but the gap remains. Clinical trials have been identified as a pain point, but components of effective clinical research infrastructure are poorly understood. As part of a multimodal research strategy, the Pediatric Device Consortia (PDC) will conduct a scoping review to better understand infrastructural barriers to and facilitators of paediatric medical device clinical research identified in the health sciences literature.

METHODS AND ANALYSIS: …

Piga Mutations And Glycosylphosphatidylinositol Anchor Dysregulation In Polyposis-Associated Duodenal Tumorigenesis, Elena Meuser, Kyle Chang, Angharad Walters, Joanna J Hurley, Hannah D West, Iain Perry, Matthew Mort, Laura Reyes-Uribe, Rebekah Truscott, Nicholas Jones, Rachel Lawrence, Gareth Jenkins, Peter Giles, Sunil Dolwani, Bilal Al-Sarireh, Neil Hawkes, Emma Short, Geraint T Williams, Melissa W Taggart, Kim Luetchford, Patrick M Lynch, Diantha Terlouw, Maartje Nielsen, Sarah-Jane Walton, Andrew Latchford, Susan K Clark, Julian R Sampson, Eduardo Vilar, Laura E Thomas

Faculty, Staff and Student Publications

The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of …

Cyp3a Mediates An Unusual C(Sp2)-C(Sp3) Bond Cleavage Via Ipso-Addition Of Oxygen In Drug Metabolism, Xuan Qin, Yong Wang, Qiuji Ye, John M Hakenjos, Jin Wang, Mingxing Teng, Lei Guo, Zhi Tan, Damian W Young, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon–carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H218O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) …

Should An Npo Order Be Placed For My Patient With Acute Pancreatitis?, Aaron Pathak, Siena Blackwell, Robert Jay Sealock

Faculty, Staff and Students Publications

No abstract provided.

Irx4204 Induces Senescence And Cell Death In Her2-Positive Breast Cancer And Synergizes With Anti-Her2 Therapy, Cassandra L Moyer, Amanda Lanier, Jing Qian, Darian Coleman, Jamal Hill, Vidyasagar Vuligonda, Martin E Sanders, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action.

EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, …

Individuals With Jak1 Variants Are Affected By Syndromic Features Encompassing Autoimmunity, Atopy, Colitis, And Dermatitis, Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, …

An Atlas Characterizing The Shared Genetic Architecture Of Inflammatory Bowel Disease With Clinical And Behavioral Traits, Vikram R Shaw, Jinyoung Byun, Rowland W Pettit, Jason K Hou, Kyle M Walsh, Younghun Han, Christopher I Amos

Faculty, Staff and Students Publications

BACKGROUND: Inflammatory bowel disease (IBD) development is a complex, multifactorial process that involves extrinsic and intrinsic factors such as host genetics, the immune system, the gut microbiome, and environmental risks. To help understand the genetic contribution of clinical, behavioral, psychiatric, and diet-related traits, we aim to provide a deep and comprehensive characterization of the shared genetic architecture between IBD and hundreds of potentially related traits.

METHODS: Utilizing publicly available summary statistics from a previously published IBD genome-wide association study and hundreds of traits from the United Kingdom BioBank (UKBB), we performed linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait …

Event-Free Survival Of Maralixibat-Treated Patients With Alagille Syndrome Compared To A Real-World Cohort From Gala., Bettina E. Hansen, Shannon M. Vandriel, Pamela Vig, Will Garner, Douglas B. Mogul, Kathleen M. Loomes, David A. Piccoli, Elizabeth B. Rand, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzińska, Emmanuel M. Gonzales, Emmanuel Jacquemin, Jérôme Bouligand, Lorenzo D'Antiga, Emanuele Nicastro, Henrik Arnell, Björn Fischler, Étienne Sokal, Tanguy Demaret, Susan Siew, Michael Stormon, Saul J. Karpen, Rene Romero, Noelle H. Ebel, Jeffrey A. Feinstein, Amin J. Roberts, Helen M. Evans, Shikha S. Sundaram, Alexander Chaidez, Winita Hardikar, Sahana Shankar, Ryan T. Fischer, Florence Lacaille, Dominique Debray, Henry C. Lin, M Kyle Jensen, Catalina Jaramillo, Palaniswamy Karthikeyan, Giuseppe Indolfi, Henkjan J. Verkade, Catherine Larson-Nath, Ruben E. Quiros-Tejeira, Pamela L. Valentino, Maria Rogalidou, Antal Dezsőfi, James E. Squires, Kathleen Schwarz, Pier Luigi Calvo, Jesus Quintero Bernabeu, Andréanne N Zizzo, Gabriella Nebbia, Pinar Bulut, Ermelinda Santos-Silva, Rima Fawaz, Silvia Nastasio, Wikrom Karnsakul, María Legarda Tamara, Cristina Molera Busoms, Deirdre A. Kelly, Thomas Damgaard Sandahl, Carolina Jimenez-Rivera, Jesus M. Banales, Quais Mujawar, Li-Ting Li, Huiyu She, Jian-She Wang, Kyung Mo Kim, Seak Hee Oh, Maria Camila Sanchez, Maria Lorena Cavalieri, Way Seah Lee, Christina Hajinicolaou, Chatmanee Lertudomphonwanit, Orith Waisbourd-Zinman, Cigdem Arikan, Seema Alam, Elisa Carvalho, Melina Melere, John Eshun, Zerrin Önal, Dev M. Desai, Sabina Wiecek, Raquel Borges Pinto, Victorien M. Wolters, Jennifer Garcia, Marisa Beretta, Nanda Kerkar, Jernej Brecelj, Nathalie Rock, Eberhard Lurz, Niviann Blondet, Uzma Shah, Richard J. Thompson, Binita M. Kamath, Global Alagille Alliance (Gala) Study Group

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.

APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 …

Specific Gravity Improves Identification Of Clinically Significant Quantitative Proteinuria From The Dipstick Urinalysis, Meredith C Mcadams, L Parker Gregg, Pin Xu, Song Zhang, Michael Li, Ella Carroll, Vaishnavi Kannan, Duwayne L Willett, S Susan Hedayati

Faculty, Staff and Students Publications

KEY POINTS: Urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio are frequently obtained and represent possible tools for screening for proteinuria and thus early CKD. Adding specific gravity to dipstick proteinuria improves the ability to screen patients with clinically significant proteinuria and can be used to identify patients with early CKD.

BACKGROUND: CKD is often underdiagnosed during early stages when GFR is preserved because of underutilization of testing for quantitative urine albumin-to-creatinine ratio (UACR) or urine protein-to-creatinine ratio (UPCR). Semiquantitative dipstick proteinuria (DSP) on urinalysis is widely obtained but not accurate for identifying clinically significant proteinuria.

METHODS: We identified all patients …

Preparing Patients For Oral Immunotherapy (Ppoint): International Delphi Consensus For Procedural Preparation And Consent, Douglas P Mack, Timothy E Dribin, Paul J Turner, Richard L Wasserman, Mariam A Hanna, Marcus Shaker, Mimi L K Tang, Pablo Rodríguez Del Río, Brad Sobolewski, Elissa M Abrams, Aikaterini Anagnostou, Stefania Arasi, Sakina Bajowala, Philippe Bégin, Scott B Cameron, Edmond S Chan, Sharon Chinthrajah, Andrew T Clark, Paul Detjen, George Du Toit, Motohiro Ebisawa, Arnon Elizur, Jeffrey M Factor, Justin Greiwe, Jonathan O'B Hourihane, Sarah W Hughes, Douglas H Jones, Antonella Muraro, Anna Nowak-Wegrzyn, Nandinee B Patel, Amy M Scurlock, Atul N Shah, Sayantani B Sindher, Stephen Tilles, Brian P Vickery, Julie Wang, Hugh H Windom, Matthew Greenhawt

Faculty, Staff and Students Publications

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process.

OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form.

METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was …

Impact Of Insomnia On Ovarian Cancer Risk And Survival: A Mendelian Randomization Study., Heming Wang, Brett M. Reid, Rebecca C. Richmond, Jacqueline M. Lane, Richa Saxena, Brian D. Gonzalez, Brooke L. Fridley, Susan Redline, Shelley S. Tworoger, Xuefeng Wang

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study.

METHODS: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations …