Digital Commons Network^™

Trust Criteria For Artificial Intelligence In Health: Normative And Epistemic Considerations, Kristin Kostick-Quenet, Benjamin H Lang, Jared Smith, Meghan Hurley, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

Rapid advancements in artificial intelligence and machine learning (AI/ML) in healthcare raise pressing questions about how much users should trust AI/ML systems, particularly for high stakes clinical decision-making. Ensuring that user trust is properly calibrated to a tool's computational capacities and limitations has both practical and ethical implications, given that overtrust or undertrust can influence over-reliance or under-reliance on algorithmic tools, with significant implications for patient safety and health outcomes. It is, thus, important to better understand how variability in trust criteria across stakeholders, settings, tools and use cases may influence approaches to using AI/ML tools in real settings. As …

First-In-Human Dose Escalation Trial To Evaluate The Clinical Safety And Efficacy Of An Anti-Magea1 Autologous Tcr-Transgenic T Cell Therapy In Relapsed And Refractory Solid Tumors, Martin Wermke, Tobias A W Holderried, Jason John Luke, Van K Morris, Winfried H Alsdorf, Katrin Wetzko, Borje S Andersson, Ignacio I Wistuba, Edwin R Parra, Mohammad B Hossain, Sandra Grund-Gröschke, Katrin Aslan, Arun Satelli, Anantha Marisetty, Swapna Satam, Mamta Kalra, Jens Hukelmann, M Alper Kursunel, Karine Pozo, Andreas Acs, Linus Backert, Melissa Baumeister, Sebastian Bunk, Claudia Wagner, Oliver Schoor, Ali S Mohamed, Andrea Mayer-Mokler, Norbert Hilf, Delfi Krishna, Steffen Walter, Apostolia M Tsimberidou, Cedrik M Britten

Faculty, Staff and Student Publications

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.

TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of …

Association Between Diabetes Mellitus And Total Hip Arthroplasty Outcomes: An Observational Study Using The Us National Inpatient Sample, Sumanth Chandrupatla, Kranti Rumalla, Jasvinder A Singh

Faculty, Staff and Students Publications

OBJECTIVES: To investigate the association of diabetes with postoperative outcomes in patients undergoing primary total hip arthroplasty (THA).

DESIGN: Retrospective cohort study using data from the US National Inpatient Sample (NIS).

SETTING: Study cohort was hospitalisations for primary THA in the USA, identified from the 2016-2020 NIS.

PARTICIPANTS: We identified 2 467 215 adults in the 2016-2020 NIS who underwent primary THA using International Classification of Diseases, 10th Revision codes. Primary THA hospitlizations were analysed as the overall group and also stratified by the underlying primary diagnosis for THA.

OUTCOME MEASURES: Outcome measures of interest were the length of hospital …

A Randomized Controlled Trial Testing The Effects Of A Social Needs Navigation Intervention On Health Outcomes And Healthcare Utilization Among Medicaid Members With Type 2 Diabetes, Amy Mcqueen, David Von Nordheim, Charlene Caburnay, Linda Li, Cynthia Herrick, Lauren Grimes, Darrell Broussard, Rachel E Smith, Dana Lawson, Yan Yan, Matthew Kreuter

2020-Current year OA Pubs

Health systems are increasingly assessing and addressing social needs with referrals to community resources. The objective of this randomized controlled trial was to randomize adult Medicaid members with type 2 diabetes to receive usual care (

Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, And Cardiovascular Disease Risk In Us Hispanics And Latinos: Results From Hchs/Sol, Yi Wang, Guo-Chong Chen, Zheng Wang, Kai Luo, Yanbo Zhang, Yang Li, Amanda C Mcclain, Marta M Jankowska, Krista M Perreira, Josiemer Mattei, Carmen R Isasi, Maria M Llabre, Bharat Thyagarajan, Martha L Daviglus, Linda Van Horn, David Goldsztajn Farelo, Luis E Maldonado, Steven R Levine, Bing Yu, Eric Boerwinkle, Rob Knight, Robert D Burk, Robert C Kaplan, Qibin Qi, Brandilyn A Peters

Faculty, Staff and Student Publications

Background: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults.

Methods: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US …

Intratumoral Microbiome Of Adenoid Cystic Carcinomas And Comparison With Other Head And Neck Cancers, Tatiana V Karpinets, Yoshitsugu Mitani, Chia-Chi Chang, Xiaogang Wu, Xingzhi Song, Ivonne I Flores, Lauren K Mcdaniel, Yasmine M Hoballah, Fabiana J Veguilla, Renata Ferrarotto, Lauren E Colbert, Nadim J Ajami, Robert R Jenq, Jianhua Zhang, Andrew P Futreal, Adel K El-Naggar

Faculty, Staff and Student Publications

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the …

27-Hydroxycholesterol Acts On Estrogen Receptor Α Expressed By Pomc Neurons In The Arcuate Nucleus To Modulate Feeding Behavior, Hui Ye, Xiaohua Yang, Bing Feng, Pei Luo, Valeria C Torres Irizarry, Leslie Carrillo-Sáenz, Meng Yu, Yongjie Yang, Benjamin P Eappen, Marcos David Munoz, Nirali Patel, Sarah Schaul, Lucas Ibrahimi, Penghua Lai, Xinyue Qi, Yuliang Zhou, Maya Kota, Devin Dixit, Madeline Mun, Chong Wee Liew, Yuwei Jiang, Chunmei Wang, Yanlin He, Pingwen Xu

Faculty, Staff and Students Publications

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of …

Community-Based Participatory Obesity Prevention Interventions In Rural Communities: A Scoping Review, Saagar Dhanjani, Haley Allen, Beatriz Varman, Chishinga Callender, Jayna M Dave, Debbe Thompson

Library Staff Publications

Child obesity is a worldwide public health concern. In America, children from rural areas have greater odds of obesity in comparison to those from urban areas. Community-engaged research is important for all communities, particularly under-represented communities. This paper reports the results of a scoping review investigating community-engaged research in obesity prevention programs tested with school-aged children in rural America. A literature search of Medline Ovid was conducted to identify interventions reporting the results of obesity prevention interventions that promoted a healthy diet or physical activity (PA) behaviors to school-age children in rural communities of the United States (US). After title …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Phase Ib Study Of Unesbulin (Ptc596) Plus Dacarbazine For The Treatment Of Locally Recurrent, Unresectable Or Metastatic, Relapsed Or Refractory Leiomyosarcoma, Brian A Van Tine, Matthew A Ingham, Steven Attia, Christian F Meyer, John D Baird, Esther Brooks-Asplund, Dhiren D'Silva, Ronald Kong, Anthony Mwatha, Kylie O'Keefe, Marla Weetall, Robert Spiegel, Gary K Schwartz

2020-Current year OA Pubs

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS).

PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m

RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m

CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m

Tfeb Safeguards Trophoblast Syncytialization In Humans And Mice, Wanshan Zheng, Yue Zhang, Peiqun Xu, Zexin Wang, Xuan Shao, Chunyan Chen, Han Cai, Yinan Wang, Ming-An Sun, Wenbo Deng, Fan Liu, Jinhua Lu, Xueqin Zhang, Dunjin Cheng, Indira U Mysorekar, Haibin Wang, Yan-Ling Wang, Xiaoqian Hu, Bin Cao

Faculty, Staff and Students Publications

The formation of multinucleated syncytiotrophoblast (STB) through cell fusion of cytotrophoblast, also termed syncytialization, ensures the proper placental structure and functions. Nutrient insufficiency and inactivation of the mechanistic target of rapamycin complex 1 (mTORC1) in trophoblasts have been shown to enhance STB formation; however, the underlying mechanism remains elusive. Here, we showed that the deficiency of a mTORC1 downstream transcriptional factor, TFEB, significantly impaired STB formation in human trophoblasts and knock-out mice. TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 and thereby promoted trophoblast syncytialization. Additionally, TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth …

Broadcasters, Receivers, Functional Groups Of Metabolites, And The Link To Heart Failure By Revealing Metabolomic Network Connectivity, Azam Yazdani, Raul Mendez-Giraldez, Akram Yazdani, Rui-Sheng Wang, Daniel J Schaid, Sek Won Kong, M Reza Hadi, Ahmad Samiei, Esmat Samiei, Clemens Wittenbecher, Jessica Lasky-Su, Clary B Clish, Jochen D Muehlschlegel, Francesco Marotta, Joseph Loscalzo, Samia Mora, Daniel I Chasman, Martin G Larson, Sarah H Elsea

Faculty, Staff and Students Publications

Background and objective: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.

Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. …

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Urban-Rural Disparities In Food Insecurity And Weight Status Among Children In The United States, Jayna M Dave, Tzuan A Chen, Alexandra N Castro, Mamie A White, Elizabeth A Onugha, Sloane Zimmerman, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

Place of residence (urban versus rural) is a contextual determinant of health that has received less attention in the food insecurity literature. The purpose of this study was to assess the urban–rural disparity in the prevalence of food insecurity and weight status among US children. Using data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 with three age groups of children (2–5, 6–11, and 12–17 years old), the associations of weight status and child and household food security status by urban–rural residence were examined using Rao–Scott Chi-square tests. Statistical significance was set at p < 0.05. Children living in urban areas were significantly more likely to experience household food insecurity (29.15%) compared to their rural counterparts (19.10%), among those aged 6–11 years. The associations between children’s weight status and child and household food security status were significant for children living in urban areas overall and different age groups but not for children living in rural areas. These trends were more pronounced in older age groups. Given the link between food insecurity and higher obesity rates, particularly among urban children, this study highlights the importance of incorporating food security interventions into future obesity prevention programs.

Predicting Nutrition And Environmental Factors Associated With Female Reproductive Disorders Using A Knowledge Graph And Random Forests., Lauren E Chan, Elena Casiraghi, Justin Reese, Quaker E Harmon, Kevin Schaper, Harshad Hegde, Giorgio Valentini, Charles Schmitt, Alison Motsinger-Reif, Janet E Hall, Christopher J Mungall, Peter N Robinson, Melissa A Haendel

Faculty Research 2024

OBJECTIVE: Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (for example, endometriosis, ovarian cyst, and uterine fibroids).

MATERIALS AND METHODS: We harmonized survey data from the Personalized Environment and Genes Study (PEGS) on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and …

Efficacy And Safety Of Odevixibat In Patients With Alagille Syndrome (Assert): A Phase 3, Double-Blind, Randomised, Placebo-Controlled Trial., Nadia Ovchinsky, Madeleine Aumar, Alastair Baker, Ulrich Baumann, Philip Bufler, Mara Cananzi, Piotr Czubkowski, Özlem Durmaz, Ryan T. Fischer, Giuseppe Indolfi, Wikrom W. Karnsakul, Florence Lacaille, Way S. Lee, Giuseppe Maggiore, Philip Rosenthal, Mathias Ruiz, Etienne Sokal, Ekkehard Sturm, Wendy Van Der Woerd, Henkjan J. Verkade, Andrew Wehrman, Christine Clemson, Qifeng Yu, Quanhong Ni, Jessica Ruvido, Susan Manganaro, Jan P. Mattsson

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome.

METHODS: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and …

Juvenile Polyposis Syndrome In Children: The Impact Of Smad4 And Bmpr1a Mutations On Clinical Phenotype And Polyp Burden., Shlomi Cohen, Anat Yerushalmy-Feler, Isabel Rojas, Claudia Phen, David A. Rudnick, Colleen B. Flahive, Steven H. Erdman, Ramit Magen-Rimon, Ivana Copova, Thomas M. Attard, Andrew Latchford, Warren Hyer

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: A constitutional disease-causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%-60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV-positive JPS compared to DCV-negative JPS.

METHODS: Demographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group.

RESULTS: A total of 124 children with JPS were included: 69 (56%) DCV-negative and 55 (44%) DCV-positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range) follow-up of 4 (2.8-6.4) …

Preeclampsia, Fetal Growth Restriction, And 24-Month Neurodevelopment In Very Preterm Infants., Jennifer Check, Coral Shuster, Julie Hofheimer, Marie Camerota, Lynne M. Dansereau, Lynne M. Smith, Brian S. Carter, Sheri A. Dellagrotta, Jennifer Helderman, Howard Kilbride, Cynthia M. Loncar, Elisabeth Mcgowan, Charles R. Neal, T Michael O'Shea, Steven L. Pastyrnak, Stephen J. Sheinkopf, Barry M. Lester

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized.

OBJECTIVE: To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care …

Psychotropic Medication Usage In Pediatric Ckd: Reporting From The Ckd In Children Cohort., Ryan C. Ward, Amy J. Kogon, Matthew B. Matheson, Anne Dawson, Stephen R. Hooper, Stephen Molitor, Cynthia Wong, Susan L. Furth, Bradley A. Warady, Lyndsay A. Harshman

Manuscripts, Articles, Book Chapters and Other Papers

Background: Mental health disorders within the pediatric CKD population are prevalent. The frequency is unknown with which psychotropic medications that commonly treat these conditions are used in this population.

Methods: Data from the CKD in Children (CKiD) cohort study were used to describe the use of psychotropic medications and patient-related characteristics of use. Medications were classified into three groups: antidepressants, central nervous system (CNS) stimulants, and antipsychotic/mood stabilizing medications. Participant age, sex, CKD severity, and duration of medication use were ascertained. Medication use was evaluated in parallel with CKD disease type, presence of urological comorbidity, and hypertension. Chi-square tests compared …

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, …

Liver Disease And Transplantation In Telomere Biology Disorders: An International Multicenter Cohort, Yunzu Michele Wang, Steven K Brennan, Sakil Kulkarni, Et Al.

2020-Current year OA Pubs

BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes.

METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study.

RESULTS: Group A ("Advanced") included 40 patients with advanced liver disease. Of …

Association Of Candidate Single-Nucleotide Polymorphism Genotypes With Plasma And Skin Carotenoid Concentrations In Adults Provided A Lycopene-Rich Juice, Anna C Norman, Daniel G Palmer, Nancy E Moran, James N Roemmich, Shanon L Casperson

Children’s Nutrition Research Center Staff Publications

Background: Carotenoids are fat-soluble phytochemicals with biological roles, including ultraviolet protective functions in skin. Spectroscopic skin carotenoid measurements can also serve as a noninvasive biomarker for carotenoid consumption. Single-nucleotide polymorphisms (SNPs) in metabolic genes are associated with human plasma carotenoid concentrations; however, their relationships with skin carotenoid concentrations are unknown.

Objectives: The objective of this study was to determine the relationship between 13 candidate SNPs with skin and plasma carotenoid concentrations before and after a carotenoid-rich tomato juice intervention.

Methods: In this randomized, controlled trial, participants (n = 80) were provided with lycopene-rich vegetable juice providing low (13.1 mg), medium …

Understanding The Genetic Complexity Of Puberty Timing Across The Allele Frequency Spectrum, Katherine A Kentistou, Lena R Kaisinger, Stasa Stankovic, Marc Vaudel, Edson Mendes De Oliveira, Andrea Messina, Robin G Walters, Xiaoxi Liu, Alexander S Busch, Hannes Helgason, Deborah J Thompson, Federico Santoni, Konstantin M Petricek, Yassine Zouaghi, Isabel Huang-Doran, Daniel F Gudbjartsson, Eirik Bratland, Kuang Lin, Eugene J Gardner, Yajie Zhao, Raina Y Jia, Chikashi Terao, Marjorie J Riggan, Manjeet K Bolla, Mojgan Yazdanpanah, Nahid Yazdanpanah, Jonathan P Bradfield, Linda Broer, Archie Campbell, Daniel I Chasman, Diana L Cousminer, Nora Franceschini, Lude H Franke, Giorgia Girotto, Chunyan He, Marjo-Riitta Järvelin, Peter K Joshi, Yoichiro Kamatani, Robert Karlsson, Jian'an Luan, Kathryn L Lunetta, Reedik Mägi, Massimo Mangino, Sarah E Medland, Christa Meisinger, Raymond Noordam, Teresa Nutile, Maria Pina Concas, Ozren Polašek, Eleonora Porcu, Susan M Ring, Cinzia Sala, Albert V Smith, Toshiko Tanaka, Peter J Van Der Most, Veronique Vitart, Carol A Wang, Gonneke Willemsen, Marek Zygmunt, Thomas U Ahearn, Irene L Andrulis, Hoda Anton-Culver, Antonis C Antoniou, Paul L Auer, Catriona L K Barnes, Matthias W Beckmann, Amy Berrington De Gonzalez, Natalia V Bogdanova, Stig E Bojesen, Hermann Brenner, Julie E Buring, Federico Canzian, Jenny Chang-Claude, Fergus J Couch, Angela Cox, Laura Crisponi, Kamila Czene, Mary B Daly, Ellen W Demerath, Joe Dennis, Peter Devilee, Immaculata De Vivo, Thilo Dörk, Alison M Dunning, Miriam Dwek, Johan G Eriksson, Peter A Fasching, Lindsay Fernandez-Rhodes, Liana Ferreli, Olivia Fletcher, Manuela Gago-Dominguez, Montserrat García-Closas, José A García-Sáenz, Anna González-Neira, Harald Grallert, Pascal Guénel, Christopher A Haiman, Per Hall, Ute Hamann, Hakon Hakonarson, Roger J Hart, Martha Hickey, Maartje J Hooning, Reiner Hoppe, John L Hopper, Jouke-Jan Hottenga, Frank B Hu, Hanna Huebner, David J Hunter, Helena Jernström, Esther M John, David Karasik, Elza K Khusnutdinova, Vessela N Kristensen, James V Lacey, Diether Lambrechts, Lenore J Launer, Penelope A Lind, Annika Lindblom, Patrik K E Magnusson, Arto Mannermaa, Mark I Mccarthy, Thomas Meitinger, Cristina Menni, Kyriaki Michailidou, Iona Y Millwood, Roger L Milne, Grant W Montgomery, Heli Nevanlinna, Ilja M Nolte, Dale R Nyholt, Nadia Obi, Katie M O'Brien, Kenneth Offit, Albertine J Oldehinkel, Sisse R Ostrowski, Aarno Palotie, Ole B Pedersen, Annette Peters, Giulia Pianigiani, Dijana Plaseska-Karanfilska, Anneli Pouta, Alfred Pozarickij, Paolo Radice, Gad Rennert, Frits R Rosendaal, Daniela Ruggiero, Emmanouil Saloustros, Dale P Sandler, Sabine Schipf, Carsten O Schmidt, Marjanka K Schmidt, Kerrin Small, Beatrice Spedicati, Meir Stampfer, Jennifer Stone, Rulla M Tamimi, Lauren R Teras, Emmi Tikkanen, Constance Turman, Celine M Vachon, Qin Wang, Robert Winqvist, Alicja Wolk, Babette S Zemel, Wei Zheng, Ko W Van Dijk, Behrooz Z Alizadeh, Stefania Bandinelli, Eric Boerwinkle, Dorret I Boomsma, Marina Ciullo, Georgia Chenevix-Trench, Francesco Cucca, Tõnu Esko, Christian Gieger, Struan F A Grant, Vilmundur Gudnason, Caroline Hayward, Ivana Kolčić, Peter Kraft, Deborah A Lawlor, Nicholas G Martin, Ellen A Nøhr, Nancy L Pedersen, Craig E Pennell, Paul M Ridker, Antonietta Robino, Harold Snieder, Ulla Sovio, Tim D Spector, Doris Stöckl, Cathie Sudlow, Nic J Timpson, Daniela Toniolo, André Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J Wareham, Elisabeth Widen, James F Wilson, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Paul D P Pharoah, Liming Li, Douglas F Easton, Pål R Njølstad, Patrick Sulem, Joanne M Murabito, Anna Murray, Despoina Manousaki, Anders Juul, Christian Erikstrup, Kari Stefansson, Momoko Horikoshi, Zhengming Chen, I Sadaf Farooqi, Nelly Pitteloud, Stefan Johansson, Felix R Day, John R B Perry, Ken K Ong

Faculty, Staff and Student Publications

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, …

Genetic Correlations Between Liver Fat Content, Metabolic Health, And Adiposity Distribution In The Fels Longitudinal Study, Ariana L Garza, Miryoung Lee, John Blangero, Cici X Bauer, Stefan A Czerwinski, Audrey C Choh

Faculty, Staff and Student Publications

Background and aims: Hepatic steatosis is known to be heritable, but its genetic basis is mostly uncharacterized. Steatosis is associated with metabolic and adiposity features; recent studies hypothesize that shared genetic effects between these traits could account for some of the unexplained heritability. This study aimed to quantify these genetic associations in a family-based sample of non-Hispanic white adults.

Methods and results: 704 participants (18-95 years, 55.8% female) from the Fels Longitudinal Study with an MRI assessment of liver fat were included. Quantitative genetic analyses estimated the age- and sex-adjusted heritability of individual traits and the genetic correlations within trait …

Association Between Participation And Satisfaction With Life Over Time In Older Adults With Traumatic Brain Injury: A Tbi Model Systems Study, Zinat Taiwo, Angelle M Sander, Shannon B Juengst, Xiangyi Liu, Luis Leon Novelo, Flora M Hammond, Therese M O'Neil-Pirozzi, Paul B Perrin, Nicholas Gut

Faculty, Staff and Student Publications

Objective: To examine the association between participation and satisfaction with life at 1, 2, 5, and 10 years after traumatic brain injury (TBI) in older adults.

Setting: Community.

Participants: Participants ( N = 2362) who sustained complicated mild to severe TBI, requiring inpatient rehabilitation, at age 60 years or older and had follow-up data on participation and satisfaction with life for at least 1 follow-up time point across 1, 2, 5, and 10 years. Age at each time period was categorized as 60 to 64 years, 65 to 75 years, and 75 years or older.

Design: Secondary data analysis of …

The Time-Dependent Association Between Irritable Bowel Syndrome And All-Cause And Cause-Specific Mortality: A Prospective Cohort Study Within The Uk Biobank, Fangyu Li, Yukiko Yano, Lola Étiévant, Carrie R Daniel, Shreela V Sharma, Eric L Brown, Ruosha Li, Erikka Loftfield, Qing Lan, Rashmi Sinha, Baharak Moshiree, Maki Inoue-Choi, Emily Vogtmann

Faculty, Staff and Student Publications

Introduction: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, but few studies have evaluated mortality risks among individuals with IBS. We explored the association between IBS and all-cause and cause-specific mortality in the UK Biobank.

Methods: We included 502,369 participants from the UK Biobank with mortality data through 2022. IBS was defined using baseline self-report and linkage to primary care or hospital admission data. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality using multivariable Cox proportional hazards regression models within partitioned follow-up time categories (0-5, >5-10, and >10 …

Response-Adapted Ultra-Low-Dose 4 Gy Radiation As Definitive Therapy Of Gastric Malt Lymphoma: A Single-Centre, Pilot Trial, Jillian R Gunther, Jie Xu, Manoop S Bhutani, Paolo Strati, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Wenli Dong, Priya R Bhosale, Christopher R Flowers, Ranjit Nair, Luis Malpica Castillo, Luis Fayad, Swaminathan P Iyer, Simrit Parmer, Michael Wang, Hun Ju Lee, Felipe Samaniego, Jason Westin, Sairah Ahmed, Chijioke C Nze, Preetesh Jain, Sattva S Neelapu, Maria A Rodriguez, Dai Chihara, Loretta J Nastoupil, Chelsea C Pinnix

Faculty, Staff and Student Publications

Background: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach.

Methods: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Long-Term Weight Loss Effects Of Semaglutide In Obesity Without Diabetes In The Select Trial, Donna H Ryan, Ildiko Lingvay, John Deanfield, Steven E Kahn, Eric Barros, Bartolome Burguera, Helen M Colhoun, Cintia Cercato, Dror Dicker, Deborah B Horn, G Kees Hovingh, Ole Kleist Jeppesen, Alexander Kokkinos, A Michael Lincoff, Sebastian M Meyhöfer, Tugce Kalayci Oral, Jorge Plutzky, André P Van Beek, John P H Wilding, Robert F Kushner

Faculty, Staff and Student Publications

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (

Progressive Thrombocytopenia, Splenomegaly, And Abnormal Tone In An Infant With Growth Faltering, Gal Barak, Gail Demmler-Harrison, Linda Rossetti, Venée N Tubman, Ameya S Walimbe, Rathi Asaithambi

Faculty, Staff and Students Publications

A 4-month-old full-term female presented with growth faltering associated with progressive feeding difficulty, rash, abdominal distension, and developmental delays. She was found to have disconjugate gaze, abnormal visual tracking, mixed tone, bruising, and splenomegaly on examination. Initial workup was notable for thrombocytopenia and positive cytomegalovirus (CMV) immunoglobulin G and immunoglobulin M antibodies. She initially presented to the infectious diseases CMV clinic, where she was noted to have severe malnutrition, prompting referral to the emergency department for hospital admission to optimize nutrition with nasogastric tube feeding and facilitate additional evaluation. An active CMV infection with viruria and viremia was confirmed, but …