Medical Sciences Commons^™

Ethical Controversies In Organ Procurement: A National Survey On Public Perceptions Of Thoracoabdominal Normothermic Regional Perfusion, Trevor M Bibler, Jill Oliver Robinson, Adam Omelianchuk, Tariq Nisar, Savitri Fedson, Ariel N Levchenko, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Thoracoabdominal normothermic regional perfusion (TA-NRP) would likely expand the quantity and quality of organs procured after controlled circulatory death donation in the United States, yet its ethical permissibility remains contested. We surveyed a representative sample of US adults (n = 975) with the goal of assessing their perspectives on the ethical permissibility of TA-NRP. After reading a neutral description of TA-NRP, participants judged its permissibility, reviewed 5 critic and 5 supporter arguments (in random order), and chose which argument they found most convincing. Multivariable logistic regression examined predictors of agreeing with critics. Before exposure to the arguments, 51.5% stated that …

Post-Dobbs Realities: Ethical Imperatives For Data Transparency And Trust In Maternal Health Care, Faith E Fletcher, Sophie L Schott, Kelley Akhiemokhali, Kari White

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

Designing Inclusive Newborn Sequencing Research: Insights From Parents In Underrepresented Communities, Maya C Del Rosario, Sheyenne A Walmsley, Barbara W Harrison, Crystal T Stephens, Bethany Zettler, Greysha Rivera-Cruz, Priyal Agrawal, Amy Brower, Stephanie Chigbu, Kurt D Christensen, Casie A Genetti, Richetta Givens, Nina B Gold, Inez V Reeves, Isabella Schichter, Habib Shariat, Sandra Simon, Hadley Stevens Smith, Melissa Uveges, Robert C Green, Ingrid A Holm, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Background: It is essential that studies of genomic sequencing (GS) in newborns and children include individuals from under-represented racial and ethnic groups (URG) to ensure future applications are equitably implemented. We conducted interviews with parents from URG to better understand their perspectives on GS research, develop strategies to reduce barriers to enrollment, and facilitate research participation.

Methods: Semi-structured interviews with 50 parents from URG.

Results: Nearly all parents said they would be interested in participating in an infant GS study. Parents were interested in participating in GS research for reasons including clinical utility, personal utility, and/or family health benefits. Deterrents …

Stakeholder Perspectives On Humanistic Implementation Of Computer Perception In Health Care: Qualitative Study, Kristin M Kostick-Quenet, Meghan E Hurley, Syed Ayaz, John D Herrington, Casey J Zampella, Julia Parish-Morris, Birkan Tunç, Gabriel Lázaro-Muñoz, Jennifer Blumenthal-Barby, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Background: Computer perception (CP) technologies-including digital phenotyping, affective computing, and related passive sensing approaches-offer unprecedented opportunities to personalize health care, especially mental health care, yet they also provoke concerns about privacy, bias, and the erosion of empathic, relationship-centered practice. At present, it remains elusive what stakeholders who design, deploy, and experience these tools in real-world settings perceive as the risks and benefits of CP technologies.

Objective: This study aims to explore key stakeholder perspectives on the potential benefits, risks, and concerns associated with integrating CP technologies into patient care. A better understanding of these concerns is crucial for responding to …

Reported Safety Practices Of Publicly Advertised Psychedelic Retreats, Amy L Mcguire, Logan Neitzke-Spruill, Jill O Robinson, Caroline S Beit, Nikita Singh, David S Mathai, Lynnette A Averill

Center for Medical Ethics and Health Policy Staff Publications

Importance: The availability of psychedelic retreats has grown to meet the demand for access to these substances. Despite centuries of use among Indigenous communities, psychedelics can pose serious risks for some users.

Objective: To determine safety precautions that retreat organizations that offer psychedelic substances currently use.

Design, setting, and participants: This qualitative study included structured interviews conducted by phone or email with representatives from 49 organizations publicly advertising psychedelic retreat offerings from July to October 2023. Organizations were eligible if they marketed their services in English, offered at least 1 psychedelic substance, and made contact information available online. Organizations were …

Putting The L In Elsi: Legal Methods For Bioethics Research, Anya E R Prince, Benjamin Berkman, Donald Ford, Dov Fox, Christi Guerrini, Amy Koopmann, Natalie Ram, Jessica L Roberts, Kayte Spector-Bagdady, Sonia Suter

Center for Medical Ethics and Health Policy Staff Publications

Lawyers and law professors are increasingly involved in interdisciplinary scientific teams and grant research to answer ethical, legal and policy questions related to biomedical topics. Yet, the methods that lawyers use to conduct legal research and analysis are not always familiar to scientists and social scientists conducting peer review of a proposed project with legal aims or a publication reporting a legal study. To better facilitate interdisciplinary ethical, legal, and social implications collaboration, there is a need to better explain how legal research methodologies can provide robust tools to address a range of nuanced biomedical questions. This paper explores …

Anything But Endo: Diagnostic Buck-Passing In Endometriosis Diagnosis, Rita Dexter, Megan Kitts, Heather Welty, Melanie Jeske

Center for Medical Ethics and Health Policy Staff Publications

People living with endometriosis, a disease in which tissue similar to the lining of the uterus grows elsewhere in the body, often experience prolonged diagnostic journeys because of symptom variability, normalisation of period pain and other symptoms, and lack of awareness of the condition. In this article, we analyse the endometriosis diagnostic journey through the lens of epistemic injustice. Drawing on in-depth interviews with 52 people living with endometriosis in the United States, we introduce the concept of diagnostic buck-passing to characterise the phenomenon wherein individuals who seek treatment for their symptoms end up stuck in a cycle of seeing …

A Narrative Review Of Dual Loyalty Conflicts In Custodial Settings And Implications For Community Practice, Michelle Suh, Marc David Robinson, Holland Kaplan

Center for Medical Ethics and Health Policy Staff Publications

Dual loyalty dilemmas are conflicts between health care professionals' obligations toward their patients and third-party interests. These conflicts are more common and starker in custodial settings, such as jails and prisons, military detention facilities, immigration detention centers, and involuntary psychiatric institutions. Despite encountering patients in custody, health care professionals (HCPs) in community settings have limited knowledge and training. In this narrative review, we examined dual loyalty conflicts faced by HCPs working in custodial settings and then applied the identified themes to community-based hospitals where HCPs care for patients in custody. We searched databases for original papers relating to patients in …

Survey Of U.S. Reproductive Medicine Clinicians’ Attitudes On Polygenic Embryo Screening, Rémy A Furrer, Dorit Barlevy, Aayushi Gandhi, Shai Carmi, Todd Lencz, Stacey Pereira, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Polygenic embryo screening (PES) is used to screen embryos for their genetic likelihood of developing complex conditions and traits. We surveyed 152 U.S. reproductive endocrinology and infertility specialists (REIs) on their views of PES. While most respondents (97%) were at least slightly familiar with PES, general approval of PES was low (12%), with the majority expressing disapproval (46%) or uncertainty (42%). A majority (58%) believed risks outweigh benefits, while only 16% felt benefits outweigh risks. Most clinicians (85-77%) were very or extremely concerned about low accuracy, confusion over results, false expectations, and eugenics. Nonetheless, when asked to vote on whether …

A Historical Cohort Comparison After Inpatient Admission For Adolescents With Anorexia Nervosa: Feasibility Of Virtual Group Therapy, Elizabeth V Franklin, Margaret Mathias, Rachel Wolfe, Duc T Nguyen, Drusilla M Rosales, Sofia Pedroza, Albert C Hergenroeder, Constance M Wiemann

Center for Medical Ethics and Health Policy Staff Publications

Objective: Access to follow-up care after a medical admission for adolescents with anorexia nervosa (AN) is important; yet access can be delayed or unavailable. This study assessed the feasibility and acceptability of a supplemental virtual 8-week outpatient group therapy program following inpatient care. A secondary aim explored the outpatient program's impact on self-reported anxiety, disordered eating, and depression symptoms, and readmission rates.

Method: A retrospective chart review study compared 68 adolescents (aged 11-18) with AN enrolled in an 8-week group therapy program (Recovery and Prevention Program [RAPP]) to 64 adolescents who were not enrolled in RAPP (historical cohort). "RAPP completers" …

Real-World Use Of Classic And Non-Classic Psychedelics In Hispanic/Latino Adults With Obsessive-Compulsive Disorder: International Findings From The Latino Study, David S Mathai, Jill O Robinson, Kevin Wagner, Logan Neitzke-Spruill, Dayan Berrones, Jacey L Anderberg, Renee M Frederick, Vanessa Zavala Cruz, Josselyn S Muñoz, Latin American Trans-Ancestry Initiative For Ocd Genomics, Brazilian Obsessive-Compulsive Spectrum Disorder Working Group;, Carolyn I Rodriguez, Lynnette A Averill, James J Crowley, Eric A Storch, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Objective: Despite growing research on the potential mental health benefits of psychedelics, there has been limited study of these drugs in populations with obsessive-compulsive disorder (OCD) and with Hispanic and Latin American (H/L) ancestry.

Methods: Demographic and clinical assessments were conducted as part of the Latin American Trans-ancestry Initiative for OCD genomics (LATINO) Study in H/L participants with OCD living throughout the Americas. Self-reported data on the prevalence of naturalistic psychedelic use and associated outcomes on OCD symptoms were collected in a subsample of 2,639 adults. Descriptive statistics and regression analyses were used to assess psychedelic use, predictors of use, …

A Qualitative Exploration Of Child, Caregiver, And Clinician Perspectives On Mental Health In Children With Osteogenesis Imperfecta, Justin H Qian, Andrew D Wiese, Clarissa Gonzalez, Whitney S Shepherd, Hannah Cho, Gianna M Colombo, Julia M Morales, Selena Guo, Kristin M Kostick-Quenet, Dianne Nguyen, Sophie C Schneider, Kara Ayers, Members Of The Bbdc, Marie-Eve Robinson, Chaya N Murali, Brendan Lee, V Reid Sutton, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Osteogenesis imperfecta (OI) is a heritable connective disorder with clinical manifestations including bone fragility and short stature. Previous research identified psychosocial themes related to mental health among children with OI and their caregivers, such as independence, social isolation, depression, and anxiety. Several studies have also examined clinicians of individuals with OI for their perspectives on mental health among their patients. However, no known studies have compared psychosocial themes among all three participant groups concurrently. This qualitative study examined mood and anxiety, along with risk and protective factors, from perspectives of youths, parents, and clinicians. Semi-structured interviews were conducted, which were …

Governance Of Polygenic Embryo Screening: A Qualitative Study On The Perspectives Of Clinicians And Patients, Jason Bach, Jonathan Frumovitz, Dorit Barlevy, Rémy A Furrer, Abigail Martinez, Ana Battaglino, Shai Carmi, Todd Lencz, Gabriel Lázaro-Muñoz, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Objective: To investigate the perspectives of stakeholders on their attitudes toward potential regulation of polygenic embryo screening (PES), a new form of preimplantation genetic testing that is used to screen embryos for the genetic chances of developing medical conditions and nonmedical traits involving hundreds or thousands of genes.

Design: We conducted individual, semistructured interviews and analyzed transcripts using thematic analysis.

Subjects: Twenty-seven US-based reproductive endocrinology and infertility specialists and 26 patients who were currently undergoing in vitro fertilization or had within the past five years.

Main outcome measures: Repeating ideas and patterned responses were organized into themes and subthemes.

Results: …

Factors Associated With Adolescents' Self-Efficacy To Meet With Their Health Care Provider Alone, Albert C Hergenroeder, Blanca Sanchez-Fournier, Cassandra Enzler, Mary Majumder, Beth H Garland, Constance M Wiemann

Center for Medical Ethics and Health Policy Staff Publications

Adolescents with special health care needs (ASHCNs) must develop self-management skills to effectively transition into adult-based care. This requires having the self-efficacy to meet with their health care provider independent of caregivers. This study aims to identify the factors associated with self-efficacy in meeting with a provider alone among ASHCN preparing for this transition.Eighty-three English-speaking 18-year olds with renal, gastrointestinal, neurologic, or rheumatologic diseases, and their English- or Spanish-speaking caregivers were recruited at a large children's hospital, and completed a one-time assessment as the historical control group for a larger intervention study. The main outcome measure was self-efficacy to meet …

Osteogenesis Imperfecta And The Family: A Qualitative Analysis Of The Experiences Of Family And Caregivers, Gianna M Colombo, Andrew D Wiese, Amelia E Mercado, Whitney S Shepherd, Michelle Fynan, Kara Ayers, W Conor Rork, Kristin M Kostick-Quenet, Dianne Nguyen, Sophie C Schneider, Julia M Morales, Saniah I Kazimi, Hannah E Cho, Members Of The Bbdc, Chaya N Murali, Marie-Eve Robinson, Brendan Lee, V Reid Sutton, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Introduction: Osteogenesis imperfecta (OI) describes a group of rare, heritable bone disorders causing bone fragility, tendency to fracture with minimal trauma, and chronic pain due to abnormal collagen synthesis. Limited research exists on the psychosocial impact of OI during childhood on caregivers and families.

Purpose: This study aimed to understand caregiver experiences, existing social support provided for families affected by OI, and the impact of OI on family life.

Method: Thirteen caregivers of individuals with OI participated in semistructured interviews. Researchers coded, abstracted, and analyzed qualitative data to develop themes on the psychosocial impact of OI on the family unit. …

A Phase 2 Trial Of Short-Term Intravenous N-Acetylcysteine In Biliary Atresia After Kasai Portoenterostomy, Sanjiv Harpavat, Kristin A Borovsky, Michael E Scheurer, Laurel Cavallo, Franca E Erhiawarie, Sanjeev Vasudevan, Adam M Vogel, Dana Cerminara, Elizabeth M Tessier, Kalyani R Patel, Sridevi Devaraj, Benjamin L Shneider

Center for Medical Ethics and Health Policy Staff Publications

Background: For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.

Methods: This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel …

Against The Phrase "Aggressive Care", Trevor M Bibler

Center for Medical Ethics and Health Policy Staff Publications

Language is the primary technology clinical ethicists use as they offer guidance about norms. Like any other piece of technology, to use the technology well requires attention, intention, skill, and knowledge. Word choice becomes a matter of professional practice. The Brief Report offers clinical ethicists several reasons for rejecting the phrase "aggressive care." Instead, ethicists should consider replacing "aggressive care" with the adjacent concept of a "recovery-focused path." The virtues of this neologism include: the opportunity to set aside the emotion of "aggression," the phrase's accuracy when capturing the intention of the patient or their representative, and an unappreciated rhetorical …

Sequencing-Based Detection Of Measles In Wastewater: Texas, January 2025, Sara Javornik Cregeen, Michael J Tisza, Blake Hanson, Marissa Cook, Anil Surathu, Rebecca Schneider, Jingjing Wu, Kirstin Short, Kaavya Domakonda, Loren Hopkins, Matthew C Ross, Joseph F Petrosino, Jennifer Deegan, Lauren B Stadler, Eric Boerwinkle, Anthony Maresso

Center for Medical Ethics and Health Policy Staff Publications

Measles is a potentially deadly viral infection spread via respiratory droplets from infected individuals. Outbreaks occur when vaccine coverage drops below the threshold of herd, or community, immunity. Using a sequencing-based approach, we report the prospective (January 7, 2025) detection of measles in nucleic acid extracts from 2 wastewater treatment plants in Houston, Texas, with a population of more than 218 000 residents. The sequencing data from 2 samples contained 53 unique reads mapping to 11 different regions of the measles virus genome with a 99.4% match to genotype B3. Importantly, no detections were observed from 821 previous samples from …

"Holy Cow, Where Do I Sign Up?" Attitudes Of Military Veterans Toward Epigenomic Biomarker Toxic Exposure Testing, Stacey Pereira, Calvin Apodaca, Kyle Slominski, Rachele K Lipsky, Cristian Coarfa, Cheryl L Walker, Amy L Mcguire, Lea Steele, Drew A Helmer

Center for Medical Ethics and Health Policy Staff Publications

Introduction: After the Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics Promise to Address Comprehensive Toxics (PACT) Act in 2022, there has been a great interest in studying toxic exposures encountered during military service. Development of epigenomic biomarkers for exposures could facilitate understanding of exposure-related health effects, but such testing could also provide unwanted information.

Materials and methods: We explored attitudes toward epigenomic biomarker research and the potential to test for past exposures using semistructured interviews with Veterans (n = 22) who experienced potentially harmful exposures.

Results: Twenty Veterans said they would hypothetically want to receive …

Multiscale Modeling Of Drug-Induced Liver Injury From Organ To Lobule, Alon Malka-Markovitz, Stelian Camara Dit Pinto, Mohammed Cherkaoui, Steven M Levine, Sharmila Anandasabapathy, Gagan K Sood, Sadhna Dhingra, Gao Yujia, John M Vierling, Nicolas R Gallo

Center for Medical Ethics and Health Policy Staff Publications

Drug-induced liver injury poses significant challenges in drug development and in clinical care. This study builds on prior work developing a Human Liver Virtual Twin by creating a Multiscale Computational Fluid Dynamics framework that integrates patient-specific anatomical data to predict acetaminophen-induced liver injury as a demonstration of its capability. The model bridges vascular, lobular, and cellular scales to simulate dynamic blood flow, drug transport, and injury mechanisms that accurately reflect clinically observed spatial heterogeneity. Results demonstrate accurate blood flow dynamics, predictions of hepatocellular damage, and a scalable framework for studying spatial heterogeneity applicable to other hepatic pathologies. This work establishes …

Comparative Effects Of Combustible Cigarette Versus Electronic Cigarette Exposures On Kras Mutant Lung Cancer Promotion, Walter V Velasco, Maria T Grimaldo, Nastaran Karimi, Michael J Clowers, Avantika Krishna, Ranran Wu, Rahmah Ejaz, Bo Yuan, Segundo Del Aguila, Iman Bouchelkia, Javier Eduardo Moreno Barragan, Katherine E Larsen, Yasmina Rezai, Farbod Khalaj, Kyler Mitra, Carlos Reyna Rodriguez, Ricardo Millares, Angelica Baca De Anda, Susana Castro-Pando, Umesh C Karandikar, Joseph F Petrosino, Florencia Mcallister, Humam Kadara, Edwin J Ostrin, Johannes F Fahrmann, Kristi Louise Hoffman, Seyed Javad Moghaddam

Center for Medical Ethics and Health Policy Staff Publications

Despite the emerging public health concern related to the use of electronic cigarette vapors (ECV), its impact on lung cancer is poorly understood. We assessed the effect of ECV on lung tumorigenesis in a mouse model of lung adenocarcinoma. Mice were exposed to either room air, combustible cigarette smoke (CCS), or ECV 2 hours daily for 8 weeks at which lung samples were harvested and studied for different outcomes. We found that CCS, but not ECV, led to a significant increase in tumor burden. Immunophenotyping of both CCS- and ECV-exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased …

Prediction Of Methotrexate Neurotoxicity Using Clinical, Sociodemographic, And Area-Based Information In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, Maria Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Center for Medical Ethics and Health Policy Staff Publications

Background: Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

Methods: We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 …

Xbp1s-Edem2 Prevents The Onset And Development Of Hfpef By Ameliorating Cardiac Lipotoxicity, Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Center for Medical Ethics and Health Policy Staff Publications

Background: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.

Methods: Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-L-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid …

Maternal Loss Of Mouse Nlrp2 Alters The Transcriptome And Dna Methylome In Gv Oocytes And Impairs Zygotic Genome Activation In Embryos, Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Background: NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.

Results: We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the …

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

Ocular Phenotyping Of Knockout Mice Identifies Genes Associated With Late Adult Retinal Phenotypes, Abraham Hang, Andy Shao, Michael Shea, Michel J Roux, Denise M Imai-Leonard, David J Adams, Takanori Amano, Oana V Amarie, Zorana Berberovic, Raphaël Bour, Lynette Bower, Brian C Leonard, Steve D Brown, Soo Young Cho, Sharon Clementson-Mobbs, Abigail J D'Souza, Mary Dickinson, Mohammad Eskandarian, Ann M Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Jason Heaney, Yann Hérault, Martin Hrabe De Angelis, Chih-Wei Hsu, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Ki-Hoan Nam, Hyuna Noh, Lauryl M J Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jason Salazar, John Richard Seavitt, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Tania Sorg, Michelle Stewart, Masaru Tamura, Heather Tolentino, Uchechukwu Udensi, Sara Wells, Wolfgang Wurst, Atsushi Yoshiki, Hamid Meziane, Glenn Yiu, Paul A Sieving, Louise Lanoue, K C Kent Lloyd, Colin Mckerlie, Ala Moshiri, International Mouse Phenotyping Consortium (Impc)

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases.

Methods: The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), …

International Society For Cell & Gene Therapy Expanded Access Working Group Position Paper: Key Considerations To Support Equitable And Ethical Expanded Access To Investigational Cell- And Gene-Based Interventions, Elena Maryamchik, Laertis Ikonomou, Beth E Roxland, Felix Grignon, Bruce L Levine, Bambi J Grilley

Center for Medical Ethics and Health Policy Staff Publications

This position paper reviews the Expanded Access pathway for cell and gene therapies, examining its critical role at the nexus of patient need, regulatory frameworks, and scientific advancement. Spearheaded by the International Society for Cell & Gene Therapy's Expanded Access Working Group, it explores how investigational therapies are accessed outside of clinical trials for patients with serious or life-threatening conditions when no approved alternatives exist. Access to cell and gene therapy products are of specific interest to patients because many times the products are bespoke, being used to treat serious and/or incurable conditions, and are potentially curative. As the field …

Joint Analysis Of The Npod-Virus Group Data: The Association Of Enterovirus With Type 1 Diabetes Is Supported By Multiple Markers Of Infection In Pancreas Tissue, Sarah J Richardson, Teresa Rodriguez-Calvo, Jutta E Laiho, John S Kaddis, Julius O Nyalwidhe, Irina Kusmartseva, Sofia Morfopoulou, Joseph F Petrosino, Vincent Plagnol, Kathrin Maedler, Margaret A Morris, Jerry L Nadler, Mark A Atkinson, Matthias Von Herrath, Richard E Lloyd, Heikki Hyoty, Noel G Morgan, Alberto Pugliese, Npod-Virus Group

Center for Medical Ethics and Health Policy Staff Publications

Aims/hypothesis: Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes.

Methods: The nPOD-Virus …

Detection Of Enterovirus Rna In Pancreas And Lymphoid Tissues Of Organ Donors With Type 1 Diabetes, Jutta E Laiho, Sami Oikarinen, Sofia Morfopoulou, Maarit Oikarinen, Ashlie Renner, Daniel Depledge, Matthew C Ross, Ivan C Gerling, Judith Breuer, Joseph F Petrosino, Vincent Plagnol, Alberto Pugliese, Antonio Toniolo, Richard E Lloyd, Heikki Hyöty, Npod-Virus Group

Center for Medical Ethics and Health Policy Staff Publications

Aims/hypothesis: The nPOD-Virus group collaboratively applied innovative technologies to detect and sequence viral RNA in pancreas and other tissues from organ donors with type 1 diabetes. These analyses involved the largest number of pancreas samples collected to date. The aim of the current work was to examine the presence of enterovirus RNA in pancreas and lymphoid tissues of organ donors with and without type 1 diabetes.

Methods: We analysed pancreas, spleen, pancreatic lymph nodes and duodenum samples from the following groups: (1) donors with type 1 diabetes (n=71) with (n=35) or without (n=36) insulin-containing islets; (2) donors with single or …

Genome-Wide Analyses Identify 30 Loci Associated With Obsessive-Compulsive Disorder, Nora I Strom, Zachary F Gerring, Marco Galimberti, Dongmei Yu, Matthew W Halvorsen, Abdel Abdellaoui, Cristina Rodriguez-Fontenla, Julia M Sealock, Tim Bigdeli, Jonathan R Coleman, Behrang Mahjani, Jackson G Thorp, Katharina Bey, Christie L Burton, Jurjen J Luykx, Gwyneth Zai, Silvia Alemany, Christine Andre, Kathleen D Askland, Julia Bäckman, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O Joseph Bienvenu, Donald Black, Michael H Bloch, Sigrid Børte, Rosa Bosch, Michael Breen, Brian P Brennan, Helena Brentani, Joseph D Buxbaum, Jonas Bybjerg-Grauholm, Enda M Byrne, Judit Cabana-Dominguez, Beatriz Camarena, Adrian Camarena, Carolina Cappi, Angel Carracedo, Miguel Casas, Maria Cristina Cavallini, Valentina Ciullo, Edwin H Cook, Jesse Crosby, Bernadette A Cullen, Elles J De Schipper, Richard Delorme, Srdjan Djurovic, Jason A Elias, Xavier Estivill, Martha J Falkenstein, Bengt T Fundin, Lauryn Garner, Christina Gironda, Fernando S Goes, Marco A Grados, Jakob Grove, Wei Guo, Jan Haavik, Kristen Hagen, Kelly Harrington, Alexandra Havdahl, Kira D Höffler, Ana G Hounie, Donald Hucks, Christina Hultman, Magdalena Janecka, Eric Jenike, Elinor K Karlsson, Kara Kelley, Julia Klawohn, Janice E Krasnow, Kristi Krebs, Christoph Lange, Nuria Lanzagorta, Daniel Levey, Kerstin Lindblad-Toh, Fabio Macciardi, Brion Maher, Brittany Mathes, Evonne Mcarthur, Nathaniel Mcgregor, Nicole C Mclaughlin, Sandra Meier, Euripedes C Miguel, Maureen Mulhern, Paul S Nestadt, Erika L Nurmi, Kevin S O'Connell, Lisa Osiecki, Olga Therese Ousdal, Teemu Palviainen, Nancy L Pedersen, Fabrizio Piras, Federica Piras, Sriramya Potluri, Raquel Rabionet, Alfredo Ramirez, Scott Rauch, Abraham Reichenberg, Mark A Riddle, Stephan Ripke, Maria C Rosário, Aline S Sampaio, Miriam A Schiele, Anne Heidi Skogholt, Laura G Sloofman, Jan Smit, María Soler Artigas, Laurent F Thomas, Eric Tifft, Homero Vallada, Nathanial Van Kirk, Jeremy Veenstra-Vanderweele, Nienke N Vulink, Christopher P Walker, Ying Wang, Jens R Wendland, Bendik S Winsvold, Yin Yao, Hang Zhou, Estonian Biobank, 23andme Inc, Arpana Agrawal, Pino Alonso, Götz Berberich, Kathleen K Bucholz, Cynthia M Bulik, Danielle Cath, Damiaan Denys, Valsamma Eapen, Howard Edenberg, Peter Falkai, Thomas V Fernandez, Abby J Fyer, J M Gaziano, Dan A Geller, Hans J Grabe, Benjamin D Greenberg, Gregory L Hanna, Ian B Hickie, David M Hougaard, Norbert Kathmann, James Kennedy, Dongbing Lai, Mikael Landén, Stéphanie Le Hellard, Marion Leboyer, Christine Lochner, James T Mccracken, Sarah E Medland, Preben B Mortensen, Benjamin M Neale, Humberto Nicolini, Merete Nordentoft, Michele Pato, Carlos Pato, David L Pauls, John Piacentini, Christopher Pittenger, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Steven A Rasmussen, Margaret A Richter, David R Rosenberg, Stephan Ruhrmann, Jack F Samuels, Sven Sandin, Paul Sandor, Gianfranco Spalletta, Dan J Stein, S Evelyn Stewart, Eric A Storch, Barbara E Stranger, Maurizio Turiel, Thomas Werge, Ole A Andreassen, Anders D Børglum, Susanne Walitza, Kristian Hveem, Bjarne K Hansen, Christian Rück, Nicholas G Martin, Lili Milani, Ole Mors, Ted Reichborn-Kjennerud, Marta Ribasés, Gerd Kvale, David Mataix-Cols, Katharina Domschke, Edna Grünblatt, Michael Wagner, John-Anker Zwart, Gerome Breen, Gerald Nestadt, Jaakko Kaprio, Paul D Arnold, Dorothy E Grice, James A Knowles, Helga Ask, Karin J Verweij, Lea K Davis, Dirk J Smit, James J Crowley, Jeremiah M Scharf, Murray B Stein, Joel Gelernter, Carol A Mathews, Eske M Derks, Manuel Mattheisen

Center for Medical Ethics and Health Policy Staff Publications

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along …