Bioethics and Medical Ethics Commons^™

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 …

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 …

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), …

A Meta-Analysis Of Diagnostic Yield And Clinical Utility Of Genome And Exome Sequencing In Pediatric Rare And Undiagnosed Genetic Diseases, Rajshree Pandey, Noemi Fluetsch Brennan, Kalliopi Trachana, Sarah Katsandres, Olaf Bodamer, John Belmont, David L Veenstra, Siyang Peng

Center for Medical Ethics and Health Policy Staff Publications

Purpose: To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.

Methods: We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models.

Results: We identified 108 studies including 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (N = 13) for GWS was 34.2% (95% CI: 27.6-41.5; I2: 86%) vs 18.1% (95% CI: 13.1-24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% …

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 …

A Multi-Site Study Of Clinician Perspectives In The Lifecycle Of An Algorithmic Risk Prediction Tool, Rita Dexter, Kristin Kostick-Quenet, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

Recent advancements in the performative capacities of artificial intelligence (AI), machine learning (ML), and algorithmic-based tools open up numerous applications in modern medicine. There are, however, few studies that track the whole lifecycle of a digital healthcare tool as it evolves from conception, to design, and deployment in real world settings-especially with a focus on the social dynamics amongst the end-users of the tool: clinicians. In this paper, we present data from a multi-site, 5-year study focused on the development and deployment of an algorithmic risk calculator (HeartMate 3 Risk Score) into a validated and efficacy tested clinical decision support …

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 …

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 …

Promises And Pitfalls Of Preimplantation Genetic Testing For Polygenic Disorders: A Narrative Review, Jaime A Roura-Monllor, Zachary Walker, Joel M Reynolds, Greysha Rivera-Cruz, Avner Hershlag, Gheona Altarescu, Sigal Klipstein, Stacey Pereira, Gabriel Lázaro-Muñoz, Shai Carmi, Todd Lencz, Ruth Bunker Lathi

Center for Medical Ethics and Health Policy Staff Publications

Preimplantation genetic testing for polygenic disorders (PGT-P) has been commercially available since 2019. PGT-P makes use of polygenic risk scores for conditions which are multifactorial and are significantly influenced by environmental and lifestyle factors. If current predictions are accurate, then absolute risk reductions range from about 0.02% to 10.1%, meaning that between 10 and 5,000 in vitro fertilization patients would need to be tested with PGT-P to prevent one offspring from becoming affected in the future, depending on the condition and the number of embryos available. Survey and interview data reveal that patients and the public have largely favorable views …

Navigating The Future Of Polygenic Risk Scores: Insights From Child And Adolescent Psychiatrists, Page M Trotter, Amanda R Merner, Lauren A Ginn, Abigail C Martinez, Ana L Battaglino, Kaitlynn P Craig, Jason Bach, Katherine J Freedberg, Takahiro Soda, Eric A Storch, Gabriel Lázaro-Muñoz, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Polygenic risk scores (PRS) are a method of calculating genetic risk for polygenic, or multi-gene, disorders. These scores have potential impacts in the realm of child and adolescent psychiatry, given the high prevalence of psychiatric disorders among youth. However, there are concerns about PRS implementation among key stakeholders, namely child and adolescent psychiatrists (CAP). We conducted interviews with 29 U.S.-based CAP to investigate clinician attitudes toward the use of PRS. The data herein correspond to a future scenario we provided CAP in which PRS are accurate and portable to patients of different racial and ethnic backgrounds. We found that CAP …

Science Tikkun: A Bioscience Pandemic Framework In A Hebrew Tradition Of Global Repair, Peter Hotez

Center for Medical Ethics and Health Policy Staff Publications

Over the past decade we have seen a steady increase in dangerous pandemic threats. They include two major Ebola epidemics and cholera in Africa; dengue, Zika, yellow fever in the Americas; a COVID-19 pandemic; and H5N1 in Texas. This is happening because of a confluence of modern forces including urbanization, deforestation, and climate change. Yet as pandemics emerge on a crowded and warming planet, anti-science disinformation and antisemitism impede our response. Science tikkun is an overarching framework for repair and redress. It honors the legacy of Maimonides, Teilhard de Chardin, and others who have sought reconciliation between science and religion.

Should Physicians Take The Rap? Normative Analysis Of Clinician Perspectives On Responsible Use Of 'Black Box' Ai Tools, Ben H Lang, Kristin Kostick-Quenet, Jared N Smith, Meghan Hurley, Rita Dexter, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

Background: Increasing interest in deploying artificial intelligence tools in clinical contexts has raised several ethical questions of both normative and empirical interest. One such question in the literature is whether "responsibility gaps" (r-gaps) are created when clinicians utilize or rely on such tools for providing care, and if so, what to do about them. These gaps are particularly likely to arise when using opaque, "black box" AI tools. Compared to normative and legal analysis of AI-generated responsibility gaps in health care, little is known, empirically, about health care providers views on this issue. The present study examines clinician perspectives on …

Germline Pathogenic Drosha Variants Are Linked To Pineoblastoma And Wilms Tumor Predisposition, Peter N Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y Lin, Angshumoy Roy, Allison Pribnow, Melissa R Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A Jackson, Mark M Sasaki, Trent Fowler, Anita Ng, Ryan J Corbett, Rebecca S Kaufman, Jeremy S Haley, David J Carey, Kuan-Lin Huang, Sharon J Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B Mcgee, Joshua D Schiffman, Kenneth S Chen, Douglas R Stewart, D Williams Parsons, Sharon E Plon, Kris Ann P Schultz, Kenan Onel

Center for Medical Ethics and Health Policy Staff Publications

Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported.

Experimental design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts.

Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a …

A Narrative Review Of Military Reverse Triage., Daniel J Hurst

Rowan-Virtua School of Osteopathic Medicine Departmental Research

INTRODUCTION: Military reverse triage has been described at several points in the literature. However, an extensive review of the concept and any gaps that may exist has not been conducted. This narrative review seeks to understand how reverse triage is used in the military literature and how it might be implemented in practice, as well as the documented historical applications of reverse triage.

MATERIALS AND METHODS: Four databases were searched manually for English-language articles: PubMed, SCOPUS, JSTOR, and Worldwide Political Science Abstracts. In addition, a manual search of references, U.S. DoD, and NATO doctrine, as well as other published works …

Ethical Considerations For Sharing Aggregate Results From Pragmatic Clinical Trials, Stephanie R Morain, Abigail Brickler, Joseph Ali, Patricia Pearl O'Rourke, Kayte Spector-Bagdady, Benjamin Wilfond, Vasiliki Rahimzadeh, Caleigh Propes, Kayla Mehl, David Wendler

Center for Medical Ethics and Health Policy Staff Publications

A growing literature has explored the ethical obligations and current practices related to sharing aggregate results with research participants. However, no prior work has examined these issues in the context of pragmatic clinical trials. Several characteristics of pragmatic clinical trials may complicate both the ethics and the logistics of sharing aggregate results. Among these characteristics include that pragmatic clinical trials may affect the rights, welfare, and interests of not only patient-subjects but also clinicians, meaning that results may be owed to a broader range of groups than typically considered in other research contexts. In addition, some pragmatic clinical trials are …

A Novel Method For Semi-Quantitative Detection Of Hpv16 And Hpv18 Mrna With A Low-Cost, Open-Source Fluorimeter, Kathryn A Kundrod, Mary E Natoli, Chelsey A Smith, Jackson B Coole, Megan M Chang, Emilie Newsham Novak, Elizabeth Chiao, Elizabeth A Stier, Jane R Montealegre, Michael E Scheurer, Philip E Castle, Kathleen M Schmeler, Rebecca R Richards-Kortum

Center for Medical Ethics and Health Policy Staff Publications

Despite global calls to eliminate cervical cancer, rates of cervical cancer incidence and mortality remain high in resource-limited settings, where it is challenging to implement and sustain screening, diagnosis, and treatment programs. The presence of high-risk HPV mRNA in cervical cells is a sensitive and specific biomarker of cervical precancer. Yet, current testing methods are too costly and complex for use in resource-limited settings. Here, we present a novel method for semi-quantitative detection of HPV16 and HPV18 mRNA with minimal infrastructure requirements. The assay relies on isothermal reverse transcription recombinase polymerase amplification (RT-RPA) with real-time fluorescence readout, demonstrated on rugged, …

Crispr/Cas9 Gene Therapy Increases The Risk Of Tumorigenesis In The Mouse Model Of Hereditary Tyrosinemia Type I, Tong Chen, Mercedes Barzi, Nika Furey, Hyunjae R Kim, Francis P Pankowicz, Xavier Legras, Sara H Elsea, Ayrea E Hurley, Diane Yang, David A Wheeler, Malgorzata Borowiak, Beatrice Bissig-Choisat, Pavel Sumazin, Karl-Dimiter Bissig

Center for Medical Ethics and Health Policy Staff Publications

Background & aims: The therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of CRISPR gene therapy in an animal model of hereditary tyrosinemia type I (HT-I). We compared the standard of care-nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)-with the deletion of the Hpd gene by CRISPR gene therapy. Both treatments block flux through tyrosine catabolism and thereby prevent the accumulation of toxic catabolites in HT-I.

Methods: We assessed the efficacy and safety of …

Amniocentesis In Pregnancies At Or Beyond 24 Weeks: An International Multicenter Study, Roni Zemet, Mohamad Ali Maktabi, Alexandra Tinfow, Jessica L Giordano, Thomas M Heisler, Qi Yan, Roni Plaschkes, Jenny Stokes, Jennifer M Walsh, Siobhán Corcoran, Erica Schindewolf, Kendra Miller, Asha N Talati, Kristen A Miller, Karin Blakemore, Kate Swanson, Jana Ramm, Ivonne Bedei, Teresa N Sparks, Angie C Jelin, Neeta L Vora, Juliana S Gebb, David A Crosby, Michal Berkenstadt, Boaz Weisz, Ronald J Wapner, Ignatia B Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Background: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse.

Objective: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation.

Study design: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages …

Association Of Messenger Rna Coronavirus Disease 2019 (Covid-19) Vaccination And Reductions In Post Covid Conditions Following Severe Acute Respiratory Syndrome Coronavirus 2 Infection In A Us Prospective Cohort Of Essential Workers, Josephine Mak, Sana Khan, Amadea Britton, Spencer Rose, Lisa Gwynn, Katherine D Ellingson, Jennifer Meece, Leora R Feldstein, Harmony Tyner, Laura J Edwards, Matthew S Thiese, Allison Naleway, Manjusha Gaglani, Natasha Solle, Jefferey L Burgess, Julie Mayo Lamberte, Meghan Shea, Taryn Hunt-Smith, Alberto Caban-Martinez, Cynthia Porter, Ryan Wiegand, Ramona Rai, Kurt T Hegmann, James Hollister, Ashley Fowlkes, Meredith Wesley, Andrew L Philips, Patrick Rivers, Robin Bloodworth, Gabriella Newes-Adeyi, Lauren E W Olsho, Sarang K Yoon, Sharon Saydah, Karen Lutrick

Center for Medical Ethics and Health Policy Staff Publications

Background: Data are limited on whether vaccination reduces post COVID conditions (PCCs) risk after less severe nonhospitalized coronavirus disease 2019 (COVID-19). This study assessed whether COVID-19 vaccination protected against PCCs in persons with mild initial infections during Delta and Omicron variant predominance.

Methods: This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with test-confirmed severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) between 28 June 2021 and 14 September 2022 were surveyed for PCCs, defined by symptoms lasting >4 weeks after initial infection. Cases self-reported PCCs and controls self-reported no PCCs. The exposure was …

Evaluating Industry Relationships And Transparency: Insights From Orthopedic Surgeons In The Cms Open Payments Database, Anesu K. Murambadoro, Mario Keko, Edward Rodriguez, John J. Wixted

Research Symposium

Introduction: Industry payments to physicians may risk introducing bias into patient care. The Open Payments (OP) database, established by Physician Payments Sunshine Act, reports these payments to promote transparency. Orthopedic surgeons receive the highest industry payments especially in the category of royalties/licensing, prompting questions about conflicts of interest and whether the database accurately reflects the status across the specialty. We hypothesize that the OP database underrepresents the relationships that orthopedic surgeons have with industry. We seek to assess the validity of reported industry payments, particularly in the categories of royalties and licensing payments to determine how to improve transparency and …

Navigating Your Us Bioscience Career Into The 2030s, Peter J Hotez

Center for Medical Ethics and Health Policy Staff Publications

The coming decade might see major cuts to the United States Government funding for biomedicine and the mainstreaming of pseudoscience. But your biosciences PhD gives you the problem-solving skills to navigate this maelstrom, especially if you maintain flexibility, optimism, and enthusiasm for uncharted paths.

Family Genetic Risk Communication And Reverse Cascade Testing In The Babyseq Project, Melissa K Uveges, Hadley Stevens Smith, Stacey Pereira, Casie Genetti, Amy L Mcguire, Alan H Beggs, Robert C Green, Ingrid A Holm

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Genomic sequencing of newborns can initiate disease surveillance and therapy for children and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and were identified as having a risk for an autosomal dominant disease.

Methods: We conducted semistructured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely pathogenic variant associated with an autosomal dominant childhood- and/or adult-onset disease returned. We used directed content analysis to derive themes.

Results: From 11 families, all first-degree relatives (n = …

Patient Consent And The Right To Notice And Explanation Of Ai Systems Used In Health Care, Meghan E Hurley, Benjamin H Lang, Kristin Marie Kostick-Quenet, Jared N Smith, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

Given the need for enforceable guardrails for artificial intelligence (AI) that protect the public and allow for innovation, the U.S. Government recently issued a Blueprint for an AI Bill of Rights which outlines five principles of safe AI design, use, and implementation. One in particular, the right to notice and explanation, requires accurately informing the public about the use of AI that impacts them in ways that are easy to understand. Yet, in the healthcare setting, it is unclear what goal the right to notice and explanation serves, and the moral importance of patient-level disclosure. We propose three normative functions …

Anesthesia And Pain Management In Conflict-Affected Regions: Addressing Global Health Barriers To Access And Quality Of Care​, Naeel Uddin, Sierra Brown, Maria Easler, Ayanda Mkhize, Marwa Hamdam, Chandu Goli, Lauren Draper

Annual Research Symposium

This poster examines how to deliver safe, effective anesthesia and pain control in areas with limited resources and ongoing security threats. Focusing on portable technology, ketamine-based protocols, and telemedicine, we highlight ethical considerations, training needs, and global collaborations. Our findings outline a pathway to reduce suffering and improve surgical outcomes in vulnerable populations by addressing challenges unique to conflict settings.

Ethical Governance For Genomic Data Science In The Cloud, Vasiliki Rahimzadeh, Sarah C Nelson, Adrian Thorogood, Jonathan Lawson, Stephanie M Fullerton

Center for Medical Ethics and Health Policy Staff Publications

Cloud platforms offer distinct advantages, but questions remain about how to ethically and efficiently manage human genomic data in the cloud. Data governance needs to be adapted to ensure transparency and security for research participants, as well as equitable and sustainable access for researchers.

Resilience And Coping: A Qualitative Analysis Of Cognitive And Behavioral Factors In Adults With Osteogenesis Imperfecta, Hannah E Cho, Whitney S Shepherd, Gianna M Colombo, Andrew D Wiese, W Conor Rork, Kristin M Kostick, Dianne Nguyen, Members Of The Bbdc, Chaya N Murali, Marie-Eve Robinson, Sophie C Schneider, Justin H Qian, Brendan Lee, V Reid Sutton, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Purpose: The aim of this qualitative study was to investigate resilience among adults with Osteogenesis Imperfecta (OI).

Materials and methods: Semi-structured interviews were conducted with 15 adults with OI. Transcripts were coded and subsequently abstracted, yielding themes specific to resilience and coping. Interview guides covered broad topics including pain challenges specific to OI, mental health issues related to OI, and priorities for future interventions for individuals with OI.

Results: Participants described resilience in the context of OI as the ability to grow from adversity, adapt to challenges resulting from OI-related injuries, and find identities apart from their condition. Psychological coping …

Incidence And Survival Of Children And Adolescents With Wilms Tumor, United States, 2001-2020, Andres F Espinoza, Ekene Onwuka, David A Siegel, Shifan Dai, Sanjeev A Vasudevan, Michael E Scheurer, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Background: Wilms tumor (WT) is the most common pediatric malignancy of the kidney. Past studies describing WT incidence and survival used surveillance data with < 30% of the US population. We evaluated differences in WT incidence and survival comparing demographic groups and tumor characteristics.

Methods: We analyzed new cases of WT among patients aged < 20 years at diagnosis by using incidence data from US Cancer Statistics (USCS) for 2003-2020 and 5-year relative survival (RS) data from the National Program of Cancer Registries (NPCR) for 2001-2019. To assess incidence trends, average annual percent change (AAPC) was calculated by using joinpoint regression. Relative survival (RS) and all-cause survival were calculated overall and by demographic and clinical variables.

Results: During 2003-2020, 8218 cases of WT were reported in USCS, which represented an age-adjusted incidence rate of 5.7 cases per million. Rates were the highest among females (6.3), children aged 0-4 years (17.2), and non-Hispanic Black patients (7.1). Overall, trends remained stable (AAPC = -0.4, 95% CI: -1.4 to 0.4). Among 7567 cases of WT in NPCR, 5-year RS was 92.6%. Patients with the lowest …

Figg At 5: An Update On Us Public Perspectives On Forensic Investigative Genetic Genealogy Five Years After Its Introduction To Criminal Investigations, Christi J Guerrini, Jill O Robinson, Mohamed I Elsaid, Whitney Bash Brooks, Ariel Levchenko, Stephanie M Fullerton, Sara Huston, Norah L Crossnohere, John F P Bridges, Jacklyn M Dahlquist, Louiza Kalokairinou, Diana Madden, Cece Moore, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

In 2018, after law enforcement announced it had used a technique called forensic investigative genetic genealogy (FIGG) to identify the Golden State Killer, we conducted a U.S. general population survey and found most respondents supported using FIGG to solve violent crimes. Since then, FIGG has helped close hundreds of criminal cases, but it also has weathered controversies. On FIGG's fifth anniversary, we conducted an expanded, follow-up survey with U.S.-based participants to determine if public opinion had changed and found continued support for FIGG across most applications. The same proportion (91 %) of respondents in the 2018 and 2023 surveys endorsed …

Improving Individualized Rhabdomyosarcoma Prognosis Predictions Using Somatic Molecular Biomarkers, Mark Zobeck, Javed Khan, Rajkumar Venkatramani, M Fatih Okcu, Michael E Scheurer, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Molecular markers increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.

Methods: Clinical variables and somatic mutation data for 20 genes from 641 patients with RMS in the United Kingdom and the United States were used to develop three Cox proportional hazard models for predicting event-free survival (EFS). The Baseline Clinical (BC) model included treatment location, age, fusion status, and risk group. The Gene Enhanced 2 (GE2) model added TP53 and MYOD1 mutations to the BC predictors. The Gene …