Public Affairs, Public Policy and Public Administration Commons^™

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 …

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 …

"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 …

Self-Collection For Cervical Cancer Screening In A Safety-Net Setting: The Prestis Randomized Clinical Trial, Jane R Montealegre, Susan G Hilsenbeck, Shaun Bulsara, Susan L Parker, Trisha L Amboree, Matthew L Anderson, Maria Daheri, Maria L Jibaja-Weiss, Kathleen M Schmeler, Ashish A Deshmukh, Elizabeth Y Chiao, Michael E Scheurer

Center for Medical Ethics and Health Policy Staff Publications

Importance: There are limited data on the effectiveness of mailed self-collection to increase cervical cancer screening (CCS) participation in underresourced health care settings.

Objective: To compare the effectiveness of mailed self-collection kits, with and without patient navigation, to telephone reminders to increase CCS in a safety-net health system.

Design, setting, and participants: This pragmatic, parallel, single-blinded, randomized clinical trial within a publicly funded safety-net health system in Houston, Texas, compared (1) telephone reminder (TR) for clinic-based screening, (2) TR with mailed self-collection (SC), and (3) TR with mailed SC and patient navigation among a random sample of CCS-eligible patients not …

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), …

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 …

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 …

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 …

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% …

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 …

How Do Parents Decide On Genetic Testing In Pediatrics? A Systematic Review, Elena Sophia Doll, Seraina Petra Lerch, Katja Maria Schmalenberger, Karla Alex, Stefan Kölker, Heiko Brennenstuhl, Stacey Pereira, Hadley Smith, Eva Caroline Winkler, Julia Mahal, Beate Ditzen

Center for Medical Ethics and Health Policy Staff Publications

Purpose: This systematic review aims to identify the factors that influence parents' decisions regarding pediatric diagnostic genetic testing (DT) and predictive genetic testing (PT). These factors are integrated into a conceptual decision-making model. Implications for genetic counseling, research, and ethics were derived.

Methods: PubMed, PsychInfo, WebofScience, and related references were searched for original publications between 2000 and 2023. The extracted factors were categorized using existing models.

Results: Of the 5843 publications, 56 met the inclusion criteria. The included studies differentiated between DT, traditional PT, and expanded PT and described factors affecting parental decisions to have the child genetically tested and …

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 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, …

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 …

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 …

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 …

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 …

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 …

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.