Digital Commons Network^™

Systemic Aging Fuels Heart Failure: Molecular Mechanisms And Therapeutic Avenues, Zhuyubing Fang, Umar Raza, Jia Song, Junyan Lu, Shun Yao, Xiaohong Liu, Wei Zhang, Shujuan Li

Faculty, Staff and Students Publications

Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age-related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age-related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional …

Differential Treatment Effects On Β-Cell Function Using Model-Based Parameters In Type 2 Diabetes: Results From The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness Study (Grade), Kristina M Utzschneider, Mark Tripputi, Nicole M Butera, Andrea Mari, Samuel P Rosin, Mary Ann Banerji, Richard M Bergenstal, Necole Brown, Anders L Carlson, Ralph A Defronzo, Michaela R Gramzinski, Tasma Harindhanavudhi, Alexandra Kozedub, William I Sivitz, Michael W Steffes, Ashok Balasubramanyam, Neda Rasouli

Faculty, Staff and Students Publications

Objective: To evaluate how model-based parameters of β-cell function change with glucose-lowering treatment and associate with glycemic deterioration in adults with type 2 diabetes (T2D).

Research design and methods: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), β-cell function parameters derived from mathematical modeling of oral glucose tolerance tests were assessed at baseline (N = 4,712) and 1, 3, and 5 years following randomization to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin. Parameters included insulin secretion rate (ISR), glucose sensitivity (insulin response to glucose), rate sensitivity (early insulin response), and potentiation. Linear mixed-effects …

Significant Increase Of Firework Induced Eye Injuries In Germany And The Netherlands- Are We Doing Enough To Protect Minors And Bystanders?, Ameli Gabel-Pfisterer, Stefan Johann Lang, Daniel Boehringer, Hansjürgen Agostini, Lotte C De Geus, Jan Tjeerd De Faber

Faculty, Staff and Students Publications

Background: After 2 years of pandemic sales ban, on New Year`s Eve 2022/23 consumer firework articles were officially available again in Germany and the Netherlands.

Methods: In the Netherlands we prospectively and anonymously collected data on patients treated for firework induced eye injuries from 2009 on, in Germany since 2016.

Results: Around New Year ́s Eve 2022/23 the number of patients with firework inflicted eye injuries increased in the Netherlands to 133 and in Germany to 838. In both countries the participation of eye departments was 90%. The incidence of firework induced eye injuries in the Netherlands was 0,8 /100 …

Subacute Neuropathy Post-Liver Transplantation In Zellweger Spectrum Disorder: A Case Report, Clarissa Gonzalez, Madelyn J Cohen, Juhee Hong, Daniel Calame, Kavitha Marri, Sanjiv Harpavat, Michael F Wangler, Krupa Mysore

Faculty, Staff and Students Publications

Peroxisome biogenesis disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare genetic disease caused by mutations in the genes involved in peroxisome biogenesis. PBD-ZSD presentations vary in severity, and treatment of PBD-ZSD remains supportive focused on specific complications. A few reported cases of the use of liver transplantation to treat either neurological symptoms or liver dysfunction and cirrhosis in PBD-ZSD have been published. In this case report, we document the course of a 16-year-old boy diagnosed with PBD-ZSD and a delayed and unexpected neuropathy that developed after undergoing orthotopic liver transplantation (OLT) for which the indication was liver cirrhosis. Following OLT, the …

Variability In Treatment Of Utis In Children With Genitourinary Anomalies In Children's Hospitals, Catherine S Forster, Alexis C Wood, Stephanie Davis-Rodriguez, Sanyukta Desai, Pearl W Chang, Michael J Tchou, John M Morrison, Rana F Hamdy, Vijaya Vemulakonda, Patrick W Brady, Cynthia Abou Zeid, Sowdhamini S Wallace, Uti In Children With Cakut Study Group

Faculty, Staff and Students Publications

Objective: In children with urinary tract anomalies, febrile urinary tract infections (UTIs) are associated with increased risks of sepsis, hospitalization, and kidney injury. However, the best treatment strategies are unknown. We aimed to describe antibiotic treatment practices and outcomes for UTIs in children with urinary tract anomalies and evaluate whether variability in UTI treatment exists between hospitals.

Methods: We conducted a multicenter retrospective cohort study of children seen in emergency departments (EDs) in 6 free-standing US children's hospitals from January 1, 2017, through December 31, 2018. We included children aged 0-17 years with an anatomic or functional urinary tract anomaly …

Inborn Errors Of Immunity Reveal Molecular Requirements For Generation And Maintenance Of Human Cd4+ Il-9-Expressing Cells, Geetha Rao, Corinne D Mack, Tina Nguyen, Natalie Wong, Kathryn Payne, Lisa Worley, Paul E Gray, Melanie Wong, Peter Hsu, Michael O Stormon, Kahn Preece, Daniel Suan, Michael O'Sullivan, Annaliesse K Blincoe, Jan Sinclair, Satoshi Okada, Sophie Hambleton, Peter D Arkwright, Kaan Boztug, Polina Stepensky, Megan A Cooper, Liliana Bezrodnik, Kari C Nadeau, Hassan Abolhassani, Roshini S Abraham, Mikko R J Seppänen, Vivien Béziat, Jacinta Bustamante, Lisa R Forbes Satter, Jennifer W Leiding, Isabelle Meyts, Emmanuelle Jouanguy, Stéphanie Boisson-Dupuis, Gulbu Uzel, Anne Puel, Jean-Laurent Casanova, Stuart G Tangye, Cindy S Ma

Faculty, Staff and Students Publications

Background: CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T-cell subsets-TH1, TH2, TH17, TH22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing TH9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human TH9 cells remain incompletely defined.

Objective: We sought to define signaling pathways that regulate IL-9 production by human CD4+ T cells.

Methods: Human naive and memory CD4+ T cells were cultured under different conditions, and …

International Multispecialty Expert Physician Preoperative Identification Of Extranodal Extension In Patients With Oropharyngeal Cancer Using Computed Tomography: Prospective Blinded Human Inter-Observer Performance Evaluation, Onur Sahin, Serageldin Kamel, Kareem A Wahid, Cem Dede, Nicolette Taku, Renjie He, Mohamed A Naser, Christina S Sharafi, Antti Mäkitie, Benjamin H Kann, Kimmo Kaski, Jaakko Sahlsten, Joel Jaskari, Moran Amit, Gregory M Chronowski, Eduardo M Diaz, Adam S Garden, Ryan P Goepfert, Jeffrey P Guenette, G Brandon Gunn, Jussi Hirvonen, Frank Hoebers, Katherine A Hutcheson, Nandita Guha-Thakurta, Jason Johnson, Diana Kaya, Shekhar D Khanpara, Kristofer Nyman, Stephen Y Lai, Miriam Lango, Kim O Learned, Anna Lee, Carol M Lewis, Anastasios Maniakas, Amy C Moreno, Jeffrey N Myers, Jack Phan, Kristen B Pytynia, David I Rosenthal, Vlad C Sandulache, Dawid Schellingerhout, Shalin J Shah, Andrew G Sikora, Abdallah S R Mohamed, Melissa M Chen, Clifton D Fuller, Multidisciplinary Oropharyngeal Cancer Extra‐Nodal Extension (Opc Ene) Assessment Working Group

Faculty, Staff and Students Publications

Background: Pathologic extranodal extension (pENE) is a crucial prognostic factor in oropharyngeal cancer (OPC), but determining pENE from imaging has high inter-observer variability. The role of clinician specialty in the accuracy of imaging-detected extranodal extension (iENE) remains unclear. The purpose of this study is to assess the influence of clinician specialty on the accuracy of preoperative iENE detection in human papillomavirus (HPV)-positive OPC using computed tomography (CT) imaging.

Methods: This prospective observational study evaluated pretherapy CT images from 24 HPV-positive OPC patients (30 scans, including duplicates). Thirty-four expert observers (11 radiologists, 12 surgeons, 11 radiation oncologists) assessed iENE and reported …

Factors Associated With Completeness Of Sex And Gender Fields In Electronic Health Records, Alex Mcdowell, Vicki Fung, David W Bates, Dinah Foer

Faculty, Staff and Students Publications

Purpose: Our purpose was to understand the completeness of sex and gender fields in electronic health record (EHR) data and patient-level factors associated with completeness of those fields. In doing so, we aimed to inform approaches to EHR sex and gender data collection.

Methods: This was a retrospective observational study using 2016-2021 deidentified EHR data from a large health care system. Our sample included adults who had an encounter at any of three hospitals within the health care system or were enrolled in the health care system's Accountable Care Organization. The sex and gender fields of interest were gender identity, …

Adverse Drug Events In Ambulatory Care: A Cross-Sectional Study, Joseph M Plasek, Mary G Amato, Abigail Salem, Dinah Foer, Stuart Lipsitz, Gretchen Purcell Jackson, David W Bates, Li Zhou

Faculty, Staff and Students Publications

Background: Adverse drug events (ADEs) are understudied in the ambulatory care setting. We aim to estimate the prevalence and characteristics of ADEs in outpatient care using electronic health records (EHRs).

Methods: This cross-sectional study included EHR data for patients who had an outpatient encounter at an academic medical center from 1 October 2018 through 31 December 2019. We developed a stratified sampling strategy based on a comprehensive set of 994 ADE-related International Classification of Disease (ICD-10) codes to identify clinical encounters and notes likely to contain ADEs. Within each ICD-10 likelihood group, clinical notes were randomly sampled and annotated for …

Between-Visit Asthma Symptom Monitoring With A Scalable Digital Intervention: A Randomized Clinical Trial, Robert S Rudin, Savanna Plombon, Jorge Sulca Flores, Jessica L Sousa, Jorge Rodriguez, Dinah Foer, Stuart Lipsitz, Maria O Edelen, David W Bates, Adriana Arcia, Anuj K Dalal

Faculty, Staff and Students Publications

Importance: Asthma affects an estimated 7.7% of the US population and 262 million people worldwide. Symptom monitoring has demonstrated benefits but has not achieved widespread use.

Objective: To assess the effect of a scalable asthma symptom monitoring intervention on asthma outcomes.

Design, setting, and participants: This randomized clinical trial was conducted between July 2020 and March 2023 at 7 primary care clinics affiliated with an academic medical center (Brigham and Women's Hospital in Boston, Massachusetts). Candidate patients with a diagnosis of asthma over a 20-month recruitment period (July 2020 to March 2022) were identified and categorized into tiers of varying …

Soluble Mesothelin-Related Peptide As A Prognosticator In Pleural Mesothelioma Patients Receiving Checkpoint Immunotherapy, Sonali Mitra, Hee-Jin Jang, Allen Kuncheria, Sung Wook Kang, Jong Min Choi, Ji Seon Shim, Claire Lee, Priyanka Ranchod, Peter Jindra, Maheshwari Ramineni, Meera Patel, R Taylor Ripley, Shawn S Groth, Shanda H Blackmon, Bryan M Burt, Hyun-Sung Lee

Faculty, Staff and Students Publications

Background: Immune checkpoint therapy (ICT) has significantly impacted the treatment of malignant pleural mesothelioma (MPM). Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT.

Methods: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of mesothelin and PD-L1. Both univariable and …

Sialidase Fusion Protein Protects Against Influenza Infection In A Cigarette Smoke-Induced Model Of Copd, Cheng-Yen Chang, Dominique Armstrong, John M Knight, Trevor V Gale, Stephen Hawley, Max Wang, Nancy Chang, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker …

Insights Into Protection Against Mycobacterium Tuberculosis Infection: Time To Officially Confirm Another Phenotype?, Todia P Setiabudiawan, Philip C Hill, Andrew R Dinardo, Reinout Van Crevel

Faculty, Staff and Students Publications

Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) remain elusive. In this issue of the JCI, Dallmann-Sauer and authors demonstrate that lack of tuberculin skin test (TST) and interferon γ release assay (IGRA) conversion among people with HIV despite years-long Mtb exposure is associated with alveolar lymphocytosis, including specific poly-cytotoxic T cells, and M1-type alveolar macrophages with a stronger ex vivo response to the pathogen. Studies in these rare individuals, termed "TB resisters" and in tuberculosis household contacts who are repeatedly IGRA negative in the months after a specific exposure event (known as "early clearers") help elucidate manipulatable …

Single-Nucleus Transcriptional Profiling Of The Placenta Reveals The Syncytiotrophoblast Stress Response To Covid-19, Rachel A Keuls, Scott A Ochsner, Mary B O'Neill, Diana R O'Day, Akihiko Miyauchi, Kadeshia M Campbell, Natalie Lanners, Jeffery A Goldstein, Connor Yee, Neil J Mckenna, Ronald J Parchem, Jacqueline G Parchem

Faculty, Staff and Students Publications

Background: COVID-19 in pregnancy is associated with placental immune activation, inflammation, and vascular malperfusion, but its impact on syncytiotrophoblast biology and function is unclear.

Objective: This study aimed to determine the effects of maternal COVID-19 on placental syncytiotrophoblasts using single-nucleus transcriptional profiling and to compare placental stress responses in COVID-19 and preeclampsia.

Study design: For transcriptional characterization of syncytiotrophoblasts, we used the single-nucleus RNA sequencing platform, single-cell combinatorial indexing RNA sequencing (sci-RNA-seq3), to profile placental villi and fetal membranes from unvaccinated patients with symptomatic COVID-19 at birth (n = 4), gestational age-matched controls (n = 4), and a case of …

Mapping The Transcriptional And Epigenetic Landscape Of Organotypic Endothelial Diversity In The Developing And Adult Mouse, Manuel E Cantu Gutierrez, Matthew C Hill, Gabrielle E Largoza, William B Gillespie, James F Martin, Joshua D Wythe

Faculty, Staff and Students Publications

The vascular endothelium features unique molecular and functional properties across different vessel types, such as between arteries, veins and capillaries, as well as between different organs, such as the leaky sinusoidal endothelium of the liver versus the impermeable vessels of the brain. However, the transcriptional networks governing endothelial organ specialization remain unclear. Here we profile the accessible chromatin and transcriptional landscapes of the endothelium from the mouse liver, lung, heart, kidney, brain and retina, across developmental time, to identify potential transcriptional regulators of endothelial heterogeneity. We then determine which of these putative regulators are conserved in human brain endothelial cells, …

A Multipronged Effort To Incorporate Professionalism Into Campuswide Programming Through A Center For Professionalism, Kyler M Godwin, Asma Ali, Larry Laufman, Ellen M Friedman

Faculty, Staff and Students Publications

Background Professionalism, a core competency for graduate medical education accreditation, has a clear educational mandate. However, the pathway to successful incorporation of professionalism within organizational culture has not been established. Integration of professionalism within the learning environment requires intentional design and formal education. Objective To describe the integration of professionalism in the learning environment through formal education and programming and report feasibility and acceptability data.

Methods The Center for Professionalism (Center) was developed in 2013 to align with the learning and clinical environments of our academic medical center. Primary drivers of a culture of professionalism were identified through input from …

Predictors And Outcomes Of First Pass Efficacy In Posterior Circulation Strokes: Insights From Star Collaboration, Muhammad U Hafeez, Muhammed A Essibayi, Daniel Raper, Omar Tanweer, Mithun Sattur, Sami Al-Kasab, Joshua Burks, Robert Townsend, Diana Alsbrook, Travis Dumont, Min S Park, Nitin Goyal, Adam S Arthur, Ilko Maier, Justin Mascitelli, Robert Starke, Stacey Wolfe, Kyle Fargen, Alejandro Spiotta, Peter T Kan

Faculty, Staff and Students Publications

Background: First-pass efficacy (FPE) has been established as an important predictor of favorable functional outcomes after endovascular thrombectomy (ET) in anterior circulation strokes. In this retrospective cohort study, we investigate predictors and clinical outcomes of FPE in posterior circulation strokes (pcAIS).

Methods: The Stroke Thrombectomy and Aneurysm Registry database was used to identify pcAIS patients who achieved FPE. Their baseline characteristics and outcomes were compared with the non-FPE group. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0-3. Univariate (UVA) and multivariate (MVA) analyses were done to evaluate predictors of FPE. Safety outcomes included distal emboli, vessel …

Foamy Monocytes And Atherogenesis In Mice With Combined Hyperlipidemia And Effects Of Antisense Knockdown Of Apociii, Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr−/− mice (Ldlr−/−ApoCIIItg) fed Western high-fat diet (WD). Tissue culture with THP-1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins on monocytes. Ldlr−/−ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr−/− mice, Ldlr−/−ApoCIIItg mice fed …

Telehealth Is Effective In The Evaluation Of Individuals With Undiagnosed Rare Disorders: An Undiagnosed Diseases Network Study, Queenie K-G Tan, Allyn Mcconkie-Rosell, Rachel Mahoney, Rebecca C Spillmann, Kelly Schoch, Sirisak Chanprasert, Maria T Acosta, Camilo Toro, Jill A Rosenfeld, James P Orengo, Daryl A Scott, Jorge L Granadillo, Kathleen Sisco, Daniel J Wegner, Mustafa Tekin, Stephanie Bivona, Léshon Peart, Lance Rodan, Devon Bonner, Matthew T Wheeler, Jonathan A Bernstein, Maura Ruzhnikov, Undiagnosed Diseases Network, David R Adams, Fuki M Hisama, Vandana Shashi

Faculty, Staff and Students Publications

Patients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassisted virtual physical examination (PE) with an in-person PE in undiagnosed individuals and also assessed participant telehealth satisfaction. Twenty-six individuals enrolled in the Undiagnosed Diseases Network study underwent an in-home synchronous virtual PE, and a subsequent in-person PE, by the same clinician. The participants completed surveys on telehealth usability and provider empathy. On PE, general appearance and craniofacial features showed near perfect agreement (κ = 0.81-1.00) between …

Most Elderly Patients With Subclinical Hypothyroidism Do Not Need To Be Treated, Risheng Xu, Nicola Abate, Nalini Ram, Kristina Little

Faculty, Staff and Students Publications

Whether subclinical hypothyroidism should be treated in elderly patients (≥ 65 years) is controversial. The authors argue for a personalized, wait-and-see approach rather than universal treatment, pointing out that randomized clinical trials have not shown that levothyroxine treatment makes any difference in terms of hard clinical end points, quality of life, or hypothyroid symptom relief in elderly patients with this condition.

Time Tracking And Comparison Of Genetic Counseling Tasks In Inpatient And Outpatient Settings, Alexandra Osborne, Emily Magness Bland, Callie Diamonstein, Kristen Fishler

Faculty, Staff and Students Publications

Genetic counselors (GCs) practice in critical care settings. Some GCs have full-time inpatient roles, while most GCs who see inpatients do so as needed or on a rotating schedule in addition to seeing patients in an outpatient setting. Few studies have tracked and compared the amount of time it takes GCs to perform tasks in the inpatient and outpatient settings. Genetic counselors were invited to participate in this study via the National Society of Genetic Counselors research listserv. Participants completed an online survey asking how their role is structured and what types of support are available to them while seeing …

Clinical And Genetic Delineation Of Autosomal Recessive And Dominant Actl6b-Related Developmental Brain Disorders, Elisa Cali, Tania Quirin, Clarissa Rocca, Stephanie Efthymiou, Antonella Riva, Dana Marafi, Maha S Zaki, Mohnish Suri, Roberto Dominguez, Hasnaa M Elbendary, Shahryar Alavi, Mohamed S Abdel-Hamid, Heba Morsy, Frederic Tran Mau-Them, Mathilde Nizon, Pavel Tesner, Lukáš Ryba, Faisal Zafar, Nuzhat Rana, Nebal W Saadi, Zahra Firoozfar, Pinar Gencpinar, Bulent Unay, Canan Ustun, Ange-Line Bruel, Christine Coubes, Jennifer Stefanich, Ozlem Sezer, Emanuele Agolini, Antonio Novelli, Gessica Vasco, Donatella Lettori, Mathieu Milh, Laurent Villard, Shimriet Zeidler, Henry Opperman, Vincent Strehlow, Mahmoud Y Issa, Hebatallah El Khassab, Prem Chand, Shahnaz Ibrahim, Ali Rashidi-Nezhad, Mohammad Miryounesi, Pegah Larki, Jennifer Morrison, Ingrid Cristian, Isabelle Thiffault, Nicole L Bertsch, Grace J Noh, John Pappas, Ellen Moran, Nikolaos M Marinakis, Joanne Traeger-Synodinos, Susan Hosseini, Mohammad Reza Abbaszadegan, Roseline Caumes, Lisenka E L M Vissers, Maedeh Neshatdoust, Mostafa Montazer Zohour, Elmostafa El Fahime, Christina Canavati, Lara Kamal, Moien Kanaan, Omar Askander, Victoria Voinova, Olga Levchenko, Shahzhad Haider, Sara S Halbach, Rayana Elias Maia, Salehi Mansoor, Vivek Jain, Sanjukta Tawde, Viveka Santhosh R Challa, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Lucas Alves Victor, Benito Pinero-Banos, Jennifer Hague, Heba Ahmed Elawady, Adelia Maria De Miranda Henriques-Souza, Huma Arshad Cheema, Muhammad Nadeem Anjum, Sara Idkaidak, Firas Alqarajeh, Osama Atawneh, Hagar Mor-Shaked, Tamar Harel, Giovanni Zifarelli, Peter Bauer, Fernando Kok, Joao Paulo Kitajima, Fabiola Monteiro, Juliana Josahkian, Gaetan Lesca, Nicolas Chatron, Dorothe Ville, David Murphy, Jeffrey L Neul, Sureni V Mullegama, Amber Begtrup, Isabella Herman, Tadahiro Mitani, Jennifer E Posey, Chee Geap Tay, Iram Javed, Lucinda Carr, Farah Kanani, Fiona Beecroft, Lee Hane, Elsayed Abdelkreem, Milan Macek, Luciana Bispo, Marwa Abd Elmaksoud, Farzad Hashemi-Gorji, Davut Pehlivan, David J Amor, Rami Abou Jamra, Wendy K Chung, Eshan Ghayoor Karimiani, Philippe M Campeau, Fowzan S Alkuraya, Alistair T Pagnamenta, Joseph G Gleeson, James R Lupski, Pasquale Striano, Andres Moreno-De-Luca, Denis L J Lafontaine, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.

Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, …

Communicating Blood Test Results In Primary Care: A Mixed-Methods Systematic Review, Helen Nankervis, Alyson L Huntley, Penny Whiting, William Hamilton, Hardeep Singh, Sarah Dawson, Rachel O'Donnell, Jane Sprackman, Anna Ferguson Montague, Jessica Watson

Faculty, Staff and Students Publications

Background: Online records access, including test results, was rolled out as part of changes to the GP contract in England in 2023. Blood test result communication is important for patient-centred care, patient safety, and primary care workload. Evidence is needed to ensure that test results are communicated safely and efficiently to patients in primary care.

Aim: To summarise existing evidence for blood test result communication between primary care providers and their patients and carers.

Design and setting: A mixed-methods systematic review was undertaken.

Method: MEDLINE, Embase, PsycInfo (Ovid), CINAHL (EBSCOhost), and the Cochrane Library were searched from January 2013-September 2023. …

Personality Factors Associated With Manner Of Death: A Psychological Autopsy Study, Christopher I Gurguis, Scott D Lane, Edison Leung, Joy M Schmitz, Consuelo Walss-Bass, Thomas D Meyer

Staff and Researcher Publications

Psychological autopsies are a well-established tool for understanding contributing factors in suicide completion. These tools have been used less often to understand personality characteristics of people with other manners of death (e.g. overdose). This study examined personality characteristics related to the manner of death in 83 autopsy cases using the UTHealth Psychological Autopsy Interview Schedule (UTH-PAIS), a psychological autopsy which assesses the presence of mental illness or substance use disorder but also includes items to capture transdiagnostic personality factors. Exploratory factor analysis of the items assessing personality factors was used to examine patterns in personality, and these factors were confirmed …

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 …

Gastroesophageal Reflux And Gastrointestinal Symptoms After Metabolic And Bariatric Surgery In Adolescents: An 8-Year Follow-Up Analysis, John B Rode, Suhail A Zeineddin, Jane C Khoury, Todd M Jenkins, Stephanie R Sisley, Anita P Courcoulas, Justin R Ryder, Marc P Michalsky, Thomas H Inge

Children’s Nutrition Research Center Staff Publications

Importance: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed metabolic and bariatric surgery (MBS) procedures in adolescents and adults. Despite their safety and effectiveness, there is concern over postoperative gastrointestinal symptoms (GIS), especially gastroesophageal reflux symptoms (GERS), in those undergoing VSG.

Objective: To evaluate the long-term prevalence of GIS in adolescents who underwent RYGB or VSG.

Design, setting, and participants: This is a prospective, multicenter, observational cohort study at five academic referral centers in the United States. Patients were enrolled from February 28, 2007, through December 30, 2011. The analysis included 228 adolescents: 161 …

Revisions To The Safety Assurance Factors For Electronic Health Record Resilience (Safer) Guides To Update National Recommendations For Safe Use Of Electronic Health Records, Dean F Sittig, Trisha Flanagan, Patricia Sengstack, Rosann T Cholankeril, Sara Ehsan, Amanda Heidemann, Daniel R Murphy, Hojjat Salmasian, Jason S Adelman, Hardeep Singh

Faculty, Staff and Student Publications

The Safety Assurance Factors for Electronic Health Record (EHR) Resilience (SAFER) Guides provide recommendations to healthcare organizations for conducting proactive self-assessments of the safety and effectiveness of their EHR implementation and use. Originally released in 2014, they were last updated in 2016. In 2022, the Centers for Medicare and Medicaid Services required their annual attestation by US hospitals.

Objectives: This case study describes how SAFER Guide recommendations were updated to align with current evidence and clinical practice.

Materials and methods: Over nine months, a multidisciplinary team updated SAFER Guides through literature reviews, iterative feedback, and online meetings.

Results: We reduced …

Glucose Uptake In Pigment Glia Suppresses Tau-Induced Inflammation And Photoreceptor Degeneration, Mikiko Oka, Sho Nakajima, Emiko Suzuki, Shinya Yamamoto, Kanae Ando

Duncan NRI Faculty and Staff Publications

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human MATP (hereafter referred to as Tau) in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by the formation of dark-stained round inclusion-like structures and swelling of the lamina cortex. We found that inclusion-like structures …

De Novo Variants In Rybp Are Associated With A Severe Neurodevelopmental Disorder And Congenital Anomalies, Monika Weisz-Hubshman, Lindsay C Burrage, Sharayu V Jangam, Jill A Rosenfeld, Sandra Von Hardenberg, Anke Bergmann, Manuela Friederike Richter, Malgorzata Rydzanicz, Rafal Ploski, Agnieszka Stembalska, Wendy K Chung, Rebecca R Hernan, Foong Y Lim, Theresa Brunet, Steffen Syrbe, Boris Keren, Solveig Heide, David R Murdock, Hongzheng Dai, Fan Xia, Shamika Ketkar, Brian Dawson, Vinodh Narayanan, Hillary K Graves, Undiagnosed Diseases Network, Michael F Wangler, Carlos Bacino, Brendan Lee

Duncan NRI Faculty and Staff Publications

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

Methods: Functional consequences of RYBP variants were assessed using in vitro cellular and in vivo Drosophila melanogaster studies.

Results: We described 7 individuals with heterozygous de novo variants of RYBP and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in RYBP localize to the N-terminal domain of …