Medicine and Health Sciences Commons^™

Blood Matters: The Hematological Signatures Of Coronavirus Infection, Ayelen Toro, Ana P Arévalo, Marianoel Pereira-Gómez, Agustina Sabater, Eric A Zizzi, Paula Perbolianachis, Gaston Pascual, Sofia Lage-Vickers, Jorge L Pórfido, Ines Achinelli, Rocio Seniuk, Juan Bizzotto, Pablo Sanchis, Alvaro Olivera, Alejandro Leyva, Pilar Moreno, Alicia Costábile, Alvaro Fajardo, Federico Carrión, Martín Fló, Natalia Olivero-Deibe, Fernando Rodriguez, Nicolas Nin, Nicolas Anselmino, Estefania Labanca, Elba Vazquez, Javier Cotignola, Daniel F Alonso, Maria P Valacco, Marcelo Marti, Francesco Gentile, Artem Cherkasov, Martina Crispo, Gonzalo Moratorio, Geraldine Gueron

Faculty, Staff and Student Publications

Recent developments have broadened our perception of SARS-CoV-2, indicating its capability to affect the body systemically beyond its initial recognition as a mere respiratory pathogen. However, the pathways of its widespread are not well understood. Employing a dual-modality approach, we integrated findings from a Murine Hepatitis Virus (MHV) infection model with corroborative clinical data to investigate the pervasive reach of Coronaviruses. The novel presence of viral particles within red blood cells (RBCs) was demonstrated via high-resolution transmission electron microscopy, with computational modeling elucidating a potential heme-mediated viral entry mechanism via Spike protein affinity. Our data affirm viral localization in RBCs, …

Host Dna Depletion On Frozen Human Respiratory Samples Enables Successful Metagenomic Sequencing For Microbiome Studies, Minsik Kim, Raymond C Parrish, Michael J Tisza, Viral S Shah, Thi Tran, Matthew Ross, Juwan Cormier, Aribah Baig, Ching-Ying Huang, Laura Brenner, Isabel Neuringer, Katrine Whiteson, J Kirk Harris, Amy D Willis, Peggy S Lai

Faculty, Staff and Students Publications

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, 99.2%, and 99.7% host reads, respectively. Host depletion effects varied by sample type, generally increasing microbial reads, species and functional richness; this was mediated by higher effective sequencing depth. Rarefaction curves showed …

Human Single Cell Rna-Sequencing Reveals A Targetable Cd8+ Exhausted T Cell Population That Maintains Mouse Low-Grade Glioma Growth, Rasha Barakat, Jit Chatterjee, Rui Mu, Xuanhe Qi, Xingxing Gu, Igor Smirnov, Olivia Cobb, Karen Gao, Angelica Barnes, Jonathan Kipnis, David H Gutmann

2020-Current year OA Pubs

In solid cancers, T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that capitalize upon this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8

Creating A Sense Of Place When Implementing A New Emergency Department In Denmark: A Qualitative Study, Jeanette Wassar Kirk, Per Nilsen, Ove Andersen, Nina Thórný Stefánsdóttir, Mette Bendtz Lindstrøm, Byron J Powell, Tine Tjørnhøj-Thomsen

2020-Current year OA Pubs

BACKGROUND: Physical locations play an essential yet often overlooked role in healthcare implementation processes. Implementation Science frameworks such as the Theoretical Domains Framework, the Consolidated Framework for Implementation Research, and the Implementation in Context framework acknowledge the importance of the physical environment, but they often treat it as a passive backdrop for change. However, from a cultural geographic perspective, spaces and places are dynamic, influencing behavior, social structures, and the acceptance of new practices. This study aims to explore how managers and emloyees develop a sense of place in a new emergency department (ED) and how these spatial dynamics influence …

Myt1l Deficiency Impairs Excitatory Neuron Trajectory During Cortical Development, Allen Yen, Simona Sarafinovska, Xuhua Chen, Dominic D Skinner, Fatjon Leti, Marialynn Crosby, Jessica Hoisington-Lopez, Yizhe Wu, Jiayang Chen, Zipeng A Li, Kevin K Noguchi, Robi D Mitra, Joseph D Dougherty

2020-Current year OA Pubs

Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. MYT1L is used as a pro-neural factor in fibroblast-to-neuron transdifferentiation and is hypothesized to influence neuronal specification and maturation, but it is not clear which neuron types are most impacted by MYT1L loss. In this study, we profile 412,132 nuclei from the forebrains of wild-type and MYT1L-deficient mice at three developmental stages: E14 at the peak of neurogenesis, P1 when cortical neurons have been born, and P21 when neurons are maturing, to examine the role of MYT1L levels on neuronal development. MYT1L deficiency …

Clinical Effects Of Dexamethasone Among Patients With Sickle Cell Disease Hospitalized With Covid-19: Outcomes From A Single Academic Health System, William M. Garneau, Matthew J. Lankiewicz, Catherine R. Lesko, Ashley P. Lauriello, Kelly A. Gebo, Sophie M. Lanzkron

Department of Medicine Faculty Papers

BACKGROUND: Dexamethasone is a steroid used in the treatment of hospitalized patients with severe COVID-19. However, the effect of dexamethasone in patients with SCD remains unclear given that steroids may precipitate vaso-occlusive crisis (VOC) in patients with SCD.

METHODS AND FINDINGS: We performed a retrospective analysis of patients with SCD who were hospitalized at Johns Hopkins Health System between June 1, 2020 and June 26, 2022. We reviewed individual charts to assess severity of illness and eligibility for dexamethasone treatment. The exposure of interest was treatment with dexamethasone. Outcomes of interest included incident VTE, length of hospital stay, ICU admission, …

Metabolite Signatures Of Chronological Age, Aging, Survival, And Longevity, Paola Sebastiani, Mary F Feitosa, Mary K Wojczynski, Gary J Patti, Et Al.

2020-Current year OA Pubs

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic …

Magrolimab Plus Rituximab In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: 3-Year Follow-Up Of A Phase 1/2 Trial, Amitkumar Mehta, Leslie Popplewell, Graham P Collins, Sonali M Smith, Ian W Flinn, Nancy L Bartlett, Nilanjan Ghosh, Gal Hacohen-Kleiman, Yanan Huo, Linda Su-Feher, Camille Renard, Ranjana Advani, Mark Roschewski

2020-Current year OA Pubs

Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining magrolimab (anti-cluster-of-differentiation [CD] 47 antibody) with the anti-CD20 antibody rituximab (M+R) has antitumor activity against R/R iNHL. We report 3-year follow-up data from this phase 1b/2 study assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 patient groups in phase 1b M+R received 10 to 45-mg/kg magrolimab doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary end points were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary end …

Rsk1 Dependency In Flt3-Itd Acute Myeloid Leukemia, Tim Kong, Angelo B A Laranjeira, Christopher T Letson, Layow Yu, Fan He, Aarthi Jayanthan, Gerrit Los, Sandra E Dunn, Grant A Challen, Stephen T Oh

2020-Current year OA Pubs

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed …

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Alexander S Shavkunov, Qi Miao, Akata Saha, Tomoyuki Minowa, Martina Molgora, Charmelle D Williams, Mehdi Chaib, Anna M Highsmith, Josué E Pineda, Sayan Alekseev, Elise Alspach, Kenneth H Hu, Marco Colonna, Kristen E Pauken, Ken Chen, Matthew M Gubin

Faculty, Staff and Student Publications

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines …

Real-World Impact Of Emicizumab And Immunosuppression On Acquired Hemophilia A: A Multicenter Us Cohort, Jacqueline N Poston, Cassandra Bryan, Annette Von Drygalski, Kadhim Al Banaa, Jenny Y Zhou, Aric Parnes, Evan C Chen, Osman Khan, Patrick Ellsworth, Lorraine Cafuir, Christopher Walsh, Miguel A Escobar, James F Wu, Lynn M Malec, Craig M Kessler, Maissaa Janbain, Rebecca Kruse-Jarres

Faculty, Staff and Student Publications

Acquired hemophilia A (AHA) is an autoimmune bleeding disorder that is caused by factor VIII (FVIII) autoantibodies with high morbidity and mortality due to bleeding and complications from immunosuppression (IST). To address the real-world implications of the FVIII mimetic antibody, emicizumab, and the role of IST, we retrospectively collected de-identified data on 62 patients with AHA who were treated off-label with emicizumab for a median of 10 weeks at 12 US-based hemophilia treatment centers. Most patients (95.2%) had acute bleeding at diagnosis, and 62.9% had partial or no control of bleeds despite the use of hemostatic agents at the time …

Protective Effect And Molecular Mechanisms Of Human Non-Neutralizing Cross-Reactive Spike Antibodies Elicited By Sars-Cov-2 Mrna Vaccination, Jordan J Clark, Ali H Ellebedy, Et Al.

2020-Current year OA Pubs

Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection against disease progression. Non-neutralizing antibodies cannot directly protect against infection but may recruit effector cells and thus contribute to the clearance of infected cells. Additionally, they often bind conserved epitopes across multiple variants. Here, we characterize 42 human monoclonal antibodies (mAbs) from coronavirus disease 2019 (COVID-19)-vaccinated individuals. Most of these antibodies exhibit no neutralizing activity in vitro, but several non-neutralizing antibodies provide protection against lethal challenge with SARS-CoV-2 …

Cd4+ T Cells Drive Corneal Nerve Damage But Not Epitheliopathy In An Acute Aqueous-Deficient Dry Eye Model, Alexia Vereertbrugghen, Manuela Pizzano, Agostina Cernutto, Florencia Sabbione, Irene A Keitelman, Douglas Vera Aguilar, Ariel Podhorzer, Federico Fuentes, Celia Corral-Vázquez, Mauricio Guzmán, Mirta N Giordano, Analía Trevani, Cintia S De Paiva, Jeremías G Galletti

Faculty, Staff and Students Publications

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, …

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Martina Molgora, Marco Colonna, Et Al.

2020-Current year OA Pubs

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1

Intervention Mapping For Refining A Sport-Based Public Health Intervention In Rural Schools, Mckenna G Major, Janette M Watkins, Janelle M Goss, Derek W Craig, Zack Waggoner, Vanessa M Martinez Kercher, Kyle A Kercher

Faculty, Staff and Student Publications

Sport-based youth development programs, delivered through campus-community partnerships, can create impactful experiences for college students, meet university objectives, and improve the health of children in under-resourced rural communities. This study aimed to pilot test intervention mapping (IM), a systematic approach to intervention development and implementation, to refine the Hoosier Sport intervention, which is a local public health initiative that utilizes the Obesity-Related Behavioral Intervention Trials (ORBITs) model to improve physical activity in middle school children. The IM process, which included a diverse IM planning and advisory group of university representatives and local schools, was guided by self-determination theory (SDT) and …

Impact Of Vitamin D On Hyperoxic Acute Lung Injury In Neonatal Mice, Thu T Tran, Jonathan Davies, Richard A Johnston, Harry Karmouty-Quintana, Huiling Li, Caroline E Crocker, Amir M Khan, Joseph L Alcorn

Faculty, Staff and Students Publications

BACKGROUND: Prolonged exposure to hyperoxia can lead to hyperoxic acute lung injury (HALI) in preterm neonates. Vitamin D (VitD) stimulates lung maturation and acts as an anti-inflammatory agent. Our objective was to determine if VitD provides a dose-dependent protective effect against HALI by reducing inflammatory cytokine expression and improving alveolarization and lung function in neonatal mice.

METHODS: C57BL/6 mouse neonates were randomized and placed in room air or hyperoxic (85% O

RESULTS: Neonatal mice treated with VitD in hyperoxic conditions had improved weight gain, reduced pulmonary edema and increased alveolar surface area compared to untreated pups in hyperoxia. No significant …

Association Of Type 2 Diabetes Mellitus With Sensorineural Hearing Loss - A Population-Based Analysis, Marwin Li, Natalie Perlov, Jena Patel, Dev Amin, Ayan Kumar, Zachary D. Urdang, Thomas O. Willcox, Rebecca C. Chiffer

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVE: To test the hypothesis that patients with poorly controlled type 2 diabetes mellitus are more likely to develop sensorineural hearing loss (SNHL) than non-diabetic patients.

STUDY DESIGN: Retrospective cohort study.

SETTING: TriNetX US Collaborative Network (2003-2022).

METHODS: Electronic medical record data from the TriNetX US Collaborative Network was queried for subjects without prior hearing loss, defined using medical billing codes (ICD-10, CPT, etc.), who were diagnosed with type 2 diabetes mellitus after January 2003. Patients were stratified by most recent HbA1c (8.0-13.9% or ≥14.0%) and by age at diagnosis (21-30, 31-40, 41-50, 51-60, 61-70, ≥71 years). Primary outcome was …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Li Ding, Et Al.

2020-Current year OA Pubs

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Mitochondrial Heteroplasmy Improves Risk Prediction For Myeloid Neoplasms, Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J Lake, Monkol Lek, Meng Ru, Megan L Grove, Anna Prizment, Corinne E Joshu, Elizabeth A Platz, Eliseo Guallar, Dan E Arking, Lukasz P Gondek

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with …

Clc-Kb Pore Mutation Disrupts Glycosylation And Triggers Distal Tubular Remodeling, Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Faculty, Staff and Student Publications

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Does Muscle Pain Induce Alterations In The Pelvic Floor Motor Unit Activity Properties In Interstitial Cystitis/Bladder Pain Syndrome? A High-Density Semg-Based Study, Monica Albaladejo-Belmonte, Michael Houston, Nicholas Dias, Theresa Spitznagle, Henry Lai, Yingchun Zhang, Javier Garcia-Casado

2020-Current year OA Pubs

Several studies have shown interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic condition that poses challenges in both diagnosis and treatment, is associated with painful pelvic floor muscles (PFM) and altered neural drive to these muscles. However, its pathophysiology could also involve other alterations in the electrical activity of PFM motor units (MUs). Studying these alterations could provide novel insights into IC/BPS and help its clinical management. This study aimed to characterize PFM activity at the MU level in women with IC/BPS and pelvic floor myalgia using high-density surface electromyography (HD-sEMG). Signals were recorded from 15 patients and 15 healthy controls …

Whole-Genome Analysis Of Plasma Fibrinogen Reveals Population-Differentiated Genetic Regulators With Putative Liver Roles, Jennifer E Huffman, Jayna Nicholas, Julie Hahn, Adam S Heath, Laura M Raffield, Lisa R Yanek, Jennifer A Brody, Florian Thibord, Laura Almasy, Traci M Bartz, Lawrence F Bielak, Russell P Bowler, Germán D Carrasquilla, Daniel I Chasman, Ming-Huei Chen, David B Emmert, Mohsen Ghanbari, Jeffrey Haessler, Jouke-Jan Hottenga, Marcus E Kleber, Ngoc-Quynh Le, Jiwon Lee, Joshua P Lewis, Ruifang Li-Gao, Jian'an Luan, Anni Malmberg, Massimo Mangino, Riccardo E Marioni, Angel Martinez-Perez, Nathan Pankratz, Ozren Polasek, Anne Richmond, Benjamin A T Rodriguez, Jerome I Rotter, Maristella Steri, Pierre Suchon, Stella Trompet, Stefan Weiss, Marjan Zare, Paul Auer, Michael H Cho, Paraskevi Christofidou, Gail Davies, Eco De Geus, Jean-François Deleuze, Graciela E Delgado, Lynette Ekunwe, Nauder Faraday, Martin Gögele, Andreas Greinacher, He Gao, Tom Howard, Peter K Joshi, Tuomas O Kilpeläinen, Jari Lahti, Allan Linneberg, Silvia Naitza, Raymond Noordam, Ferran Paüls-Vergés, Stephen S Rich, Frits R Rosendaal, Igor Rudan, Kathleen A Ryan, Juan Carlos Souto, Frank J A Van Rooij, Heming Wang, Wei Zhao, Lewis C Becker, Andrew Beswick, Michael R Brown, Brian E Cade, Harry Campbell, Kelly Cho, James D Crapo, Joanne E Curran, Moniek P M De Maat, Margaret Doyle, Paul Elliott, James S Floyd, Christian Fuchsberger, Niels Grarup, Xiuqing Guo, Sarah E Harris, Lifang Hou, Ivana Kolcic, Charles Kooperberg, Cristina Menni, Matthias Nauck, Jeffrey R O'Connell, Valeria Orrù, Bruce M Psaty, Katri Räikkönen, Jennifer A Smith, Jose Manuel Soria, David J Stott, Astrid Van Hylckama Vlieg, Hugh Watkins, Gonneke Willemsen, Peter W F Wilson, Yoav Ben-Shlomo, John Blangero, Dorret Boomsma, Simon R Cox, Abbas Dehghan, Johan G Eriksson, Edoardo Fiorillo, Myriam Fornage, Torben Hansen, Caroline Hayward, M Arfan Ikram, J Wouter Jukema, Sharon L R Kardia, Leslie A Lange, Winfried März, Rasika A Mathias, Braxton D Mitchell, Dennis O Mook-Kanamori, Pierre-Emmanuel Morange, Oluf Pedersen, Peter P Pramstaller, Susan Redline, Alexander Reiner, Paul M Ridker, Edwin K Silverman, Tim D Spector, Uwe Völker, Nicholas J Wareham, James F Wilson, Jie Yao, David-Alexandre Trégouët, Andrew D Johnson, Alisa S Wolberg, Paul S De Vries, Maria Sabater-Lleal, Alanna C Morrison, Nicholas L Smith

Faculty, Staff and Student Publications

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 …

Teen Dating Violence And The Covid-19 Pandemic: Trends From A Longitudinal Study In Texas, Leila Wood, Elizabeth Baumler, Morgan E Pettyjohn, Jeff R Temple

Faculty, Staff and Student Publications

Purpose: Teen dating violence (TDV) is a global public health and safety issue causing health impacts to youth people. This study aimed to examine: (1) the impact of the pandemic on TDV victimisation rates and (2) socioecological factors associated with sustained risk for TDV victimisation during the first year of COVID-19.

Methods: Data are from an ongoing randomised controlled trial of a TDV prevention programme in Texas (n=2768). We conducted annual assessments in 2019-2021. We used regression modelling to assess demographic, individual, peer and family factors associated with TDV risks.

Results: TDV rates declined from 11.9% in 2019 to 5.2% …

Firearm Access, Carriage And Use In An Ethnically Diverse Sample Of Young Adults In Texas, Usa, Yu Lu, Elizabeth Baumler, Annalyn Saludares Demello, Leila Wood, Hillary Mcguire, Jeff R Temple

Faculty, Staff and Student Publications

Background Despite the high rates of firearm ownership and firearm-related injuries and mortalities in Southern US states, understandings on the factors contributing to these are lacking.

Methods Using wave 10 (2021) data from a longitudinal study, we examined firearm-related experiences among 636 ethnically diverse young adults (mean age=26 years; 62% female) in Texas, USA.

Results Just over half of participants had ready access to firearms, with 22.3% having carried a firearm outside of their home, 4.9% having been threatened with a firearm by a romantic partner and 4.4% by a non-romantic partner. More firearm access and carriage were reported in …

Genetic Risk Stratification And Outcomes Among Treatment-Naive Patients With Aml Treated With Venetoclax And Azacitidine, Hartmut Döhner, Keith W Pratz, Courtney D Dinardo, Andrew H Wei, Brian A Jonas, Vinod A Pullarkat, Michael J Thirman, Christian Récher, Andre C Schuh, Sunil Babu, Xiaotong Li, Grace Ku, Zihuan Liu, Yan Sun, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most …

Comparison Of The Bristol Stool Scale And Modified Version For Children: Use By Providers Vs Children, James Orozco, Mariella M Self, Sara Grisales, Bruno P Chumpitazi, Danita I Czyzewski, Meagan S Mcmullen, Rebecca Berger, Clarissa A Gonzalez, Amber L Cunha, Robert J Shulman

Faculty, Staff and Students Publications

Introduction: Accurate report of stool form is essential to diagnosis and assessment of treatment response. The modified Bristol Stool Form Scale for Children (mBSFS-C) classifies stool form into 5 types and is reliable and valid. However, a direct comparison of provider's and children's ratings using the mBSFS-C vs the traditional BSFS that uses 7 stool form types has not been done.

Methods: Pediatric gastroenterology providers and children rated the same 35 stool photographs, reflecting diverse stool forms, using both scales. The order of photograph presentation and scale use were randomized. For each photograph, the most common rating (modal rating) was …

Genotype-Specific Effects Of Elamipretide In Patients With Primary Mitochondrial Myopathy: A Post Hoc Analysis Of The Mmpower-3 Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russekk Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, Anthony Abbruscato, David A Brown, Alana Sullivan, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Students Publications

BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those …

Analyzing Longitudinal Trait Trajectories Using Gwas Identifies Genetic Variants For Kidney Function Decline, Simon Wiegrebe, Mathias Gorski, Janina M Herold, Klaus J Stark, Barbara Thorand, Christian Gieger, Carsten A Böger, Johannes Schödel, Florian Hartig, Han Chen, Thomas W Winkler, Helmut Küchenhoff, Iris M Heid

Faculty, Staff and Student Publications

Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use seven statistical approaches to analyze the UK Biobank data and simulated data, finding that a linear mixed model is a powerful approach with unbiased effect estimates which is viable …