Medical Specialties Commons^™

Author Correction: Orthogonal And Multiplexable Genetic Perturbations With An Engineered Prime Editor And A Diverse Rna Array, Qichen Yuan, Hongzhi Zeng, Tyler C Daniel, Qingzhuo Liu, Yongjie Yang, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M Abramson, Boyang Zhang, Yong Xu, Xue Gao

Faculty, Staff and Students Publications

Correction to: Nature Communications 10.1038/s41467-024-55134-9, published online 30 December 2024

In the version of the article initially published, there were errors in Fig. 3d, where in the x-axis labels now reading “GPP-shRNA1, GPP-shRNA2, GPP-shRNA3…,” the second and third labels were duplicates of the first. The figure is amended in the HTML and PDF versions of the article.

Long-Read Sequencing Of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity And Disease Susceptibility, Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Chinese Pangenome Consortium (Cpc), Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan

Faculty, Staff and Students Publications

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could …

Contrast-Enhanced Magnetic Resonance Imaging Based Calf Muscle Perfusion And Machine Learning In Peripheral Artery Disease, Bijen Khagi, Tatiana Belousova, Christina M Short, Addison A Taylor, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

Peripheral artery disease (PAD) remains underdiagnosed and undertreated and is associated with an increased risk for adverse cardiovascular outcomes. Imaging provides an approach to identifying patients with PAD. However, the role of integrating imaging with machine learning to identify PAD patients and potentially assess disease severity remains understudied. A total of 56 participants, including 36 PAD patients with intermittent claudication and 20 matched controls, underwent contrast-enhanced magnetic resonance imaging (CE-MRI) calf muscle perfusion scanning. CE-MRI-derived dynamic muscle perfusion maps were developed to quantify alterations of the microvascular circulation in the calf muscles based on voxel contrast enhancement. These dynamic muscle …

Red Meat Consumption And Hypertension: An Updated Review, Tara S Allen, Michael Najem, Alexis C Wood, Danielle J Lee, Lorena S Pacheco, Lori B Daniels, Matthew A Allison

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: Hypertension (HTN) is a major risk factor for cardiovascular diseases (CVD). The global prevalence of HTN and related CVD mortality continues to rise. The development of HTN is influenced by genetic predisposition and modifiable risk factors, including diet. One area of ongoing debate is the relationship between red meat consumption and risk of HTN.

RECENT FINDINGS: Processed red meat has become increasingly implicated in the pathogenesis and morbidity of HTN, though randomized control trials comparing HTN-related outcomes associated with red meat subtypes have yielded heterogenous results. This review summarizes the existing relevant literature and highlights the methodological …

Neuronal Network Activation Induced By Forniceal Deep Brain Stimulation In Mice, Bin Tang, Zhenyu Wu, Qi Wang, Jianrong Tang

Faculty, Staff and Students Publications

Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry …

Motor Pool Selectivity Of Neuromuscular Degeneration In Type I Spinal Muscular Atrophy Is Conserved Between Human And Mouse, Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson

Faculty, Staff and Students Publications

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support …

Bi-Allelic Kics2 Mutations Impair Kicstor Complex-Mediated Mtorc1 Regulation, Causing Intellectual Disability And Epilepsy, Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack

Faculty, Staff and Students Publications

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and …

Characterizing Features Affecting Local Ancestry Inference Performance In Admixed Populations, Jessica Honorato-Mauer, Nirav N Shah, Adam X Maihofer, Clement C Zai, Sintia Belangero, Caroline M Nievergelt, Marcos Santoro, Elizabeth G Atkinson

Faculty, Staff and Students Publications

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR). Simulating linkage-disequilibrium-informed admixed haplotypes under a variety of 2- and 3-way admixture models, we implemented a standard LAI pipeline, testing the impact of reference panel composition, DNA data type, demography, and …

Dna-Binding Affinity And Specificity Determine The Phenotypic Diversity In Bcl11b-Related Disorders, Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar De La Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Undiagnosed Diseases Network, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel

Faculty, Staff and Students Publications

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Acute Mecp2 Loss In Adult Mice Reveals Transcriptional And Chromatin Changes That Precede Neurological Dysfunction And Inform Pathogenesis, Sameer S Bajikar, Jian Zhou, Ryan O'Hara, Harini P Tirumala, Mark A Durham, Alexander J Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari Krishna Yalamanchili, Ying-Wooi Wan, Laura A Banaszynski, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we …

Novel Intraoperative Applications Of Fluorescence Imaging Using Indocyanine Green In Pediatric Urology, Albert S T Lee, Ching Man Carmen Tong

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: Near-infrared fluorescence imaging (NIRF) with the use of indocyanine green (ICG) has been recently adopted in pediatric urology after its well-published use in the adult population. As a powerful tool that can help delineate complex anatomy and congenital anomalies, we discuss the various applications of this imaging in minimally invasive and open surgery in pediatric urology.

RECENT FINDINGS: The most reported applications of ICG in pediatric urology are within minimally invasive surgery, particularly varicoceles, renal surgery such as nephrectomies and renal tumor excision, mimicking its use in adult urology. ICG has also been applied to reconstructive urology …

Neutralizing Antibody Immune Correlates For A Recombinant Protein Vaccine In The Covail Trial, Youyi Fong, Lauren Dang, Bo Zhang, Jonathan Fintzi, Shiyu Chen, Jing Wang, Nadine G Rouphael, Angela R Branche, David J Diemert, Ann R Falsey, Cecilia Losada, Lindsey R Baden, Sharon E Frey, Jennifer A Whitaker, Susan J Little, Satoshi Kamidani, Emmanuel B Walter, Richard M Novak, Richard Rupp, Lisa A Jackson, Chenchen Yu, Craig A Magaret, Cindy Molitor, Bhavesh Borate, Tara M Babu, Angelica C Kottkamp, Anne F Luetkemeyer, Lilly C Immergluck, Rachel M Presti, Martín Bäcker, Patricia L Winokur, Siham M Mahgoub, Paul A Goepfert, Dahlene N Fusco, Robert L Atmar, Christine M Posavad, Jinjian Mu, Mat Makowski, Mamodikoe K Makhene, Seema U Nayak, Paul C Roberts, Dean Follmann, Peter B Gilbert

Faculty, Staff and Students Publications

For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Targeting Tiam1 Enhances Hippocampal-Dependent Learning And Memory In The Adult Brain And Promotes Nmda Receptor-Mediated Synaptic Plasticity And Function, Francisco A Blanco, Md Ali Bin Saifullah, Jinxuan X Cheng, Carlota Abella, Federico Scala, Karen Firozi, Sanyong Niu, Jin Park, Jeannie Chin, Kimberley F Tolias

Faculty, Staff and Students Publications

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO) and assessed …

Update On Cancer Screening In Children With Syndromes Of Bone Lesions, Hereditary Leiomyomatosis And Renal Cell Carcinoma Syndrome, And Other Rare Syndromes, Orli Michaeli, Sun Young Kim, Sarah G Mitchell, Marjolijn C J Jongmans, Jonathan D Wasserman, Melissa R Perrino, Anirban Das, Suzanne P Macfarland, Sarah R Scollon, Mary-Louise C Greer, Nara Sobreira, Bailey Gallinger, Philip J Lupo, David Malkin, Kami Wolfe Schneider, Kris Ann P Schultz, William D Foulkes, Emma R Woodward, Douglas R Stewart

Faculty, Staff and Students Publications

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline …

Characterizing The Genetic Basis For Inherited Retinal Disease: Lessons Learned From The Foundation Fighting Blindness Clinical Consortium's Gene Poll, Kari Branham, Lassana Samarakoon, Isabelle Audo, Allison R Ayala, Janet K Cheetham, Stephen P Daiger, Patty Dhooge, Jacque L Duncan, Todd A Durham, Abigail T Fahim, Rachel M Huckfeldt, Robert B Hufnagel, Susanne Kohl, Ramiro S Maldonado, Michele Melia, Michel Michaelides, Mark E Pennesi, José-Alain Sahel, Juliana M Ferraz Sallum, Mandeep S Singh, Dror Sharon, Kimberly Stepien, Kaylie Jones, Christina Y Weng

Faculty, Staff and Students Publications

PURPOSE: The Foundation Fighting Blindness (FFB) Consortium is a collaboration of 41 international clinical centers that manage patients affected with inherited retinal diseases (IRDs). The annual Consortium gene poll was initiated in 2020 to capture the genetic cause of disease in patients with IRD and associated clinical practices of Consortium sites. Data from the 2022 gene poll are reported here.

METHODS: In 2022, academic, private practice, and government ophthalmology clinics that are members of the Consortium centers were polled to identify per-case IRD genetic causality from a list of 387 syndromic and nonsyndromic IRD genes. The survey also assessed how …

From Bench To Bedside: Murine Models Of Inherited And Sporadic Brain Arteriovenous Malformations, Ashely R Ricciardelli, Gael Genet, Nafiisha Genet, Samuel T Mcclugage, Peter T Kan, Karen K Hirschi, Jason E Fish, Joshua D Wythe

Faculty, Staff and Students Publications

Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in …

Dairy Consumption And The Colonic Mucosa-Associated Gut Microbiota In Humans-A Preliminary Investigation, Ellie Chen, Nadim J Ajami, Donna L White, Yanhong Liu, Shawn Gurwara, Kristi Hoffman, David Y Graham, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

Background: Dairy consumption has been associated with various health outcomes that may be mediated by changes in gut microbiota.

Methods: This cross-sectional study investigated the association between the colonic mucosa-associated gut microbiota and the self-reported intake of total dairy, milk, cheese, and yogurt. A total of 97 colonic mucosal biopsies collected from 34 polyp-free individuals were analyzed. Dairy consumption in the past year was assessed using a food frequency questionnaire. The 16S rRNA gene V4 region was amplified and sequenced. Operational taxonomic unit (OTU) classification was performed using the UPARSE and SILVA databases. OTU diversity and relative abundance were compared …

Use Of Immunoglobulin Replacement Therapy In Clinical Practice: A Review, Jibran Ahmed, Yeonjoo Choi, Taeyeong Ko, Joann Lim, Joud Hajjar

Faculty, Staff and Students Publications

Immunoglobulins (Igs) are produced by B lymphocytes and play a key role in humoral immunity. Igs are classified into five isotypes (IgG, IgA, IgM, IgE, and IgD). Their primary function is to recognize and bind to foreign antigens. When Igs bind to antigens, they facilitate phagocytosis and promote clearance mediated by other immune cells. It is an essential component in protecting the host from outside pathogens. Hypogammaglobulinemia predisposes an individual to severe and recurrent infections. Therefore, replacement therapy is recommended to maintain optimal Ig level. In addition, Igs can modulate immune responses by to neutralizing proteins such as endotoxins or …

Disease Activity Of Rheumatoid Arthritis And Kidney Function Decline: A Large Prospective Registry Study, Sho Fukui, Wolfgang C Winkelmayer, Sara K Tedeschi, Javier Marrugo, Hongshu Guan, Leslie Harrold, Heather J Litman, Tomohiro Shinozaki, Daniel H Solomon

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain.

Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR< 60 mL/min/1.73 m2) and stage G3b (eGFR< 45 mL/min/1.73 m2). Results were adjusted for relevant time-fixed and time-varying covariates.

Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m2) contributed 234 973 visits and 146 778 person-years …

Oxidative Stress Promotes Lipid-Laden Macrophage Formation Via Cyp1b1, Yin Zhu, Saugata Dutta, Yohan Han, Dooyoung Choi, Francesca Polverino, Caroline A Owen, Payaningal R Somanath, Xiaoyun Wang, Duo Zhang

Faculty, Staff and Students Publications

Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 …

Emapalumab Treatment In Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis In The United States: A Retrospective Medical Chart Review Study, Shanmuganathan Chandrakasan, Carl E Allen, Deepika Bhatla, John Carter, May Chien, Robert Cooper, Lauren Draper, Olive S Eckstein, Rabi Hanna, J Allyson Hays, Michelle L Hermiston, Ashley P Hinson, Patricia M Hobday, Michael S Isakoff, Michael B Jordan, Jennifer W Leiding, Renee Modica, Taizo A Nakano, Abiola Oladapo, Sachit A Patel, Priti Pednekar, Mona Riskalla, Susmita N Sarangi, Prakash Satwani, Anand Tandra, Kelly J Walkovich, John D Yee, Adi Zoref-Lorenz, Edward M Behrens

Faculty, Staff and Students Publications

Objective: Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.

Methods: REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.

Results: Fifteen of 105 patients …

Pancreatic Organogenesis Mapped Through Space And Time, Marissa A Scavuzzo, Wojciech J Szlachcic, Matthew C Hill, Natalia M Ziojla, Jessica Teaw, Jeffrey C Carlson, Jonathan Tiessen, Jolanta Chmielowiec, James F Martin, Malgorzata Borowiak

Faculty, Staff and Students Publications

The spatial organization of cells within a tissue is dictated throughout dynamic developmental processes. We sought to understand whether cells geometrically coordinate with one another throughout development to achieve their organization. The pancreas is a complex cellular organ with a particular spatial organization. Signals from the mesenchyme, neurons, and endothelial cells instruct epithelial cell differentiation during pancreatic development. To understand the cellular diversity and spatial organization of the developing pancreatic niche, we mapped the spatial relationships between single cells over time. We found that four transcriptionally unique subtypes of mesenchyme in the developing pancreas spatially coordinate throughout development, with each …

Acute-On-Chronic Liver Failure (Aclf): The ‘Kyoto Consensus’-Steps From Asia, Ashok Choudhury, Anand V Kulkarni, Vinod Arora, A S Soin, Abdul Kadir Dokmeci, Abhijeet Chowdhury, Abraham Koshy, Ajay Duseja, Ajay Kumar, Ajay Kumar Mishra, Ajay Kumar Patwa, Ajit Sood, Akash Roy, Akash Shukla, Albert Chan, Aleksander Krag, Amar Mukund, Ameet Mandot, Amit Goel, Amna Subhan Butt, Amrish Sahney, Ananta Shrestha, Andrés Cárdenas, Angelo Di Giorgio, Anil Arora, Anil Chandra Anand, Anil Dhawan, Ankur Jindal, Anoop Saraya, Anshu Srivastava, Anupam Kumar, Apichat Kaewdech, Apurva Pande, Archana Rastogi, Arun Valsan, Ashish Goel, Ashish Kumar, Ashwani K Singal, Atsushi Tanaka, Audrey Coilly, Ayaskanta Singh, Babu Lal Meena, Barath Jagadisan, Barjesh Chander Sharma, Bikrant Bihari Lal, C E Eapen, Cesar Yaghi, Chandan Kumar Kedarisetty, Chang Wook Kim, Charles Panackel, Chen Yu, Chetan R Kalal, Chhagan Bihari, Chien Hao Huang, Chitranshu Vasishtha, Christian Jansen, Christian Strassburg, Chun Yen Lin, Constantine J Karvellas, Cosmas Rinaldi Adithya Lesmana, Cyriac Abby Philips, Debbie Shawcross, Dharmesh Kapoor, Dhiraj Agrawal, Diana Alcantara Payawal, Dibya Lochan Praharaj, Dinesh Jothimani, Do Seon Song, Dong Joon Kim, Dong-Sik Kim, Duan Zhongping, Fazal Karim, Francois Durand, Gamal E Shiha, Gennaro D'Amico, George K Lau, Girish Kumar Pati, Graciela Elia Castro Narro, Guan-Huei Lee, Gupse Adali, Guru Prasad Dhakal, Gyongyi Szabo, H C Lin, Hai Li, Hari Kumar Nair, Harshad Devarbhavi, Harshvardhan Tevethia, Hasmik Ghazinian, Hemamala Ilango, Hong Ling Yu, Irsan Hasan, J Fernandez, Jacob George, Jaideep Behari, James Fung, Jasmohan Bajaj, Jaya Benjamin, Jennifer C Lai, Jidong Jia, Jin Hua Hu, Jin Jun Chen, Jin Lin Hou, Jin Mo Yang, Johannes Chang, Jonel Trebicka, Jörg C Kalf, Jose D Sollano, Joy Varghese, Juan Pablo Arab, Jun Li, K Rajender Reddy, Kaiser Raja, Kalpana Panda, Kamal Kajal, Karan Kumar, Kaushal Madan, Kemal Fariz Kalista, Kessarin Thanapirom, Khin Maung Win, Ki Tae Suk, Krishnadas Devadas, Laurentius A Lesmana, Lubna Kamani, Madhumita Premkumar, Madunil A Niriella, Mamun Al Mahtab, Man Fung Yuen, Manal Hel Sayed, Manasa Alla, Manav Wadhawan, Manoj Kumar Sharma, Manoj Sahu, Manya Prasad, Mark Dhinesh Muthiah, Martin Schulz, Meenu Bajpai, Mettu Srinivas Reddy, Michael Praktiknjo, Ming Lung Yu, Mithra Prasad, Mithun Sharma, Mohamed Elbasiony, Mohammed Eslam, Mohd Golam Azam, Mohd Rela, Moreshwar S Desai, Mukul Vij, Nadim Mahmud, Narendra Singh Choudhary, Navin Kumar Marannan, Necati Ormeci, Neeraj Saraf, Nipun Verma, Nobuaki Nakayama, Norifumi Kawada, Oidov Baatarkhuu, Omesh Goyal, Osamu Yokosuka, P N Rao, Paolo Angeli, Pathik Parikh, Patrick S Kamath, Paul J Thuluvath, Philipp Lingohr, Piyush Ranjan, Prashant Bhangui, Pravin Rathi, Puja Sakhuja, Puneet Puri, Qin Ning, R K Dhiman, Rahul Kumar, Rajan Vijayaraghavan, Rajeev Khanna, Rakhi Maiwall, Ravi Mohanka, Richard Moreau, Rino Alvani Gani, Rohit Loomba, Rohit Mehtani, Ruveena Bhavani Rajaram, S S Hamid, Sachin Palnitkar, Sadhna Lal, Sagnik Biswas, Sakkarin Chirapongsathorn, Samagra Agarwal, Sanjeev Sachdeva, Sanjiv Saigal, Santhosh E Kumar, Sargsyan Violeta, Satender Pal Singh, Satoshi Mochida, Saurabh Mukewar, Seema Alam, Seng Gee Lim, Shahinul Alam, Shalimar, Shantan Venishetty, Shikha S Sundaram, Shiran Shetty, Shobna Bhatia, Shweta A Singh, Shyam Kottilil, Simone Strasser, S M Shasthry, Soe Thiha Maung, Soek Siam Tan, Sombat Treeprasertsuk, Sonal Asthana, Steffen Manekeller, Subhash Gupta, Subrat Kumar Acharya, Sudhamshu K C, Sudhir Maharshi, Sumeet Asrani, Sunil Dadhich, Sunil Taneja, Suprabhat Giri, Surender Singh, Tao Chen, Tarana Gupta, Tatsuo Kanda, Tawesak Tanwandee, Teerha Piratvishuth, Ulrich Spengler, V G Mohan Prasad, Vandana Midha, Venera Rakhmetova, Vicente Arroyo, Vikrant Sood, Vinay Kumar Br, Vincent Wai-Sun Wong, Viniyendra Pamecha, Virendra Singh, Vishwa Mohan Dayal, Vivek A Saraswat, Wray Kim, Wasim Jafri, Wenyi Gu, Wong Yu Jun, Xiaolong Qi, Yogesh K Chawla, Yoon Jun Kim, Yu Shi, Zaigham Abbas, Guresh Kumar, Shuichiro Shiina, Lai Wei, Masao Omata, Shiv Kumar Sarin, Apasl-Aclf Research Consortium (Aarc) For Apasl-Aclf Working Party

Faculty, Staff and Students Publications

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the …

American Cochlear Implant Alliance Position Statement On Newborn Congenital Cytomegalovirus Screening, Megan Honor Pesch, Kevin David Brown, Amy L Birath, Gail J Demmler-Harrison, Cailtin Sapp, Anne Morgan Selleck, Alex D Sweeney

Faculty, Staff and Students Publications

It is estimated that 1 in every 200 US newborns has congenital cytomegalovirus (cCMV). Delayed identification of cCMV in newborns precludes timely intervention to mitigate sequelae of the infection such as hearing loss and other neurological complications. Newborn testing for cCMV enables appropriate diagnosis and intervention by multidisciplinary teams to properly manage the immediate sequelae of cCMV, avoid unnecessary additional testing that can result from delayed diagnosis, and monitor for future complications. It is the position of the American Cochlear Implant Alliance, the National CMV Foundation, and the American Academy of Otolaryngology-Head and Neck Surgery that universal newborn cCMV screening …

Hospice Patients In The Emergency Department: Challenging High-Risk Encounters With Unanswered Questions And Unquestioned Answers, Jason K Bowman, Joan M Teno, Kei Ouchi

Faculty, Staff and Students Publications

No abstract provided.

Hybrid Versus Vaccine Immunity Of Mrna-1273 Among People Living With Hiv In East And Southern Africa: A Prospective Cohort Analysis From The Multicentre Covpn 3008 (Ubuntu) Study, Nigel Garrett, Asa Tapley, Aaron Hudson, Sufia Dadabhai, Bo Zhang, Nyaradzo M Mgodi, Jessica Andriesen, Azwidihwi Takalani, Leigh H Fisher, Jia Jin Kee, Craig A Magaret, Manuel Villaran, John Hural, Erica Andersen-Nissen, Guido Ferarri, Maurine D Miner, Bert Le Roux, Eduan Wilkinson, Richard Lessells, Tulio De Oliveira, Jackline Odhiambo, Parth Shah, Laura Polakowski, Margaret Yacovone, Taraz Samandari, Zvavahera Chirenje, Peter James Elyanu, Joseph Makhema, Ethel Kamuti, Harriet Nuwagaba-Biribonwoha, Sharlaa Badal-Faesen, William Brumskine, Soritha Coetzer, Rodney Dawson, Sinead Delany-Moretlwe, Andreas Henri Diacon, Samantha Fry, Katherine Margaret Gill, Zaheer Ahmed Ebrahim Hoosain, Mina C Hosseinipour, Mubiana Inambao, Craig Innes, Steve Innes, Dishiki Kalonji, Margaret Kasaro, Priya Kassim, Noel Kayange, William Kilembe, Fatima Laher, Moelo Malahleha, Vongane Louisa Maluleke, Grace Mboya, Kirsten Mcharry, Essack Mitha, Kathryn Mngadi, Pamela Mda, Tumelo Moloantoa, Cissy Kityo Mutuluuza, Nivashnee Naicker, Vimla Naicker, Anusha Nana, Annet Nanvubya, Maphoshane Nchabeleng, Walter Otieno, Elsje Louise Potgieter, Disebo Potloane, Zelda Punt, Jamil Said, Yashna Singh, Mohammed Siddique Tayob, Yacoob Vahed, Deo Ogema Wabwire, M Juliana Mcelrath, James G Kublin, Linda-Gail Bekker, Peter B Gilbert, Lawrence Corey, Glenda E Gray, Yunda Huang, Philip Kotze, Covpn 3008 Ubuntu Study Team

Faculty, Staff and Students Publications

BACKGROUND: With limited access to mRNA COVID-19 vaccines in lower income countries, and people living with HIV (PLWH) largely excluded from clinical trials, Part A of the multicentre CoVPN 3008 (Ubuntu) study aimed to assess the safety of mRNA-1273, the relative effectiveness of hybrid versus vaccine immunity, and SARS-CoV-2 viral persistence among PLWH in East and Southern Africa during the omicron outbreak.

METHODS: Previously unvaccinated adults with HIV and/or other comorbidities associated with severe COVID-19 received either one (hybrid immunity) or two (vaccine immunity) 100-mcg doses of ancestral strain mRNA-1273 in the first month, depending on baseline evidence of prior …

Hes V20 Outperforms Galad For Detection Of Hcc: A Phase 3 Biomarker Study In The United States, Hashem B El-Serag, Qingchun Jin, Nabihah Tayob, Emad Salem, Michelle Luster, Abeer Alsarraj, Saira Khaderi, Amit G Singal, Jorge A Marrero, Sumeet K Asrani, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: The original hepatocellular carcinoma early detection screening (HES) score, which combines alpha-fetoprotein (AFP) with age, alanine aminotransferase, and platelets, has better performance than AFP alone for early HCC detection. We have developed HES V2.0 by adding AFP-L3 and des-gamma-carboxy prothrombin to the score and compared its performance to GALAD and ASAP scores among patients with cirrhosis.

APPROACH AND RESULTS: We conducted a prospective-specimen collection, retrospective-blinded-evaluation phase 3 biomarker cohort study in patients with cirrhosis enrolled in imaging and AFP surveillance. True-positive rate (TPR)/sensitivity and false-positive rate for any or early HCC were calculated for GALAD, ASAP, and …

Exploring Individual Differences In Amygdala-Mediated Memory Modulation, Martina K Hollearn, Joseph R Manns, Lou T Blanpain, Stephan B Hamann, Kelly Bijanki, Robert E Gross, Daniel L Drane, Justin M Campbell, Krista L Wahlstrom, Griffin F Light, Aydin Tasevac, Phillip Demarest, Peter Brunner, Jon T Willie, Cory S Inman

Faculty, Staff and Students Publications

Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without …