Digital Commons Network^™

Tocilizumab In Hospitalized Patients With Severe Covid-19 Pneumonia, Ivan O Rosas, Norbert Bräu, Michael Waters, Ronaldo C Go, Bradley D Hunter, Sanjay Bhagani, Daniel Skiest, Mariam S Aziz, Nichola Cooper, Ivor S Douglas, Sinisa Savic, Taryn Youngstein, Lorenzo Del Sorbo, Antonio Cubillo Gracian, David J De La Zerda, Andrew Ustianowski, Min Bao, Sophie Dimonaco, Emily Graham, Balpreet Matharu, Helen Spotswood, Larry Tsai, Atul Malhotra

Faculty, Staff and Students Publications

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.

METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants …

Blood N-3 Fatty Acid Levels And Total And Cause-Specific Mortality From 17 Prospective Studies, William S Harris, Nathan L Tintle, Fumiaki Imamura, Frank Qian, Andres V Ardisson Korat, Matti Marklund, Luc Djoussé, Julie K Bassett, Pierre-Hugues Carmichael, Yun-Yu Chen, Yoichiro Hirakawa, Leanne K Küpers, Federica Laguzzi, Maria Lankinen, Rachel A Murphy, Cécilia Samieri, Mackenzie K Senn, Peilin Shi, Jyrki K Virtanen, Ingeborg A Brouwer, Kuo-Liong Chien, Gudny Eiriksdottir, Nita G Forouhi, Johanna M Geleijnse, Graham G Giles, Vilmundur Gudnason, Catherine Helmer, Allison Hodge, Rebecca Jackson, Kay-Tee Khaw, Markku Laakso, Heidi Lai, Danielle Laurin, Karin Leander, Joan Lindsay, Renata Micha, Jaako Mursu, Toshiharu Ninomiya, Wendy Post, Bruce M Psaty, Ulf Risérus, Jennifer G Robinson, Aladdin H Shadyab, Linda Snetselaar, Aleix Sala-Vila, Yangbo Sun, Lyn M Steffen, Michael Y Tsai, Nicholas J Wareham, Alexis C Wood, Jason H Y Wu, Frank Hu, Qi Sun, David S Siscovick, Rozenn N Lemaitre, Dariush Mozaffarian, Fatty Acids And Outcomes Research Consortium (Force)

Children’s Nutrition Research Center Staff Publications

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

Genetic And Non-Genetic Factors Affecting The Expression Of Covid-19-Relevant Genes In The Large Airway Epithelium, Silva Kasela, Victor E Ortega, Molly Martorella, Suresh Garudadri, Jenna Nguyen, Elizabeth Ampleford, Anu Pasanen, Srilaxmi Nerella, Kristina L Buschur, Igor Z Barjaktarevic, R Graham Barr, Eugene R Bleecker, Russell P Bowler, Alejandro P Comellas, Christopher B Cooper, David J Couper, Gerard J Criner, Jeffrey L Curtis, Meilan K Han, Nadia N Hansel, Eric A Hoffman, Robert J Kaner, Jerry A Krishnan, Fernando J Martinez, Merry-Lynn N Mcdonald, Deborah A Meyers, Robert Paine, Stephen P Peters, Mario Castro, Loren C Denlinger, Serpil C Erzurum, John V Fahy, Elliot Israel, Nizar N Jarjour, Bruce D Levy, Xingnan Li, Wendy C Moore, Sally E Wenzel, Charles Langelier, Prescott G Woodruff, Tuuli Lappalainen, Stephanie A Christenson

Faculty, Staff and Student Publications

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with …

Decade-Long Nationwide Trends And Disparities In Use Of Comfort Care Interventions For Patients With Ischemic Stroke, Kristie M Chu, Erica M Jones, Jennifer R Meeks, Alan P Pan, Kathryn L Agarwal, George E Taffet, Farhaan S Vahidy

Faculty, Staff and Students Publications

Background Stroke remains one of the leading causes of disability and death in the United States. We characterized 10-year nationwide trends in use of comfort care interventions (CCIs) among patients with ischemic stroke, particularly pertaining to acute thrombolytic therapy with intravenous tissue-type plasminogen activator and endovascular thrombectomy, and describe in-hospital outcomes and costs. Methods and Results We analyzed the National Inpatient Sample from 2006 to 2015 and identified adult patients with ischemic stroke with or without thrombolytic therapy and CCIs using validated

Dexmedetomidine Or Propofol For Sedation In Mechanically Ventilated Adults With Sepsis, Christopher G Hughes, Patrick T Mailloux, John W Devlin, Joshua T Swan, Robert D Sanders, Antonio Anzueto, James C Jackson, Aimee S Hoskins, Brenda T Pun, Onur M Orun, Rameela Raman, Joanna L Stollings, Amy L Kiehl, Matthew S Duprey, Lan N Bui, Hollis R O'Neal, Allison Snyder, Michael A Gropper, Kalpalatha K Guntupalli, Gregg J Stashenko, Mayur B Patel, Nathan E Brummel, Timothy D Girard, Robert S Dittus, Gordon R Bernard, E Wesley Ely, Pratik P Pandharipande, Mends2 Study Investigators

Faculty, Staff and Students Publications

BACKGROUND: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.

METHODS: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale …

Conditional Survival Among Patients With Oropharyngeal Cancer Treated With Radiation Therapy And Alive Without Recurrence 5 Years After Diagnosis, Kristina R Dahlstrom, Juhee Song, Peter F Thall, Clifton D Fuller, Katherine A Hutcheson, Faye M Johnson, G Brandon Gunn, Jack Phan, Steven J Frank, William H Morrison, Renata Ferrarotto, David I Rosenthal, Erich M Sturgis, Adam S Garden

Faculty, Staff and Students Publications

BACKGROUND: Risk of recurrence among patients with oropharyngeal cancer (OPC) who survive 5 years is low. The goal of this study was to assess long-term survival of patients with OPC alive without recurrence 5 years after diagnosis.

METHODS: This study included newly diagnosed patients with OPC, who had been treated with radiation and were alive without recurrence 5 years after diagnosis. Overall survival (OS) probabilities beyond 5 years were estimated using the Kaplan-Meier method. Factors associated with OS were determined using Bayesian piecewise exponential survival regression. Standardized mortality ratios for all-cause death were estimated controlling for study year, age, and …

Medical School To Residency: How Can We Trust The Process?, Gary L Beck Dallaghan, Irene Alexandraki, Jennifer Christner, Meg Keeley, Sorabh Khandelwal, Beat Steiner, Paul A Hemmer

Faculty, Staff and Students Publications

Background To say that the transition from undergraduate medical education (UME) to graduate medical education (GME) is under scrutiny would be an understatement. Findings from a panel discussion at the 2018 Association of American Medical Colleges Annual meeting entitled, "Pass-Fail in Medical School and the Residency Application Process and Graduate Medical Education Transition" addressed what and when information should be shared with residency programs, and how and when that information should be shared. Materials and Methods Over 250 participants representing UME and GME (e.g. leadership, faculty, medical students) completed worksheets addressing these questions. During report-back times, verbal comments were transcribed …

Functional Interpretation Of Atad3a Variants In Neuro-Mitochondrial Phenotypes, Zheng Yie Yap, Yo Han Park, Saskia B Wortmann, Adam C Gunning, Shlomit Ezer, Sukyeong Lee, Lita Duraine, Ekkehard Wilichowski, Kate Wilson, Johannes A Mayr, Matias Wagner, Hong Li, Usha Kini, Emily Davis Black, Kristin G Monaghan, James R Lupski, Sian Ellard, Dominik S Westphal, Tamar Harel, Wan Hee Yoon

Faculty, Staff and Students Publications

BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.

METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 …

Proteogenomic And Metabolomic Characterization Of Human Glioblastoma, Liang-Bo Wang, Alla Karpova, Marina A Gritsenko, Jennifer E Kyle, Song Cao, Yize Li, Dmitry Rykunov, Antonio Colaprico, Joseph H Rothstein, Runyu Hong, Vasileios Stathias, Macintosh Cornwell, Francesca Petralia, Yige Wu, Boris Reva, Karsten Krug, Pietro Pugliese, Emily Kawaler, Lindsey K Olsen, Wen-Wei Liang, Xiaoyu Song, Yongchao Dou, Michael C Wendl, Wagma Caravan, Wenke Liu, Daniel Cui Zhou, Jiayi Ji, Chia-Feng Tsai, Vladislav A Petyuk, Jamie Moon, Weiping Ma, Rosalie K Chu, Karl K Weitz, Ronald J Moore, Matthew E Monroe, Rui Zhao, Xiaolu Yang, Seungyeul Yoo, Azra Krek, Alexis Demopoulos, Houxiang Zhu, Matthew A Wyczalkowski, Joshua F Mcmichael, Brittany L Henderson, Caleb M Lindgren, Hannah Boekweg, Shuangjia Lu, Jessika Baral, Lijun Yao, Kelly G Stratton, Lisa M Bramer, Erika Zink, Sneha P Couvillion, Kent J Bloodsworth, Shankha Satpathy, Weiva Sieh, Simina M Boca, Stephan Schürer, Feng Chen, Maciej Wiznerowicz, Karen A Ketchum, Emily S Boja, Christopher R Kinsinger, Ana I Robles, Tara Hiltke, Mathangi Thiagarajan, Alexey I Nesvizhskii, Bing Zhang, D R Mani, Michele Ceccarelli, Xi S Chen, Sandra L Cottingham, Qing Kay Li, Albert H Kim, David Fenyö, Kelly V Ruggles, Henry Rodriguez, Mehdi Mesri, Samuel H Payne, Adam C Resnick, Pei Wang, Richard D Smith, Antonio Iavarone, Milan G Chheda, Jill S Barnholtz-Sloan, Karin D Rodland, Tao Liu, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM …

Obstructive Sleep Apnea And Dementia-Common Gene Associations Through Network-Based Identification Of Common Driver Genes, Hyun-Hwan Jeong, Arvind Chandrakantan, Adam C Adler

Faculty, Staff and Students Publications

BACKGROUND: Obstructive Sleep Apnea (OSA) occurs in 7% of the adult population. The relationship between neurodegenerative diseases such as dementia and sleep disorders have long attracted clinical attention; however, no comprehensive data exists elucidating common gene expression between the two diseases. The objective of this study was to (1) demonstrate the practicability and feasibility of utilizing a systems biology approach called network-based identification of common driver genes (NICD) to identify common genomic features between two associated diseases and (2) utilize this approach to identify genes associated with both OSA and dementia.

METHODS: This study utilized 2 public databases (PCNet, DisGeNET) …

Zno Nucleation Into Trititanate Nanotubes By Ald Equipment Techniques, A New Way To Functionalize Layered Metal Oxides, Mabel Moreno, Miryam Arredondo, Quentin M Ramasse, Matthew Mclaren, Philine Stötzner, Stefan Förster, Eglantina Benavente, Caterina Salgado, Sindy Devis, Paula Solar, Luis Velasquez, Guillermo González

Faculty, Staff and Students Publications

In this contribution, we explore the potential of atomic layer deposition (ALD) techniques for developing new semiconductor metal oxide composites. Specifically, we investigate the functionalization of multi-wall trititanate nanotubes, H2Ti3O7 NTs (sample T1) with zinc oxide employing two different ALD approaches: vapor phase metalation (VPM) using diethylzinc (Zn(C2H5)2, DEZ) as a unique ALD precursor, and multiple pulsed vapor phase infiltration (MPI) using DEZ and water as precursors. We obtained two different types of tubular H2Ti3O7 species containing ZnO in their structures. Multi-wall trititanate nanotubes with ZnO intercalated inside the tube wall sheets were the main products from the VPM infiltration …

Sirt3 Is Required For Liver Regeneration But Not For The Beneficial Effect Of Nicotinamide Riboside, Sarmistha Mukherjee, James Mo, Lauren M Paolella, Caroline E Perry, Jade Toth, Mindy M Hugo, Qingwei Chu, Qiang Tong, Karthikeyani Chellappa, Joseph A Baur

Children’s Nutrition Research Center Staff Publications

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for …

Genetic Discovery And Risk Characterization In Type 2 Diabetes Across Diverse Populations, Linda M Polfus, Burcu F Darst, Heather Highland, Xin Sheng, Maggie C Y Ng, Jennifer E Below, Lauren Petty, Stephanie Bien, Xueling Sim, Wei Wang, Pierre Fontanillas, Yesha Patel, Michael Preuss, Claudia Schurmann, Zhaohui Du, Yingchang Lu, Suhn K Rhie, Joseph M Mercader, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Cassandra N Spracklen, Brian E Cade, Richard A Jensen, Meng Sun, Yoonjung Yoonie Joo, Ping An, Lisa R Yanek, Lawrence F Bielak, Salman Tajuddin, Aude Nicolas, Guanjie Chen, Laura Raffield, Xiuqing Guo, Wei-Min Chen, Girish N Nadkarni, Mariaelisa Graff, Ran Tao, James S Pankow, Martha Daviglus, Qibin Qi, Eric A Boerwinkle, Simin Liu, Lawrence S Phillips, Ulrike Peters, Chris Carlson, Lynne R Wikens, Loic Le Marchand, Kari E North, Steven Buyske, Charles Kooperberg, Ruth J F Loos, Daniel O Stram, Christopher A Haiman

Faculty, Staff and Student Publications

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the

Structure, Function And Inhibition Of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 And Its Fusion Oncoproteins, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains …

Regional Variations In Heart Failure Quality And Outcomes: Get With The Guidelines-Heart Failure Registry, Luke C Cunningham, Gregg C Fonarow, Clyde W Yancy, Shubin Sheng, Roland A Matsouaka, Adam D Devore, Hani Jneid, Anita Deswal

Faculty, Staff and Students Publications

Background

Regional patient characteristics, care quality, and outcomes may differ based on a variety of factors among patients hospitalized for heart failure (HF). Regional disparities in outcomes of cardiovascular disease have been suggested across various regions in the United States. This study examined whether there are significant differences by region in quality of care and short‐term outcomes of hospitalized patients with HF across the United States.

Methods and Results

We examined regional demographics, quality measures, and short‐term outcomes across 4 US Census Bureau regions in patients hospitalized with HF and enrolled in the GWTG‐HF (Get With The Guidelines–Heart Failure) registry …

Late Gadolinium Enhancement Magnetic Resonance Imaging Evaluation Of Post-Atrial Fibrillation Ablation Esophageal Thermal Injury Across The Spectrum Of Severity, Qussay Marashly, Chaitra Gopinath, Alex Baher, Madan Acharya, Mobin Kheirkhahan, Benjamin Hardisty, Mossab Aljuaid, Ibrahim Tawhari, Mark Ibrahim, Alan K Morris, Eugene G Kholmovski, Brent D Wilson, Nassir F Marrouche, Mihail G Chelu

Faculty, Staff and Students Publications

Background Esophageal thermal injury (ETI) is a byproduct of atrial fibrillation (AF) ablation using thermal sources. The most severe form of ETI is represented by atrioesophageal fistula, which has a high mortality rate. Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) allows identification of ETI. Hence, we sought to evaluate the utility of LGE-MRI as a method to identify ETI across the entire spectrum of severity. Methods and Results All AF radiofrequency ablations performed at the University of Utah between January 2009 and December 2017 were reviewed. Patients with LGE-MRI within 24 hours following AF ablation as well as patients …

Mitochondrial Transfer From Mesenchymal Stem Cells Improves Neuronal Metabolism After Oxidant Injury In Vitro: The Role Of Miro1, Nancy Tseng, Scott C Lambie, Christopher Q Huynh, Bridget Sanford, Manisha Patel, Paco S Herson, D Ryan Ormond

Faculty, Staff and Students Publications

Stroke-induced cerebral ischemia is a major cause of death and disability. The disruption of blood flow results in neuronal and glial cell death leading to brain injury. Reperfusion restores oxygen to the affected tissue, but can also cause damage through an enhanced oxidative stress and inflammatory response. This study examines mitochondrial transfer from MSC to neurons and the role it plays in neuronal preservation after oxidant injury. We observed the transfer of mitochondria from MSC to mouse neurons in vitro following hydrogen peroxide exposure. The observed transfer was dependent on cell-to-cell contact and led to increased neuronal survival and improved …

Mechanisms, Diagnosis, Prevention And Management Of Perioperative Opioid-Induced Hyperalgesia, Sylvia H Wilson, Kevin M Hellman, Dominika James, Adam C Adler, Arvind Chandrakantan

Faculty, Staff and Students Publications

Opioid-induced hyperalgesia (OIH) occurs when opioids paradoxically enhance the pain they are prescribed to ameliorate. To address a lack of perioperative awareness, we present an educational review of clinically relevant aspects of the disorder. Although the mechanisms of OIH are thought to primarily involve medullary descending pathways, it is likely multifactorial with several relevant therapeutic targets. We provide a suggested clinical definition and directions for clinical differentiation of OIH from other diagnoses, as this may be confusing but is germane to appropriate management. Finally, we discuss prevention including patient education and analgesic management choices. As prevention may serve as the …

The Impact Of Covid-19 On Kidney Transplantation And The Kidney Transplant Recipient – One Year Into The Pandemic, Pascale Khairallah, Nidhi Aggarwal, Ahmed A Awan, Chandan Vangala, Medha Airy, Jenny S Pan, Bhamidipati V R Murthy, Wolfgang C Winkelmayer, Venkat Ramanathan

Faculty, Staff and Students Publications

The COVID‐19 pandemic has significantly changed the landscape of kidney transplantation in the United States and worldwide. In addition to adversely impacting allograft and patient survival in postkidney transplant recipients, the current pandemic has affected all aspects of transplant care, including transplant referrals and listing, organ donation rates, organ procurement and shipping, and waitlist mortality. Critical decisions were made during this period by transplant centers and individual transplant physicians taking into consideration patient safety and resource utilization. As countries have begun administering the COVID vaccines, new and important considerations pertinent to our transplant population have arisen. This comprehensive review focuses …

Clinical And Economic Burden Of Stroke Among Young, Midlife, And Older Adults In The United States, 2002-2017, Safi U Khan, Muhammad Zia Khan, Muhammad U Khan, Muhammad Shahzeb Khan, Mamas A Mamas, Muhammad Rashid, Ron Blankstein, Salim S Virani, Michelle C Johansen, Michael D Shapiro, Michael J Blaha, Miguel Cainzos-Achirica, Farhaan S Vahidy, Khurram Nasir

Faculty, Staff and Students Publications

OBJECTIVE: To assess trends of stroke hospitalization rates, inpatient mortality, and health care resource use in young (aged ≤44 years), midlife (aged 45-64 years), and older (aged ≥65 years) adults.

PATIENTS AND METHODS: We studied the National Inpatient Sample database (January 1, 2002 to December 31, 2017) to analyze stroke-related hospitalizations. We identified data using the

RESULTS: Of 11,381,390 strokes, 79% (n=9,009,007) were ischemic and 21% (n=2,372,383) were hemorrhagic. Chronic diseases were more frequent in older adults; smoking, alcoholism, and migraine were more prevalent in midlife adults; and coagulopathy and intravenous drug abuse were more common in young patients with …

Rev-Erb In Gabaergic Neurons Controls Diurnal Hepatic Insulin Sensitivity, Guolian Ding, Xin Li, Xinguo Hou, Wenjun Zhou, Yingyun Gong, Fuqiang Liu, Yanlin He, Jia Song, Jing Wang, Paul Basil, Wenbo Li, Sichong Qian, Pradip Saha, Jinbang Wang, Chen Cui, Tingting Yang, Kexin Zou, Younghun Han, Christopher I Amos, Yong Xu, Li Chen, Zheng Sun

Faculty, Staff and Students Publications

Systemic insulin sensitivity shows diurnal rhythm with a peak at wakening1,2. The molecular mechanism underlying such a temporal pattern is unclear. Here we demonstrate that nuclear receptors Rev-erbα/β in the GABAergic neurons in the suprachiasmatic nucleus (SCNGABA) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviors under the regular light-dark cycles. Rev-erb regulates the rhythmic expression of genes involved in neurotransmission in the SCN and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at wakening causes glucose intolerance, while restoration …

Automated Software-Assisted Diagnosis Of Esophageal Squamous Cell Neoplasia Using High-Resolution Microendoscopy, Mimi C Tan, Sheena Bhushan, Timothy Quang, Richard Schwarz, Kalpesh H Patel, Xinying Yu, Zhengqi Li, Guiqi Wang, Fan Zhang, Xueshan Wang, Hong Xu, Rebecca R Richards-Kortum, Sharmila Anandasabapathy

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is an optical biopsy technology that provides subcellular imaging of esophageal mucosa but requires expert interpretation of these histopathology-like images. We compared endoscopists with an automated software algorithm for detection of esophageal squamous cell neoplasia (ESCN) and evaluated the endoscopists' accuracy with and without input from the software algorithm.

METHODS: Thirteen endoscopists (6 experts, 7 novices) were trained and tested on 218 post-hoc HRME images from 130 consecutive patients undergoing ESCN screening/surveillance. The automated software algorithm interpreted all images as neoplastic (high-grade dysplasia, ESCN) or non-neoplastic. All endoscopists provided their interpretation (neoplastic or non-neoplastic) …

A Millifluidic Perfusion Cassette For Studying The Pathogenesis Of Enteric Infections Using Ex-Vivo Organoids, Reid L Wilson, Sarah A Hewes, Anubama Rajan, Shih-Ching Lin, Carolyn Bomidi, Takanori Iida, Mary K Estes, Anthony W Maresso, K Jane Grande-Allen

Faculty, Staff and Students Publications

To generate physiologically-relevant experimental models, the study of enteric diarrheal diseases is turning increasingly to advanced in vitro models that combine ex vivo, stem cell-derived "organoid" cell lines with bioengineered culture environments that expose them to mechanical stimuli, such as fluid flow. However, such approaches require considerable technical expertise with both microfabrication and organoid culture, and are, therefore, inaccessible to many researchers. For this reason, we have developed a perfusion system that is simple to fabricate, operate, and maintain. Its dimensions approximate the volume and cell culture area of traditional 96-well plates and allow the incorporation of fastidious primary, stem …

Sars-Cov-2 Infects Human Engineered Heart Tissues And Models Covid-19 Myocarditis, Adam L Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Emma S Winkler, Sanja Sviben, Erin Brooks, Ajith P Nair, Kent A Heck, Aniket S Rali, Leo Simpson, Mehrdad Saririan, Dan Hobohm, W Tom Stump, James A Fitzpatrick, Xuping Xie, Xianwen Zhang, Pei-Yong Shi, J Travis Hinson, Weng-Tein Gi, Constanze Schmidt, Florian Leuschner, Chieh-Yu Lin, Michael S Diamond, Michael J Greenberg, Kory J Lavine

Faculty, Staff and Student Publications

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology …

Cell Signaling Regulation In Salivary Gland Development, Akiko Suzuki, Kenichi Ogata, Junichi Iwata

Faculty, Staff and Student Publications

The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian salivary gland development, particularly on the differentiation of acinar, ductal, and myoepithelial cells. We discuss recent studies that provide conceptual advances in the understanding of the molecular mechanisms of salivary gland development. In addition, we describe the organogenesis of submandibular glands (SMGs), model systems used for the study of SMG development, and the key signaling pathways as well as cellular processes involved in salivary gland development. The findings from the recent studies elucidating the identity of …

Efficacy, Pharmacokinetics, And Safety Over 48 Weeks With Ibalizumab-Based Therapy In Treatment-Experienced Adults Infected With Hiv-1: A Phase 2a Study, Joseph C Gathe, Robin L Hardwicke, Fernando Garcia, Steven Weinheimer, Stanley T Lewis, Robert Brandon Cash

Faculty, Staff and Student Publications

Ibalizumab, a humanized monoclonal antibody targeting CD4, blocks HIV-1 entry into cells and is the first Food and Drug Adminstration-approved long-acting agent for HIV-1 treatment. In this phase 2a study, 82 HIV-infected adults failing antiretroviral therapy were assigned an individually optimized background regimen (OBR) and randomized 1:1:1 to arm A (15 mg/kg ibalizumab q2wk), arm B (10 mg/kg weekly for 9 weeks, then q2wk), or placebo. Subjects with an inadequate response at week 16 were permitted to cross over to a new OBR plus 15 mg/kg ibalizumab q2wk. At week 16, viral load (VL) reduction was significantly greater than placebo …

Distraction Osteogenesis With Temporal Bone Remodeling For Unicoronal Craniosynostosis, Phuong D Nguyen, Ahmed Belal, George N Washington, Matthew R Greives, David I Sandberg, Stephen A Fletcher, Manish N Shah

Faculty, Staff and Student Publications

Unicoronal craniosynostosis correction with fronto-orbital advancement and cranial vault remodeling has traditionally been the gold standard. Distraction osteogenesis has the advantage of increased size of movement without constriction of the scalp and decreased morbidity. Although fronto-orbital advancement and cranial vault remodeling are usually performed at 6 months of age or later, distraction osteogenesis is performed at a younger age, between 3 and 6 months, to take advantage of the infant bony physiology. Herein, the authors demonstrate a case of distraction osteogenesis for unicoronal craniosynostosis in a 3-month-old female with significant improvement of her orbital, nasal, and frontal symmetry.

The video …

Discovery And Fine-Mapping Of Height Loci Via High-Density Imputation Of Gwass In Individuals Of African Ancestry, Mariaelisa Graff, Anne E Justice, Kristin L Young, Eirini Marouli, Xinruo Zhang, Rebecca S Fine, Elise Lim, Victoria Buchanan, Kristin Rand, Mary F Feitosa, Mary K Wojczynski, Lisa R Yanek, Yaming Shao, Rebecca Rohde, Adebowale A Adeyemo, Melinda C Aldrich, Matthew A Allison, Christine B Ambrosone, Stefan Ambs, Christopher Amos, Donna K Arnett, Larry Atwood, Elisa V Bandera, Traci Bartz, Diane M Becker, Sonja I Berndt, Leslie Bernstein, Lawrence F Bielak, William J Blot, Erwin P Bottinger, Donald W Bowden, Jonathan P Bradfield, Jennifer A Brody, Ulrich Broeckel, Gregory Burke, Brian E Cade, Qiuyin Cai, Neil Caporaso, Chris Carlson, John Carpten, Graham Casey, Stephen J Chanock, Guanjie Chen, Minhui Chen, Yii-Der I Chen, Wei-Min Chen, Alessandra Chesi, Charleston W K Chiang, Lisa Chu, Gerry A Coetzee, David V Conti, Richard S Cooper, Mary Cushman, Ellen Demerath, Sandra L Deming, Latchezar Dimitrov, Jingzhong Ding, W Ryan Diver, Qing Duan, Michele K Evans, Adeyinka G Falusi, Jessica D Faul, Myriam Fornage, Caroline Fox, Barry I Freedman, Melissa Garcia, Elizabeth M Gillanders, Phyllis Goodman, Omri Gottesman, Struan F A Grant, Xiuqing Guo, Hakon Hakonarson, Talin Haritunians, Tamara B Harris, Curtis C Harris, Brian E Henderson, Anselm Hennis, Dena G Hernandez, Joel N Hirschhorn, Lorna Haughton Mcneill, Timothy D Howard, Barbara Howard, Ann W Hsing, Yu-Han H Hsu, Jennifer J Hu, Chad D Huff, Dezheng Huo, Sue A Ingles, Marguerite R Irvin, Esther M John, Karen C Johnson, Joanne M Jordan, Edmond K Kabagambe, Sun J Kang, Sharon L Kardia, Brendan J Keating, Rick A Kittles, Eric A Klein, Suzanne Kolb, Laurence N Kolonel, Charles Kooperberg, Lewis Kuller, Abdullah Kutlar, Leslie Lange, Carl D Langefeld, Loic Le Marchand, Hampton Leonard, Guillaume Lettre, Albert M Levin, Yun Li, Jin Li, Yongmei Liu, Youfang Liu, Simin Liu, Kurt Lohman, Vaneet Lotay, Yingchang Lu, William Maixner, Joann E Manson, Barbara Mcknight, Yan Meng, Keri L Monda, Kris Monroe, Jason H Moore, Thomas H Mosley, Poorva Mudgal, Adam B Murphy, Rajiv Nadukuru, Mike A Nalls, Katherine L Nathanson, Uma Nayak, Amidou N'Diaye, Barbara Nemesure, Christine Neslund-Dudas, Marian L Neuhouser, Sarah Nyante, Heather Ochs-Balcom, Temidayo O Ogundiran, Adesola Ogunniyi, Oladosu Ojengbede, Hayrettin Okut, Olufunmilayo I Olopade, Andrew Olshan, Badri Padhukasahasram, Julie Palmer, Cameron D Palmer, Nicholette D Palmer, George Papanicolaou, Sanjay R Patel, Curtis A Pettaway, Patricia A Peyser, Michael F Press, D C Rao, Laura J Rasmussen-Torvik, Susan Redline, Alex P Reiner, Suhn K Rhie, Jorge L Rodriguez-Gil, Charles N Rotimi, Jerome I Rotter, Edward A Ruiz-Narvaez, Benjamin A Rybicki, Babatunde Salako, Michele M Sale, Maureen Sanderson, Eric Schadt, Pamela J Schreiner, Claudia Schurmann, Ann G Schwartz, Daniel A Shriner, Lisa B Signorello, Andrew B Singleton, David S Siscovick, Jennifer A Smith, Shad Smith, Elizabeth Speliotes, Margaret Spitz, Janet L Stanford, Victoria L Stevens, Alex Stram, Sara S Strom, Lara Sucheston, Yan V Sun, Salman M Tajuddin, Herman Taylor, Kira Taylor, Bamidele O Tayo, Michael J Thun, Margaret A Tucker, Dhananjay Vaidya, David J Van Den Berg, Sailaja Vedantam, Mara Vitolins, Zhaoming Wang, Erin B Ware, Sylvia Wassertheil-Smoller, David R Weir, John K Wiencke, Scott M Williams, L Keoki Williams, James G Wilson, John S Witte, Margaret Wrensch, Xifeng Wu, Jie Yao, Neil Zakai, Krista Zanetti, Babette S Zemel, Wei Zhao, Jing Hua Zhao, Wei Zheng, Degui Zhi, Jie Zhou, Xiaofeng Zhu, Regina G Ziegler, Joe Zmuda, Alan B Zonderman, Bruce M Psaty, Ingrid B Borecki, L Adrienne Cupples, Ching-Ti Liu, Christopher A Haiman, Ruth Loos, Maggie C Y Ng, Kari E North

Faculty, Staff and Student Publications

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two …

Value Of Emergent Neurovascular Imaging For "Seat Belt Injury": A Multi-Institutional Study, F G Sherbaf, B Chen, T Pomeranz, M Shahriari, M E Adin, S Mirbagheri, E Beheshtian, R Jalilianhasanpour, J Pakpoor, J W Lazor, A Kamali, D M Yousem

Faculty, Staff and Student Publications

BACKGROUND AND PURPOSE: Screening for blunt cerebrovascular injury in patients after motor vehicle collision (MVC) solely based on the presence of cervical seat belt sign has been debated in the literature without consensus. Our aim was to assess the value of emergent neurovascular imaging in patients after an MVC who present with a seat belt sign through a large-scale multi-institutional study.

MATERIALS AND METHODS: The electronic medical records of patients admitted to the emergency department with CTA/MRAs performed with an indication of seat belt injury of the neck were retrospectively reviewed at 5 participating institutions. Logistic regression analysis was used …

A Phase Ii Study Of Autologous Mesenchymal Stromal Cells And C-Kit Positive Cardiac Cells, Alone Or In Combination, In Patients With Ischaemic Heart Failure: The Cctrn Concert-Hf Trial, Roberto Bolli, Raul D Mitrani, Joshua M Hare, Carl J Pepine, Emerson C Perin, James T Willerson, Jay H Traverse, Timothy D Henry, Phillip C Yang, Michael P Murphy, Keith L March, Ivonne H Schulman, Sohail Ikram, David P Lee, Connor O'Brien, Joao A Lima, Mohammad R Ostovaneh, Bharath Ambale-Venkatesh, Gregory Lewis, Aisha Khan, Ketty Bacallao, Krystalenia Valasaki, Bangon Longsomboon, Adrian P Gee, Sara Richman, Doris A Taylor, Dejian Lai, Shelly L Sayre, Judy Bettencourt, Rachel W Vojvodic, Michelle L Cohen, Lara Simpson, David Aguilar, Catalin Loghin, Lem Moyé, Ray F Ebert, Barry R Davis, Robert D Simari

Faculty, Staff and Student Publications

AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.

METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association …