Digital Commons Network^™

Identification Of Functional Regulatory Elements In The Human Genome Using Pooled Crispr Screens., Samantha M. Borys, Scott T. Younger

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genome-scale pooled CRISPR screens are powerful tools for identifying genetic dependencies across varied cellular processes. The vast majority of CRISPR screens reported to date have focused exclusively on the perturbation of protein-coding gene function. However, protein-coding genes comprise < 2% of the sequence space in the human genome leaving a substantial portion of the genome uninterrogated. Noncoding regions of the genome harbor important regulatory elements (e.g. promoters, enhancers, silencers) that influence cellular processes but high-throughput methods for evaluating their essentiality have yet to be established.

RESULTS: Here, we describe a CRISPR-based screening approach that facilitates the functional profiling of thousands of noncoding regulatory elements in parallel. We selected the tumor suppressor p53 as a model system and designed a pooled CRISPR library targeting thousands of p53 binding sites throughout the genome. Following transduction into dCas9-KRAB-expressing cells we identified several regulatory elements that influence cell proliferation. Moreover, …

The Relationship Between Grit And Selected Personality Measures In Medical Students, Gerald A. Isenberg, Andrew Brown, Jennifer Desantis, Jon Veloski, Mohammadreza Hojat

CRMEHC Faculty Papers

OBJECTIVES: To test the hypothesis that scores on a Grit scale are positively associated with personality measures that are conducive to relationship building (Empathy, Self-Esteem, Activity, and Sociability), but inversely associated with personality measures that are detrimental to interpersonal relationships (Neuroticism-Anxiety, Aggression-Hostility, Impulsive Sensation Seeking, and Loneliness).

METHODS: Convenient sampling was used that included 241 medical students at Sidney Kimmel Medical College at Thomas Jefferson University who participated in this ex post facto research. Validated instruments were used to measure Grit, Empathy, Self-Esteem, Activity, Sociability, Neuroticism-Anxiety, Aggression-Hostility, Impulsive Sensation Seeking, and Loneliness. Bivariate correlations and multivariate regression were used to …

Dynamic Phosphorylation And Dephosphorylation Of Cyclase-Associated Protein 1 By Antagonistic Signaling Through Cyclin-Dependent Kinase 5 And Camp Are Critical For The Protein Functions In Actin Filament Disassembly And Cell Adhesion, Haitao Zhang, Auburn Ramsey, Yitong Xiao, Uddhab Karki, Jennifer Y. Xie, Jianfeng Xu, Thomas Kelly, Shoichiro Ono, Guo-Lei Zhou

Arkansas Biosciences Institute

yclase-ssociated rotein (CAP1) is a conserved actin-regulating protein that enhances actin filament dynamics and also regulates adhesion in mammalian cells. We previously found that phosphorylation at the Ser307/Ser309 tandem site controls its association with cofilin and actin and is important for CAP1 to regulate the actin cytoskeleton. Here, we report that transient Ser307/Ser309 phosphorylation is required for CAP1 function in both actin filament disassembly and cell adhesion. Both the phosphomimetic and the nonphosphorylatable CAP1 mutant, which resist transition between phosphorylated and dephosphorylated forms, had defects in rescuing the reduced rate of actin filament disassembly in the CAP1 knockdown HeLa cells. …

Metabolic Dysregulation In The Atp7b-/- Wilson's Disease Mouse Model, Clavia Ruth Wooton-Kee, Matthew Robertson, Ying Zhou, Bingning Dong, Zhen Sun, Kang Ho Kim, Hailan Liu, Yong Xu, Nagireddy Putluri, Pradip Saha, Cristian Coarfa, David D Moore, Alli M Nuotio-Antar

Faculty, Staff and Students Publications

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented …

Proteome Alterations In Pancreatic Ductal Adenocarcinoma, Sheng Pan, Teresa A Brentnall, Ru Chen

Faculty, Staff and Students Publications

Proteins are the essential functional biomolecules profoundly implicated in all aspects of pancreatic tumorigenesis and its progression. While common genomic factors, such as KRAS, TP53, SMAD4, and CDKN2A have been well recognized in association of pancreatic ductal adenocarcinoma (PDAC), our understanding of functional changes at the proteome level merits further investigation. Malignance associated proteome alterations can be attributed to the convoluted outcomes from genetic, epigenetic and environmental factors in initiating and progressing PDAC, and may reflect on changes in protein expressional level, structure, localization, as well as post-translational modifications (PTMs) status. The study of localized or systemic proteome alterations in …

The Mitochondrial Hsp90 Paralog Trap1 Forms An Oxphos-Regulated Tetramer And Is Involved In Mitochondrial Metabolic Homeostasis, Abhinav Joshi, Li Dai, Yanxin Liu, Jungsoon Lee, Nastaran Mohammadi Ghahhari, Gregory Segala, Kristin Beebe, Lisa M Jenkins, Gaelyn C Lyons, Lilia Bernasconi, Francis T F Tsai, David A Agard, Len Neckers, Didier Picard

Faculty, Staff and Students Publications

BACKGROUND: The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other.

RESULTS: We show that the disruption of the gene for TRAP1 in …

Infection-Induced Signals Generated At The Plasma Membrane Epigenetically Regulate Wnt Signaling In Vitro And In Vivo, Ishfaq Ahmed, Badal Chandra Roy, Laxmi Uma Maheswar Rao Jakkula, Dharmalingam Subramaniam, Prasad Dandawate, Shrikant Anant, Venkatesh Sampath, Shahid Umar

Manuscripts, Articles, Book Chapters and Other Papers

Wnt signaling regulates immunomodulatory functions during infection and inflammation. Employing NCCIT and HCT116 cells, having high endogenous Wnt signaling, we observed elevated levels of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) and Frizzled class receptor 10 (FZD10) and increases in β-catenin, doublecortin-like kinase 1 (DCLK1), CD44 molecule (CD44), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). siRNA-induced knockdown of these receptors antagonized TOPflash reporter activity and spheroid growth in vitro and elevated Wnt-inhibitory factor 1 (WIF1) activity. Elevated mRNA and protein levels of LRP5/6 and FZD10 paralleled expression of WNT2b and WNT4 in colonic crypts at days 6 and 12 post-infection …

Deficient Histone H3 Propionylation By Brpf1-Kat6 Complexes In Neurodevelopmental Disorders And Cancer., Kezhi Yan, Justine Rousseau, Keren Machol, Laura A. Cross, Katherine E. Agre, Cynthia Forster Gibson, Anne Goverde, Kendra Engleman, Hannah Verdin, Elfride De Baere, Lorraine Potocki, Dihong Zhou, Maxime Cadieux-Dion, Gary A. Bellus, Monisa D. Wagner, Rebecca J. Hale, Natacha Esber, Alan F. Riley, Benjamin D. Solomon, Megan T. Cho, Kirsty Mcwalter, Roy Eyal, Meagan K. Hainlen, Bryce A. Mendelsohn, Hillary M. Porter, Brendan C. Lanpher, Andrea M. Lewis, Juliann Savatt, Isabelle Thiffault, Bert Callewaert, Philippe M. Campeau, Xiang-Jiao Yang

Manuscripts, Articles, Book Chapters and Other Papers

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the …

Review Of Alterations In Perlecan-Associated Vascular Risk Factors In Dementia, Amanda L. Trout, Ibolya Rutkai, Ifechukwude J. Biose, Gregory J. Bix

Neurology Faculty Publications

Perlecan is a heparan sulfate proteoglycan protein in the extracellular matrix that structurally and biochemically supports the cerebrovasculature by dynamically responding to changes in cerebral blood flow. These changes in perlecan expression seem to be contradictory, ranging from neuroprotective and angiogenic to thrombotic and linked to lipid retention. This review investigates perlecan's influence on risk factors such as diabetes, hypertension, and amyloid that effect Vascular contributions to Cognitive Impairment and Dementia (VCID). VCID, a comorbidity with diverse etiology in sporadic Alzheimer's disease (AD), is thought to be a major factor that drives the overall clinical burden of dementia. Accordingly, changes …

Rhoa-Rock Signaling As A Therapeutic Target In Traumatic Brain Injury, Shalaka Mulherkar, Kimberley F Tolias

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBIs, which range in severity from mild to severe, occur when a traumatic event, such as a fall, a traffic accident, or a blow, causes the brain to move rapidly within the skull, resulting in damage. Long-term consequences of TBI can include motor and cognitive deficits and emotional disturbances that result in a reduced quality of life and work productivity. Recovery from TBI can be challenging due to a lack of effective treatment options for repairing TBI-induced neural damage and alleviating functional impairments. Central nervous system (CNS) …

Evidence For The Misfolding Of The A1 Domain Within Multimeric Von Willebrand Factor In Type 2 Von Willebrand Disease, Alexander Tischer, Maria A Brehm, Venkata R Machha, Laurie Moon-Tasson, Linda M Benson, Katelynn J Nelton, Rachel R Leger, Tobias Obser, Marina Martinez-Vargas, Steven T Whitten, Dong Chen, Rajiv K Pruthi, H Robert Bergen, Miguel A Cruz, Reinhard Schneppenheim, Matthew Auton

Faculty, Staff and Students Publications

Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfold the native structure of the isolated platelet GPIbα-adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 …

Development And Characterization Of A Wee1 Kinase Degrader, Zhengnian Li, Benika J Pinch, Calla M Olson, Katherine A Donovan, Radosław P Nowak, Caitlin E Mills, David A Scott, Zainab M Doctor, Nicholas A Eleuteri, Mirra Chung, Peter K Sorger, Eric S Fischer, Nathanael S Gray

Faculty, Staff and Students Publications

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses …

Clinical Diagnostics And Treatment Strategies For Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia, Richard C. Harvey, Sarah K. Tasian

Pathology Research and Scholarship

Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like ALL) accounts for 15% to 30% of B-cell acute lymphoblastic leukemia in older children, adolescents, and adults and is associated with high rates of conventional treatment failure and relapse. Current clinical trials are assessing the efficacy of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy for children and adults with Ph-like ALL harboring ABL class translocations or CRLF2 rearrangements and other JAK pathway alterations. However, real-time diagnosis of patients can be quite challenging given the genetic heterogeneity of this disease and the often cytogenetically cryptic nature of Ph-like ALL-associated alterations. In this …

Assessment Of Outcomes And Novel Immune Biomarkers In Metaplastic Breast Cancer: A Single Institution Retrospective Study., Evan Morgan, Anupama Suresh, Akaansha Ganju, Daniel G Stover, Robert Wesolowski, Sagar Sardesai, Anne Noonan, Raquel Reinbolt, Jeffrey Vandeusen, Nicole Williams, Mathew A Cherian, Zaibo Li, Gregory Young, Marilly Palettas, Julie Stephens, Joseph Liu, Amanda Luff, Bhuvaneswari Ramaswamy, Maryam Lustberg

Women’s Health Articles

BACKGROUND: Metaplastic breast cancer remains poorly characterized given its rarity and heterogeneity. The majority of metaplastic breast cancers demonstrate a phenotype of triple-negative breast cancer; however, differences in clinical outcomes between metaplastic breast cancer and triple-negative breast cancer in the era of third-generation chemotherapy remain unclear.

METHODS: We compared the clinical outcomes between women with metaplastic breast cancer and women with triple-negative breast cancer diagnosed between 1994 and 2014. Metaplastic breast cancer patients were matched 1:3 to triple-negative breast cancer patients by stage and age at diagnosis. Distant disease-free survival (DDFS) and overall survival (OS) were estimated using Kaplan Meier …

Toward Improving Practices For Submission Of Diagnostic Tissue Blocks For National Cancer Institute Clinical Trials, Hala Makhlouf, Mark A Watson, Heather A Lankes, Carol Weil, Maura Dickler, Michael Birrer, Christopher Moskaluk, Nilsa C Ramirez, Nader Okby, Edgar Alonsozana, Mark Barnes, Edward B Goldman, Rebecca Enos, Irina Lubensky

2020-Current year OA Pubs

OBJECTIVES: The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.

METHODS: The NCI convened a 1-day workshop of multidisciplined experts to discuss barriers and strategic solutions to facilitate diagnostic block submission for clinical trial science, from the perspective …

Global Survey On Pancreatic Surgery During The Covid-19 Pandemic., A. Oba, T. F. Stoop, M. Löhr, T. Hackert, N. Zyromski, W. H. Nealon, M. Unno, R. D. Schulick, M. H. Al-Musawi, M. Del Chiaro, +6 Additional Authors

Journal Articles

OBJECTIVE:The aim of this study was to clarify the role of pancreatic surgery during the COVID-19 pandemic to optimize patients' and clinicians' safety and safeguard health care capacity. SUMMARY BACKGROUND DATA:The COVID-19 pandemic heavily impacts health care systems worldwide. Cancer patients appear to have an increased risk for adverse events when infected by COVID-19, but the inability to receive oncological care seems may be an even larger threat, particularly in case of pancreatic cancer. METHODS:An online survey was submitted to all members of seven international pancreatic associations and study groups, investigating the impact of the COVID-19 pandemic on pancreatic surgery …

Blood Eosinophil Counts In Clinical Trials For Chronic Obstructive Pulmonary Disease, Dave Singh, Mona Bafadhel, Christopher E. Brightling, Frank C. Sciurba, Jeffrey L. Curtis, Fernando J. Martinez, Cara B. Pasquale, Debora D. Merrill, Norbert Metzdorf, Stefano Petruzzelli, Ruth Tal-Singer, Christopher Compton, Stephen I. Rennard, Ubaldo J. Martin

Journal Articles: Pulmonary & Critical Care Med

No abstract provided.

Heme Metabolism Genes Downregulated In Copd Cachexia, Ava C. Wilson, Preeti L. Kumar, Sool Lee, Margaret M. Parker, Itika Arora, Jarrett D. Morrow, Emiel F.M. Wouters, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Alvar Agusti, Ruth Tal-Singer, Mark T. Dransfield, J. Michael Wells, Surya P. Bhatt, George Washko, Victor J. Thannickal, Hemant K. Tiwari, Craig P. Hersh, Peter J. Castaldi, Edwin K. Silverman, Merry-Lynn N. Mcdonald

Journal Articles: Pulmonary & Critical Care Med

INTRODUCTION: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

METHODS: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (<  20 kg/m

RESULTS: The prevalence of …

Agonist-Specific Desensitization Of Pge2-Stimulated Camp Signaling Due To Upregulated Phosphodiesterase Expression In Human Lung Fibroblasts, Francisco J. Nunez, Nancy Schulte, David M. Fogel, Joel Michalski, Stephen I. Rennard, Raymond B. Penn, Myron L. Toews, Rennolds S. Ostrom

Journal Articles: Pulmonary & Critical Care Med

Pulmonary fibrosis is characterized by fibroblasts persisting in an activated form, producing excessive fibrous material that destroys alveolar structure. The second messenger molecule cyclic 3',5'-adenosine monophosphate (cAMP) has antifibrotic properties, and prostaglandin E2 (PGE2) can stimulate cAMP production through prostaglandin E (EP)2 and EP4 receptors. Although EP receptors are attractive therapeutic targets, the effects of long-term exposure to PGE2 have not been characterized. To determine the effects of long-term exposure of lung fibroblasts to PGE2, human fetal lung (HFL)-1 cells were treated for 24 h with 100 nM PGE2 or other cAMP-elevating agents. cAMP levels stimulated by acute exposure to …

Structural Equation Modeling To Detect Correlates Of Childhood Vaccination: A Moderated Mediation Analysis, Abraham Degarege, Karl Krupp, Vijaya Srinivas, Boubakari Ibrahimou, Purnima Madhivanan

Journal Articles: Epidemiology

OBJECTIVES: This study used a health belief theory derived framework and structural equation model to examine moderators, mediators, and direct and indirect predictors of childhood vaccination.

METHODS: A secondary analysis was conducted using data collected from a cross-sectional survey of a random sample of 1599 parents living in urban and rural areas of Mysore district, India. Applying two-stage probability proportionate-to-size sampling, adolescent girls attending 7th through 10th grades in 23 schools were selected to take home a questionnaire to be answered by their parents to primarily assess HPV vaccine intentions. Parents were also asked whether their children had received one …

Does Knowing The Mental Health History Of A Mass Shooter Heighten Stigma And Negative Attitudes Toward Mental Illness?, Lianna Artessa

PCOM Psychology Dissertations

Mass-shooting incidents are an ongoing epidemic that continues to take countless lives. Despite the prevalence of gun-related mass-shooting events, the research on this phenomenon is scarce. Following these events, individuals often receive news from differing media outlets and programs. The current media portrayal of mass-shooting events often appears to support a widely accepted connection between mass shootings and mental illness. This portrayal may reflect an existing and perhaps growing misunderstanding and negative stigma toward individuals diagnosed with a psychiatric disorder. This experimental study sought to determine the degree to which individuals’ attitudes toward and opinions of a perpetrator of a …

Transcriptional And Immunohistological Assessment Of Immune Infiltration In Pancreatic Cancer., Brady Bernard, Venkatesh Rajamanickam, Christopher Dubay, Brian D. Piening, Emilio Alonso, Zeljka Jutric, Ephraim Tang, Pippa Newell, Paul D Hansen, Terry R Medler, Andrew J Gunderson, Kristina H Young, Carlo Bifulco, Joanna Pucilowska, Marka R Crittenden, Michael J. Gough

Articles, Abstracts, and Reports

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq …

Single Cell Transcriptomics Implicate Novel Monocyte And T Cell Immune Dysregulation In Sarcoidosis, Lori Garman, Richard C. Pelikan, Astrid Rasmussen, Caleb A. Lareau, Kathryn A. Savoy, Umesh S. Deshmukh, Harini Bagavant, Albert M. Levin, Salim Daouk, Wonder P. Drake, Courtney G. Montgomery

Public Health Sciences Articles

Sarcoidosis is a systemic inflammatory disease characterized by infiltration of immune cells into granulomas. Previous gene expression studies using heterogeneous cell mixtures lack insight into cell-type-specific immune dysregulation. We performed the first single-cell RNA-sequencing study of sarcoidosis in peripheral immune cells in 48 patients and controls. Following unbiased clustering, differentially expressed genes were identified for 18 cell types and bioinformatically assessed for function and pathway enrichment. Our results reveal persistent activation of circulating classical monocytes with subsequent upregulation of trafficking molecules. Specifically, classical monocytes upregulated distinct markers of activation including adhesion molecules, pattern recognition receptors, and chemokine receptors, as well …

Editorial: Structure, Isotypes, Targets, And Post-Translational Modifications Of Immunoglobulins And Their Role In Infection, Inflammation And Autoimmunity, Jean Harb, Bridget S. Wilson, Sylvie Hermouet

Pathology Research and Scholarship

EDITORIAL published: 07 August 2020 doi: 10.3389/fimmu.2020.01761 Frontiers in Immunology | www.frontiersin.org 1 August 2020 | Volume 11 | Article 1761 Edited by: Deborah K. Dunn-Walters, University of Surrey, United Kingdom Reviewed by: Roberta Pelanda, University of Colorado School of Medicine, United States *Correspondence: Sylvie Hermouet [email protected] Specialty section: This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology Received: 29 May 2020 Accepted: 30 June 2020 Published: 07 August 2020 Citation: Harb J, Wilson BS and Hermouet S (2020) Editorial: Structure, Isotypes, Targets, and Post-translational Modifications of Immunoglobulins and Their Role in Infection, …

A Head-To-Head Comparison Of The Efficacy And Safety Of Ixekizumab And Adalimumab In Biological-Naïve Patients With Active Psoriatic Arthritis: 24-Week Results Of A Randomised, Open-Label, Blinded-Assessor Trial., Philip Mease, Josef S Smolen, Frank Behrens, Peter Nash, Soyi Liu Leage, Lingnan Li, Hasan Tahir, Melinda Gooderham, Eswar Krishnan, Hong Liu-Seifert, Paul Emery, Sreekumar G Pillai, Philip S Helliwell

Articles, Abstracts, and Reports

OBJECTIVES: To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological disease-modifying antirheumatic drug-naïve patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARDs).

METHODS: Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the …

Unmet Need In Rheumatology: Reports From The Targeted Therapies Meeting 2019., Kevin L Winthrop, Michael E Weinblatt, Joan Bathon, Gerd R Burmester, Philip Mease, Leslie Crofford, Vivian Bykerk, Maxime Dougados, James Todd Rosenbaum, Xavier Mariette, Joachim Sieper, Fritz Melchers, Bruce N Cronstein, Ferry C Breedveld, Joachim Kalden, Josef S Smolen, Daniel Furst

Articles, Abstracts, and Reports

OBJECTIVES: To detail the greatest areas of unmet scientific and clinical needs in rheumatology.

METHODS: The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general …

Comparative Analysis Of Covid-19 Guidelines From Six Countries: A Qualitative Study On The Us, China, South Korea, The Uk, Brazil, And Haiti, Ji Youn Yoo, Samia Valeria Ozorio Dutra, Dany Fanfan, Sarah Sniffen, Hao Wang, Jamile Siddiqui, Hyo-Suk Song, Sung Hwan Bang, Dong Eun Kim, Shihoon Kim, Maureen Groer

All publications

Background: In late January, a worldwide crisis known as COVID-19 was declared a Public Health Emergency of International Concern by the WHO. Within only a few weeks, the outbreak took on pandemic proportions, affecting over 100 countries. It was a significant issue to prevent and control COVID-19 on both national and global scales due to the dramatic increase in confirmed cases worldwide. Government guidelines provide a fundamental resource for communities, as they guide citizens on how to protect themselves against COVID-19, however, they also provide critical guidance for policy makers and healthcare professionals on how to take action to decrease …

Quantifying The Impact Of Covid-19 Control Measures Using A Bayesian Model Of Physical Distancing, Sean C. Anderson, Andrew M. Edwards, Madi Yerlanov, Nicola Mulberry, Jessica E. Stockdale, Sarafa A. Iyaniwura, Rebeca C. Falcao, Michael C. Otterstatter, Michael A. Irvine, Naveed Z. Janjua, Daniel Coombs, Caroline Colijn

All publications

Extensive non-pharmaceutical and physical distancing measures are currently the primary interventions against coronavirus disease 2019 (COVID-19) worldwide. It is therefore urgent to estimate the impact such measures are having. We introduce a Bayesian epidemiological model in which a proportion of individuals are willing and able to participate in distancing, with the timing of distancing measures informed by survey data on attitudes to distancing and COVID-19. We fit our model to reported COVID-19 cases in British Columbia (BC), Canada, and five other jurisdictions, using an observation model that accounts for both underestimation and the delay between symptom onset and reporting. We …

Development And Validation Of A Model For Individualized Prediction Of Hospitalization Risk In 4,536 Patients With Covid-19, Lara Jehi, Xinge Ji, Alex Milinovich, Serpil Erzurum, Amy Merlino, Steve Gordon, James B. Young, Michael W. Kattan

All publications

Background: Coronavirus Disease 2019 is a pandemic that is straining healthcare resources, mainly hospital beds. Multiple risk factors of disease progression requiring hospitalization have been identified, but medical decision-making remains complex.

Objective: To characterize a large cohort of patients hospitalized with COVID-19, their outcomes, develop and validate a statistical model that allows individualized prediction of future hospitalization risk for a patient newly diagnosed with COVID-19.

Design: Retrospective cohort study of patients with COVID-19 applying a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm to retain the most predictive features for hospitalization risk, followed by validation in a temporally …

Modeling The Role Of Asymptomatics In Infection Spread With Application To Sars-Cov-2, Hana M. Dobrovolny

All publications

SARS-CoV-2 started causing infections in humans in late 2019 and has spread rapidly around the world. While the number of symptomatically infected and severely ill people is high and has overwhelmed the medical systems of many countries, there is mounting evidence that some of the rapid spread of this virus has been driven by asymptomatic infections. In this study, we use a compartmental mathematical model of a viral epidemic that includes asymptomatic infection to examine the role of asymptomatic individuals in the spread of the infection. We apply the model to epidemics in California, Florida, New York, and Texas, finding …