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Trial Of Sodium Phenylbutyrate–Taurursodiol For Amyotrophic Lateral Sclerosis, Sabrina Paganoni, Timothy M. Miller, Et Al

Open Access Publications

No abstract provided.

Context Is Key: Delineating The Unique Functions Of Ifnα And Ifnβ In Disease, Lindsey E Fox, Marissa C Locke, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In …

Sars-Cov-2 Viral Rna Shedding For More Than 87 Days In An Individual With An Impaired Cd8+ T Cell Response, Jackson S Turner, Aaron Day, Wafaa B Alsoussi, Zhuoming Liu, Jane A O'Halloran, Rachel M Presti, Bruce K Patterson, Sean P J Whelan, Ali H Ellebedy, Philip A Mudd

Open Access Publications

Prolonged shedding of viral RNA occurs in some individuals following SARS-CoV-2 infection. We perform comprehensive immunologic evaluation of one individual with prolonged shedding. The case subject recovered from severe COVID-19 and tested positive for SARS-CoV-2 viral RNA repeatedly as many as 87 days after the first positive test, 97 days after symptom onset. The subject did not have any associated rise in anti-Spike protein antibody titers or plasma neutralization activity, arguing against re-infection. This index subject exhibited a profoundly diminished circulating CD8+ T cell population and correspondingly low SARS-CoV-2-specific CD8+ T cell responses when compared with a cohort of other …

The Complex Interactions Between Rotavirus And The Gut Microbiota, Andrew Hyoungjin Kim, Michael P Hogarty, Vanessa C Harris, Megan T Baldridge

Open Access Publications

Human rotavirus (HRV) is the leading worldwide cause of acute diarrhea-related death in children under the age of five. RV infects the small intestine, an important site of colonization by the microbiota, and studies over the past decade have begun to reveal a complex set of interactions between RV and the gut microbiota. RV infection can temporarily alter the composition of the gut microbiota and probiotic administration alleviates some symptoms of infection

A Single Amino Acid Change To Taq Dna Polymerase Enables Faster Pcr, Reverse Transcription And Strand-Displacement, Wayne M Barnes, Zhian Zhang, Milko B Kermekchiev

Open Access Publications

A change of an aspartic acid to asparagine of Taq (

Blood Biomarkers For Detection Of Brain Injury In Covid-19 Patients, Steven T. Dekosky, Lawrence Lewis, Stacey House, Et Al.

Open Access Publications

No abstract provided.

Consumptive Coagulopathy Of Severe Yellow Fever Occurs Independently Of Hepatocellular Tropism And Massive Hepatic Injury, Adam L. Bailey, Liang-I Kang, Luiz Gonzaga Francisco De Assis Barros D'Elia Zanella, Cássia G. T. Silveira, Yeh-Li Ho, Lander Foquet, Greg Bial, Broc T. Mccune, Amaro Nunes Duarte-Neto, Archana Thomas, Hans-Peter Raué, Kathleen Byrnes, Esper G. Kallas, Mark K. Slifka, Michael S. Diamond

Open Access Publications

No abstract provided.

Postural Directionality And Head Tremor In Cervical Dystonia, Qiyu Chen, Jeanne P Vu, Elizabeth Cisneros, Casey N Benadof, Zheng Zhang, Richard L Barbano, Christopher G Goetz, Joseph Jankovic, Hyder A Jinnah, Joel S Perlmutter, Mark I Appelbaum, Glenn T Stebbins, Cynthia L Comella, David A Peterson

Open Access Publications

Background: Although abnormal head and neck postures are defining features of cervical dystonia (CD), head tremor (HT) is also common. However, little is known about the relationship between abnormal postures and HT in CD.

Methods: We analyzed clinical data and video recordings from 185 patients enrolled by the Dystonia Coalition. We calculated the likelihood of their HT and HT type ("regular" vs. "jerky") given directionality of abnormal head postures, disease duration, sex, and age.

Results: Patients with retrocollis were more likely to have HT than patients with anterocollis (X

Discussion: We found that HT is more likely for CD patients …

Community Health Behaviors And Geographic Variation In Early-Onset Colorectal Cancer Survival Among Women, Andreana N. Holowatyj, Marvin E. Langston, Yunan Han, Richard Viskochil, Jose Perea, Yin Cao, Charles R. Rogers, Christopher H. Lieu, Justin X. Moore

Open Access Publications

No abstract provided.

Prevalence Of Cryptococcal Antigen And Outcomes In People With Human Immunodeficiency Virus In Honduras: A Cohort Study, Julio C. Zuniga-Moya, Jane A. O'Halloran, Andrej Spec, Et Al

Open Access Publications

Background: Cryptococcal meningitis is a major cause of death among people with human immunodeficiency virus (PWH). Cryptococcal antigen (CrAg) testing of asymptomatic patients is an important public health measure to reduce mortality in high-incidence areas. However, limited data exist on CrAg prevalence in Central America.

Methods: We conducted a prospective cohort study at the 2 largest human immunodeficiency virus (HIV) clinics and hospitals in Honduras. Cryptococcal antigen in serum and cerebrospinal fluid was performed in individuals with HIV who had CD4 ≤100 cells/mm

Results: A total of 220 PWH were tested for CrAg, 12.7% (n = 28) of which tested …

Determinants Of Mammographic Breast Density By Race Among A Large Screening Population, Justin X. Moore, Yunan Han, Catherine Appleton, Graham Colditz, Adetunji T. Toriola

Open Access Publications

Background: Because of the mixed reports from smaller studies, we examined associations of race with mammographic breast density and evaluated racial differences in the determinants of breast density.

Methods: Participants included 37 839 women (23 166 non-Hispanic white and 14 673 African American) receiving screening mammograms at the Joanne Knight Breast Health Center at Washington University School of Medicine from June 2010 to December 2015. Mammographic breast density was assessed using the Breast Imaging Reporting and Data System (5th edition). To determine the association of race and participant characteristics with mammographic breast density, we used multivariable polytomous logistic regression models …

A Recommended "Minimum Data Set" Framework For Sd-Oct Retinal Image Acquisition And Analysis From The Atlas Of Retinal Imaging In Alzheimer's Study (Arias), Jessica Alber, Gregory Van Stavern, Et Al

Open Access Publications

Introduction: We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross-validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD.

Methods: The proposed minimum data set framework is based on the Atlas of …

The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale And Methodology, Benjamin L Handen, Anne M Fagan, Beau Ances, Et Al

Open Access Publications

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.

Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression.

Results: Approximately 400 individuals …

Cerebrospinal Fluid Biomarkers Of Alzheimer's Disease In A Cohort Of Adults With Down Syndrome, Rachel L Henson, Eric Doran, Bradley T Christian, Benjamin L Handen, William E Klunk, Florence Lai, Joseph H Lee, H Diana Rosas, Nicole Schupf, Shahid H Zaman, Ira T Lott, Anne M Fagan

Open Access Publications

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS.

Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer's Biomarker …

The Prescription Opioids And Depression Pathways Cohort Study, Jeffrey F Scherrer, Brian Ahmedani, Kirsti Autio, Lynn Debar, Patrick J Lustman, Lisa R Miller-Matero, Joanne Salas, Scott Secrest, Mark D Sullivan, Lauren Wilson, Sarah Skiold-Hanlin

Open Access Publications

BACKGROUND: Results from studies using medical record data indicate chronic (>90 days) opioid analgesic use (OAU) is associated with new depressive episodes (NDE), worsening depression and risk for depression recurrence. This body of evidence is based on retrospective cohort studies and medical record data. Limitations of existing research are overcome in a new prospective cohort study of the opioid-depression relationship.

METHODS: Prospective cohort of 1500 adult patients recruited from two health care systems. Eligible subjects started a new period of OAU and have 30 to 90 days of OAU at baseline. Diagnostic assessments for psychiatric disorders, structured measures of …

Sexually Dimorphic Impact Of The Iron-Regulating Gene, Hfe, On Survival In Glioblastoma, Darya S Nesterova, Vishal Midya, Brad E Zacharia, Elizabeth A Proctor, Sang Y Lee, Lindsay C Stetson, Justin D Lathia, Joshua B Rubin, Kristin A Waite, Michael E Berens, Jill S Barnholtz-Sloan, James R Connor

Open Access Publications

BACKGROUND: The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males. The molecular mechanism of this difference has not yet been established. Iron is essential for many biological processes supporting tumor growth and its regulation is impacted by sex. Therefore, we interrogated the expression of a key component of cellular iron regulation, the

METHODS: We analyzed …

Gliomas Display Distinct Sex-Based Differential Methylation Patterns Based On Molecular Subtype, Mette L Johansen, L C Stetson, Vachan Vadmal, Kristin Waite, Michael E Berens, James R Connor, Justin Lathia, Joshua B Rubin, Jill S Barnholtz-Sloan

Open Access Publications

BACKGROUND: Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes.

METHODS: Molecular and clinical data from glioma patients …

Insights Into The Role Of The Jak/Stat Signaling Pathway In Graft-Versus-Host Disease, Ramzi Abboud, Jaebok Choi, Peter Ruminski, Mark A Schroeder, Sena Kim, Camille N Abboud, John F Dipersio

Open Access Publications

Allogeneic hematopoietic transplantation (allo-HCT) is a curative therapy for a variety of hematologic malignancies, primarily through immune-mediated clearance of malignant cells. This graft-

Comparing Sensitivity To Change Using The 6-Item Versus The 17-Item Hamilton Depression Rating Scale In The Guided Randomized Controlled Trial, Boadie W Dunlop, Sagar V Parikh, Anthony J Rothschild, Michael E Thase, Charles Debattista, Charles R Conway, Brent P Forester, Francis M Mondimore, Richard C Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F Greden

Open Access Publications

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. …

Multicenter Clinical Evaluation Of Etest Meropenem-Vaborbactam (Biomérieux) For Susceptibility Testing Of Enterobacterales (Enterobacteriaceae) And Pseudomonas Aeruginosa, Sophonie Jean, Sheri Garrett, Claire Anglade, Laurence Bridon, Leanne Davies, Omai B Garner, Jennifer Richards, Meghan Wallace, Mandy Wootton, Carey-Ann D. Burnham

Open Access Publications

Meropenem-vaborbactam (MEV) is a novel carbapenem-beta-lactamase inhibitor combination antibiotic approved by the U.S. Food and Drug Administration (FDA) for treatment of complicated urinary tract infections, including pyelonephritis, in adults. In this study, we evaluated the performance of Etest MEV (bioMérieux, Marcy l'Etoile, France) compared to that of broth microdilution for 629

A Qualitative Study Of Older Adults' Perspectives On Initiating Exercise And Mindfulness Practice, Diana C Parra, Julie Loebach Wetherell, Alexandria Van Zandt, Ross C Brownson, Janardan Abhishek, Eric J Lenze

Open Access Publications

BACKGROUND: Mindfulness practice and exercise are ways by which older adults can improve and maintain their physical, emotional and cognitive health.

METHODS: This single-site qualitative study gathered insights of older adults' perceptions about initiating and maintaining mindfulness and exercise practices. We carried out focus groups with 41 adults aged 65-85 who had recently initiated Mindfulness Based Stress Reduction (MBSR), structured exercise, or their combination as part of participation in a clinical trial. We used a semi-structured interview to ask them open-ended questions regarding the benefits, barriers and facilitators of participating in mindfulness and/or exercise interventions. The interview also included questions …

Humanized Zebrafish Enhance Human Hematopoietic Stem Cell Survival And Promote Acute Myeloid Leukemia Clonal Diversity, Vinothkumar Rajan, Nicole Melong, Wing Hing Wong, Benjamin King, R. Spencer Tong, Nithin Mahajan, Daniel Gaston, Troy Lund, David Rittenberg, Graham Dellaire, Clinton J. V. Campbell, Todd Druley, Jason N. Berman

Open Access Publications

Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted …

The Role Of Glia In Epilepsy, Intellectual Disability, And Other Neurodevelopmental Disorders In Tuberous Sclerosis Complex, Michael Wong

Open Access Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, …

Adaptation Of The Clinical Dementia Rating Scale For Adults With Down Syndrome, Christina N Lessov-Schlaggar, Olga L Del Rosario, John C Morris, Beau M Ances, Bradley L Schlaggar, John N Constantino

Open Access Publications

BACKGROUND: Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients.

METHODS: We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR-a …

Cytogps: A Web-Enabled Karyotype Analysis Tool For Cytogenetics, Zachary B Abrams, Lin Zhang, Lynne V Abruzzo, Nyla A Heerema, Suli Li, Tom Dillon, Ricky Rodriguez, Kevin R Coombes, Philip R O Payne

Open Access Publications

SUMMARY: Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes …

Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond

Open Access Publications

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

Gantenerumab Reduces Amyloid-Β Plaques In Patients With Prodromal To Moderate Alzheimer's Disease: A Pet Substudy Interim Analysis, Gregory Klein, Paul Delmar, Nicola Voyle, Sunita Rehal, Carsten Hofmann, Danielle Abi-Saab, Mirjana Andjelkovic, Smiljana Ristic, Guoqiao Wang, Randall Bateman, Geoffrey A Kerchner, Monika Baudler, Paulo Fontoura, Rachelle Doody

Open Access Publications

BACKGROUND: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).

METHODS: A subset of patients enrolled in …

Let-7 Micrornas Regulate Microglial Function And Suppress Glioma Growth Through Toll-Like Receptor 7, Alice Buonfiglioli, David H Gutmann, Et Al

Open Access Publications

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 …

Assessing Somatization In Urologic Chronic Pelvic Pain Syndrome, C S North, B A Hong, H H Lai, D H Alpers

Open Access Publications

BACKGROUND: This study examined the prevalence of somatization disorder in Urological Chronic Pelvic Pain Syndrome (UCPPS) and the utility of two self-report symptom screening tools for assessment of somatization in patients with UCPPS.

METHODS: The study sample included 65 patients with UCPPS who enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study at Washington University. Patients completed the PolySymptomatic PolySyndromic Questionnaire (PSPS-Q) (n = 64) and the Patient Health Questionnaire-15 Somatic Symptom Severity Scale (PHQ-15) (n = 50). Review of patient medical records found that only 47% (n = 30) contained sufficient documentation to assess …