SARS-CoV-2 screening testing in schools for children with intellectual and developmental disabilities
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 31, .
Sherby, M.R.a , Walsh, T.J.b , Lai, A.M.c , Neidich, J.A.d , Balls-Berry, J.E.e , Morris, S.M.a , Head, R.f , Prener, C.G.g , Newland, J.G.b , Gurnett, C.A.a , Baldenweck, M.h , Bono, K.h , Brodsky, V.B.h , Caburnay, C.A.h , Constantino, J.N.h , Dougherty, N.L.h , Dubois, J.M.h , Fritz, S.A.h , Gotto, G.S., IVh , Imbeah, A.h , Kalb, L.G.h , Liu, J.h , Maricque, B.B.h , McKay, V.R.h , Myers, L.S.h , Poor, T.J.h , Powell, B.J.h , Mueller, N.B.h , Schlaggar, B.L.h , Schmidt, A.h , Snider, E.h , Traughber, M.C.h , van Stone, M.h , Vestal, L.h , Wilcher-Roberts, M.h , for the COMPASS-T Study Grouph
a Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University in St. Louis, 660 S. Euclid Avenue Campus, Box 8111, St. Louis, MO 63110, United States
b Department of Pediatrics, Division of Pediatric Infectious Diseases, Washington University in St. Louis, St. Louis, MO, United States
c Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, Division of Memory and Aging, Washington University in St. Louis, St. Louis, MO, United States
f Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
g Department of Sociology and Anthropology, Saint Louis University, St. Louis, MO, United States
Abstract
Background: Transmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD. Methods: From November 23, 2020, to May, 28, 2021, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies. Results: A total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening. Conclusions: During 24 weeks that included the peak of the COVID-19 pandemic in winter 2020-21, we found lower rates of SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure. However, the impact of the emerging SARS-CoV-2 Delta variant on the effectiveness of these proven mitigation strategies remains unknown. Trial registration: Prior to enrollment, this study was registered at ClinicalTrials.gov on September 25, 2020, identifier NCT04565509, titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic. © 2021, The Author(s).
Author Keywords
Children with IDD; COVID-19; COVID-19 School tests; Intellectual and developmental disabilities; SARS-CoV-2 testing
Funding details
National Institutes of HealthNIH3P50HD103525-01S1
National Center for Advancing Translational SciencesNCATS
Washington University in St. LouisWUSTL
University of WashingtonUW
Institute of Clinical and Translational SciencesICTSUL1TR002345
University of Missouri-Kansas CityUMKC
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
Partitioning of gene expression among zebrafish photoreceptor subtypes
(2021) Scientific Reports, 11 (1), art. no. 17340, .
Ogawa, Y., Corbo, J.C.
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
Abstract
Vertebrate photoreceptors are categorized into two broad classes, rods and cones, responsible for dim- and bright-light vision, respectively. While many molecular features that distinguish rods and cones are known, gene expression differences among cone subtypes remain poorly understood. Teleost fishes are renowned for the diversity of their photoreceptor systems. Here, we used single-cell RNA-seq to profile adult photoreceptors in zebrafish, a teleost. We found that in addition to the four canonical zebrafish cone types, there exist subpopulations of green and red cones (previously shown to be located in the ventral retina) that express red-shifted opsin paralogs (opn1mw4 or opn1lw1) as well as a unique combination of cone phototransduction genes. Furthermore, the expression of many paralogous phototransduction genes is partitioned among cone subtypes, analogous to the partitioning of the phototransduction paralogs between rods and cones seen across vertebrates. The partitioned cone-gene pairs arose via the teleost-specific whole-genome duplication or later clade-specific gene duplications. We also discovered that cone subtypes express distinct transcriptional regulators, including many factors not previously implicated in photoreceptor development or differentiation. Overall, our work suggests that partitioning of paralogous gene expression via the action of differentially expressed transcriptional regulators enables diversification of cone subtypes in teleosts. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHEY030075
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Japan Society for the Promotion of ScienceKAKEN202060618
Document Type: Article
Publication Stage: Final
Source: Scopus
Molecular Characterization of Microbiota in Cerebrospinal Fluid From Patients With CSF Shunt Infections Using Whole Genome Amplification Followed by Shotgun Sequencing
(2021) Frontiers in Cellular and Infection Microbiology, 11, art. no. 699506, .
Hodor, P.a , Pope, C.E.b , Whitlock, K.B.c , Hoffman, L.R.a b , Limbrick, D.L.d , McDonald, P.J.e , Hauptman, J.S.a b , Ojemann, J.G.a b , Simon, T.D.f g , Cerebrospinal FLuId MicroBiota in Shunts Study (CLIMB) Grouph
a Seattle Children’s Hospital, Seattle, WA, United States
b Department of Pediatrics, University of Washington, Seattle, WA, United States
c New Harmony Statistical Consulting LLC, Clinton, WA, United States
d Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
e Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
f Children’s Hospital Los Angeles, Los Angeles, CA, United States
g Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Abstract
Understanding the etiology of cerebrospinal fluid (CSF) shunt infections and reinfections requires detailed characterization of associated microorganisms. Traditionally, identification of bacteria present in the CSF has relied on culture methods, but recent studies have used high throughput sequencing of 16S rRNA genes. Here we evaluated the method of shotgun DNA sequencing for its potential to provide additional genomic information. CSF samples were collected from 3 patients near the beginning and end of each of 2 infection episodes. Extracted total DNA was sequenced by: (1) whole genome amplification followed by shotgun sequencing (WGA) and (2) high-throughput sequencing of the 16S rRNA V4 region (16S). Taxonomic assignments of sequences from WGA and 16S were compared with one another and with conventional microbiological cultures. While classification of bacteria was consistent among the 3 approaches, WGA provided additional insights into sample microbiological composition, such as showing relative abundances of microbial versus human DNA, identifying samples of questionable quality, and detecting significant viral load in some samples. One sample yielded sufficient non-human reads to allow assembly of a high-quality Staphylococcus epidermidis genome, denoted CLIMB1, which we characterized in terms of its MLST profile, gene complement (including putative antimicrobial resistance genes), and similarity to other annotated S. epidermidis genomes. Our results demonstrate that WGA directly applied to CSF is a valuable tool for the identification and genomic characterization of dominant microorganisms in CSF shunt infections, which can facilitate molecular approaches for the development of better diagnostic and treatment methods. © Copyright © 2021 Hodor, Pope, Whitlock, Hoffman, Limbrick, McDonald, Hauptman, Ojemann and Simon.
Author Keywords
cerebrospinal fluid; CSF shunt infection; high throughput DNA sequencing; microbiota; Staphylococcus epidermidis CLIMB1
Funding details
Cosmetic Surgery FoundationCSF
Document Type: Article
Publication Stage: Final
Source: Scopus
Amyloid β-Binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu Positron Emission Tomography Imaging in Alzheimer’s Disease
(2021) Inorganic Chemistry, 60 (16), pp. 12610-12620.
Wang, Y.a , Huynh, T.T.b c , Cho, H.-J.a , Wang, Y.-C.a , Rogers, B.E.b , Mirica, L.M.a d
a Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
b Department of Radiation Oncology, Washington University, School of Medicine, St. Louis, MO 63108, United States
c Department of Chemistry, Washington University, St. Louis, MO 63130, United States
d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable 64Cu-radiolabeled complexes. Among the five compounds tested, the 64Cu-YW-7 and 64Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log Doct) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis. © 2021 American Chemical Society.
Funding details
National Institutes of HealthNIHR01GM114588
Document Type: Article
Publication Stage: Final
Source: Scopus
A comparison of prediction approaches for identifying prodromal Parkinson disease
(2021) PLoS ONE, 16 (8 August), art. no. e0256592, .
Warden, M.N.a , Nielsen, S.S.a , Camacho-Soto, A.a , Garnett, R.b , Racette, B.A.a c
a Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
b Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, MO, United States
c Faculty of Health Sciences, School of Public Heath, University of the Witwatersrand, Johannesburg, South Africa
Abstract
Identifying people with Parkinson disease during the prodromal period, including via algorithms in administrative claims data, is an important research and clinical priority. We sought to improve upon an existing penalized logistic regression model, based on diagnosis and procedure codes, by adding prescription medication data or using machine learning. Using Medicare Part D beneficiaries age 66-90 from a population-based case-control study of incident Parkinson disease, we fit a penalized logistic regression both with and without Part D data. We also built a predictive algorithm using a random forest classifier for comparison. In a combined approach, we introduced the probability of Parkinson disease from the random forest, as a predictor in the penalized regression model. We calculated the receiver operator characteristic area under the curve (AUC) for each model. All models performed well, with AUCs ranging from 0.824 (simplest model) to 0.835 (combined approach). We conclude that medication data and random forests improve Parkinson disease prediction, but are not essential. © 2021 Warden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Gut microbiome is associated with multiple sclerosis activity in children
(2021) Annals of Clinical and Translational Neurology, .
Horton, M.K.a , McCauley, K.b , Fadrosh, D.b , Fujimura, K.b , Graves, J.c , Ness, J.d , Wheeler, Y.d , Gorman, M.P.e , Benson, L.A.e , Weinstock-Guttman, B.f , Waldman, A.g , Rodriguez, M.h , Tillema, J.-M.h , Krupp, L.i , Belman, A.i , Mar, S.j , Rensel, M.k , Chitnis, T.l , Casper, T.C.m , Rose, J.m , Hart, J.n , Shao, X.a , Tremlett, H.o , Lynch, S.V.b , Barcellos, L.F.a , Waubant, E.n , the U.S. Network of Pediatric MS Centersp
a Division of Epidemiology, University of California, Berkeley, Berkeley, CA, United States
b Department of Medicine- Gastroenterology, University of California, San Francisco, San Francisco, CA, United States
c Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
d Division of Pediatric Neurology, University of Alabama, Birmingham, AL, United States
e Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
f Department of Neurology, State University of New York, Buffalo, NY, United States
g Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
h Department of Neurology, Mayo Clinic, Rochester, MN, United States
i Pediatric Multiple Sclerosis Center, New York University Langone Medical Center, New York, NY, United States
j Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
k Department of Neurology, Cleveland Clinic, Cleveland, OH, United States
l Division of Child Neurology, Massachusetts General Hospital, Boston, MA, United States
m School of Medicine, University of Utah School, Salt Lake City, UT, United States
n Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
o Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Abstract
Objective: To identify features of the gut microbiome associated with multiple sclerosis activity over time. Methods: We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric-onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice-Williams-Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium-enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease-modifying therapies. Results: Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co-occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium-enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. Interpretation: Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association
Funding details
National Institute of Neurological Disorders and StrokeNINDSF13NS108668, R01NS071463
National Multiple Sclerosis SocietyHC150906233, RG4861A13
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Safety and tolerability of srx246, a vasopressin 1a antagonist, in irritable huntington’s disease patients—a randomized phase 2 clinical trial
(2020) Journal of Clinical Medicine, 9 (11), art. no. 3682, pp. 1-14.
Brownstein, M.J.a , Simon, N.G.a b , Long, J.D.c , Yankey, J.c , Maibach, H.T.a , Cudkowicz, M.d , Coffey, C.c , Conwit, R.A.e , Lungu, C.e , Anderson, K.E.f , Hersch, S.M.d g , Ecklund, D.J.c , Damiano, E.M.a , Itzkowitz, D.E.a , Lu, S.a b , Chase, M.K.d , Shefner, J.M.h i j , McGarry, A.k , Thornell, B.d , Gladden, C.d , Costigan, M.c , O’suilleabhain, P.l , Marshall, F.J.m , Chesire, A.M.m , Deritis, P.m , Adams, J.L.m , Hedera, P.n , Lowen, K.n , Diana Rosas, H.d , Hiller, A.L.o , Quinn, J.o , Keith, K.o , Duker, A.P.p , Gruenwald, C.p , Molloy, A.p , Jacob, C.p , Factor, S.q , Sperin, E.q , Bega, D.r , Brown, Z.R.r , Seeberger, L.C.s , Sung, V.W.t , Benge, M.t , Kostyk, S.K.u , Daley, A.M.u , Perlman, S.v , Suski, V.w , Conlon, P.w , Barrett, M.J.x , Lowenhaupt, S.x , Quigg, M.x , Perlmutter, J.S.y , Wright, B.A.z , Most, E.y , Schwartz, G.J.aa , Lamb, J.aa , Chuang, R.S.ab , Singer, C.ac , Marder, K.ad , Moran, J.A.ad , Singleton, J.R.ae , Zorn, M.ae , Wall, P.V.ae , Dubinsky, R.M.af , Gray, C.af , Drazinic, C.ag
a Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, United States
b Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, United States
c Department of Biostatistics, University of Iowa, Iowa City, IA 52242, United States
d Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
e National Institutes of Health, NINDS, Bethesda, MD 20852, United States
f Department of Neurology, Medstar Georgetown University Hospital, Washington, DC 20007, United States
g Voyager Therapeutics Inc., Cambridge, MA 02139, United States
h Barrow Neurological Institute, Phoenix, AZ 85013, United States
i Department of Neurology, College of Medicine, The University of Arizona, Phoenix, AZ 85004, United States
j Department of Neurology, College of Medicine, Creighton University, Phoenix, AZ 85013, United States
k Department of Neurology, Cooper University Hospital, Camden, NJ 08103, United States
l Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, United States
m Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, United States
n Department of Neurology, Vanderbilt University, Nashville, TN 37212, United States
o Department of Neurology, Oregon Health and Science University, Portland, OR 97239, United States
p Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, United States
q Department of Neurology, Emory University, Atlanta, GA 30322, United States
r Department of Neurology, Northwestern University, Chicago, IL 60611, United States
s Department of Neurology, University of Colorado Denver, Aurora, CO 80045, United States
t Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, United States
u Department of Neurology, Ohio State University, Columbus, OH 43210, United States
v Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, United States
w Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
x Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, United States
y Department of Neurology, Washington University, Saint Louis, MO 63110, United States
z Department of Neurosciences, University of California San Diego, La JollaCA 92121, United States
aa Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, United States
ab Department of Neurology, Swedish Medical Center, Seattle, WA 98122, United States
ac Department of Neurology, University of Miami, Miami, FL 33136, United States
ad Department of Neurology, Columbia University, New York, NY 10032, United States
ae Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, United States
af Department of Neurology, University of Kansas, Medical Center, Kansas City, KS 66160, United States
ag Department of Clinical Sciences, Florida State University, Tallahassee, FL 32306, United States
Abstract
SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood‐brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple‐ascending dose clinical trials. The present study was a 3‐arm, multicenter, randomized, placebo‐controlled, double‐blind, 12‐week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty‐two out of 106 subjects randomized completed the trial on their assigned dose of drug. One‐sided exact‐method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Huntington’s disease; Safety; Tolerability; Vasopressin 1a receptor antagonist
Document Type: Article
Publication Stage: Final
Source: Scopus