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WashU weekly Neuroscience publications

“Progressive anemia of prematurity is associated with a critical increase in cerebral oxygen extraction” (2020) Early Human Development

Progressive anemia of prematurity is associated with a critical increase in cerebral oxygen extraction
(2020) Early Human Development, 140, art. no. 104891, . 

Whitehead, H.V.a , Vesoulis, Z.A.a , Maheshwari, A.b , Rambhia, A.a , Mathur, A.M.c

a Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, United States
b Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, United States
c Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saint Louis University School of Medicine, United States

Abstract
Background: Elevated cerebral fractional tissue oxygen extraction (cFTOE) is an adaptation to anemia of prematurity (AOP). cFTOE ≥0.4 is associated with brain injury in infants ≤30 weeks. This longitudinal study sought to investigate the utility of cFTOE in the evaluation of AOP. Methods: Infants ≤30 weeks estimated gestational age (EGA) underwent weekly hemoglobin, cerebral saturation, and pulse oximetry recordings from the second through 36 weeks post-menstrual age (PMA). Recordings were excluded if they were under 1 h or if hemoglobin was not measured within 7 days of recording. Mean cFTOE was calculated for each recording. Statistical analysis used linear mixed-effects modeling and receiver operating characteristic analysis. Results: 144 recordings from 39 infants (mean EGA 27.6 ± 2.2 weeks, BW 1139 ± 286 g) were included of whom 39% (15/39) were transfused. The mean recording length was 2.8 ± 1.3 h. There was a significant negative correlation between hemoglobin and cFTOE (R = −0.423, p ≤.001). In a multivariate model, adjusting for EGA, PMA, and patent ductus arteriosus treatment the AUC was 0.821. A critical increase in cFTOE occurred at a hemoglobin level of 9.6 g/dL. Conclusions: AOP is associated with a critical increase in cFTOE that occurs at a significantly higher hemoglobin level than standard clinical thresholds for transfusion. © 2019 Elsevier B.V.

Author Keywords
Anemia of prematurity;  Cerebral NIRS;  Oxygen extraction;  Prematurity

Document Type: Article
Publication Stage: Final
Source: Scopus

“Nerve transfer as a novel treatment for West Nile virus-associated acute flaccid paralysis” (2019) Journal of the Neurological Sciences

Nerve transfer as a novel treatment for West Nile virus-associated acute flaccid paralysis
(2019) Journal of the Neurological Sciences, 407, art. no. 116502, . 

Wilks, A.W.a , Ray, W.Z.b , Al-Lozi, M.T.a , Bucelli, R.C.a

a Department of Neurology, Washington University School of Medicine, United States
b Department of Neurosurgery, Washington University School of Medicine, United States

Author Keywords
Acute flaccid paralysis;  Nerve transfer;  West Nile neuroinvasive disease;  West Nile virus

Document Type: Letter
Publication Stage: Final
Source: Scopus

“PTSD symptom decrease and use of weight loss programs” (2019) Journal of Psychosomatic Research

PTSD symptom decrease and use of weight loss programs
(2019) Journal of Psychosomatic Research, 127, art. no. 109849, . 

Scherrer, J.F.a b , Salas, J.a b , Chard, K.M.c , Tuerk, P.d , van den Berk-Clark, C.a , Schneider, F.D.e , Cohen, B.E.f , Lustman, P.J.g , Schnurr, P.P.h , Friedman, M.J.h , Norman, S.B.i

a Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
c Trauma Recovery Center Cincinnati VAMC, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States
d Sheila C. Johnson Center for Clinical Services, Department of Human Services, University of Virginia, Charlottesville, VA, United States
e Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
f Department of Medicine, University of California San Francisco School of Medicine and San Francisco VAMC, United States
g Department of Psychiatry, Washington University School of Medicine, St. Louis MO. and The Bell Street Clinic Opioid Addiction Treatment Programs, VA St. Louis Healthcare System, St. Louis, MO, United States
h National Center for PTSD and Department of Psychiatry, Geisel School of Medicine at Dartmouth, United States
i National Center for PTSD and Department of Psychiatry, University of California San Diego, United States

Abstract
Objective: Posttraumatic stress disorder (PTSD) is associated with poor health behaviors, including low utilization of Veteran Health Affairs (VHA) weight loss programs. It is not known if clinically meaningful PTSD improvement is associated with increased use of weight loss programs. Methods: Medical record data was obtained from VHA patients who received PTSD specialty care between Fiscal Year (FY) 2008 to FY2012. Clinically meaningful PTSD improvement was defined as ≥20 point PTSD Checklist (PCL) decrease between the first PCL ≥ 50 and a second PCL at least 8 weeks later and within 12 months of the first PCL. Eligible patients, n = 993, were followed through FY2015. Propensity scores and inverse probability of exposure weighting controlled confounding. Cox proportional hazard models estimated the association between clinically meaningful PCL decrease and weight loss clinic utilization. Supplemental analysis compared both PTSD groups vs. no PTSD. Results: Patients were 44.8 (SD ±14) years of age, 88.9% male and 66.8% white. Patients with vs. without a clinically meaningful PCL decrease were more likely to use a weight loss clinic (HR = 1.37; 95%CI:1.02–1.85). Among those with a weight loss encounter, PCL decrease was not associated with the number of encounters (RR = 1.13; 95%CI:0.70–1.81). Compared to no PTSD, patients with PTSD improvement had more weight loss encounters. Conclusions: Large improvements in PTSD are associated with increased utilization of weight loss programs, and PTSD is not a barrier to seeking weight loss counseling. Research to understand why improvement in PTSD is not related to better weight loss outcomes is needed. © 2019 Elsevier Inc.

Author Keywords
Cohort;  Epidemiology;  Health services;  Nutrition;  Posttraumatic stress disorder;  Veteran;  Weight

Document Type: Article
Publication Stage: Final
Source: Scopus

“Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder” (2019) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder
(2019) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 4 (11), pp. 956-965. 

Karcher, N.R.a , Rogers, B.P.b , Woodward, N.D.c

a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Vanderbilt University Institute of Imaging Science, Nashville, TN, United States
c Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States

Abstract
Background: The striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder. Methods: We examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed–based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed–based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex. Results: Cortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed–based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder. Conclusions: The current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders. © 2019 Society of Biological Psychiatry

Author Keywords
Cortex;  Psychosis;  Psychotic bipolar disorder;  Resting-state fMRI;  Schizophrenia;  Striatum

Document Type: Article
Publication Stage: Final
Source: Scopus

“Targeting tauopathy with engineered tau-degrading intrabodies” (2019) Molecular Neurodegeneration

Targeting tauopathy with engineered tau-degrading intrabodies
(2019) Molecular Neurodegeneration, 14 (1), p. 38. 

Gallardo, G.a b , Wong, C.H.a b c , Ricardez, S.M.a b , Mann, C.N.a b , Lin, K.H.a b , Leyns, C.E.G.a b d e , Jiang, H.a b d , Holtzman, D.M.a b d

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
b Hope Center for Neurological Disorders, Washington University, Campus Box 8111, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
c Department of Molecular Genetics and Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, TX, Dallas, 75390, United States
d Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA
e Neuroscience Discovery, Merck Research Laboratories, MA, Boston, 02115, United States

Abstract
BACKGROUND: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the majority of pathological tau remains in the cytosol of cells, not typically accessible to an extracellular antibody. Therefore, we reasoned targeting intracellular tau might be more efficacious in preventing or decreasing tauopathy. METHODS: By utilizing our anti-tau scFv, we generated anti-tau intrabodies for the expression in the cytosol of neurons. To enhance the degradation capacity of conventional intrabodies, we engineered chimeric anti-tau intrabodies fused to ubiquitin harboring distinct mutations that shuttle intracellular tau for either the proteasome or lysosomal mediated degradation. To evaluate the efficacy in delaying or eliminating tauopathy, we expressed our tau degrading intrabodies or controls in human tau transgenic mice by adeno-associated virus prior to overt tau pathology and after tau deposition. RESULTS: Our results demonstrate, the expression of chimeric anti-tau intrabodies significantly reduce tau protein levels in primary neuronal cultures expression human tau relative to a non-modified anti-tau intrabody. We found the expression of engineered tau-degrading intrabodies destined for proteasomal-mediated degradation are more effective in delaying or eliminating tauopathy than a conventional intrabody in aged human tau transgenic mice. CONCLUSION: This study, harnesses the strength of intrabodies that are amendable for targeting specific domains or modifications with the cell-intrinsic mechanisms that regulate protein degradation providing a new immunotherapeutic approach with potentially improved efficacy.

Author Keywords
Alzheimer’s disease;  Immunotherapy;  Intrabodies;  Tau degradation;  Tauopathy

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Categorical encoding of decision variables in orbitofrontal cortex” (2019) PLoS Computational Biology

Categorical encoding of decision variables in orbitofrontal cortex
(2019) PLoS Computational Biology, 15 (10), p. e1006667. 

Onken, A.a b , Xie, J.c , Panzeri, S.a , Padoa-Schioppa, C.c

a Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto, Italy
b School of Informatics, University of Edinburgh, Edinburgh, United Kingdom
c Department of Neuroscience, Washington University in St Louis, St Louis, MO, United States

Abstract
A fundamental and recurrent question in systems neuroscience is that of assessing what variables are encoded by a given population of neurons. Such assessments are often challenging because neurons in one brain area may encode multiple variables, and because neuronal representations might be categorical or non-categorical. These issues are particularly pertinent to the representation of decision variables in the orbitofrontal cortex (OFC)-an area implicated in economic choices. Here we present a new algorithm to assess whether a neuronal representation is categorical or non-categorical, and to identify the encoded variables if the representation is indeed categorical. The algorithm is based on two clustering procedures, one variable-independent and the other variable-based. The two partitions are then compared through adjusted mutual information. The present algorithm overcomes limitations of previous approaches and is widely applicable. We tested the algorithm on synthetic data and then used it to examine neuronal data recorded in the primate OFC during economic decisions. Confirming previous assessments, we found the neuronal representation in OFC to be categorical in nature. We also found that neurons in this area encode the value of individual offers, the binary choice outcome and the chosen value. In other words, during economic choice, neurons in the primate OFC encode decision variables in a categorical way.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“High-density speckle contrast optical tomography of cerebral blood flow response to functional stimuli in the rodent brain” (2019) Neurophotonics

High-density speckle contrast optical tomography of cerebral blood flow response to functional stimuli in the rodent brain
(2019) Neurophotonics, 6 (4), art. no. 045001, . 

Dragojević, T.a , Rosas, E.E.V.a , Hollmann, J.L.a , Culver, J.P.b c , Justicia, C.d e , Durduran, T.a f

a Institut de Ciències Fotòniques, Barcelona Institute of Science and Technology, Barcelona, Spain
b Washington University, School of Medicine, Department of Radiology, St. Louis, MO, United States
c Washington University, Department of Physics, St. Louis, MO, United States
d Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Department of Brain Ischemia and Neurodegeneration, Barcelona, Spain
e Institut d’Investigacions Biomèdiques August Pi i Sunyer, Àrea de Neurociències, Barcelona, Spain
f Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Abstract
Noninvasive, three-dimensional, and longitudinal imaging of cerebral blood flow (CBF) in small animal models and ultimately in humans has implications for fundamental research and clinical applications. It enables the study of phenomena such as brain development and learning and the effects of pathologies, with a clear vision for translation to humans. Speckle contrast optical tomography (SCOT) is an emerging optical method that aims to achieve this goal by directly measuring three-dimensional blood flow maps in deep tissue with a relatively inexpensive and simple system. High-density SCOT is developed to follow CBF changes in response to somatosensory cortex stimulation. Measurements are carried out through the intact skull on the rat brain. SCOT is able to follow individual trials in each brain hemisphere, where signal averaging resulted in comparable, cortical images to those of functional magnetic resonance images in spatial extent, location, and depth. Sham stimuli are utilized to demonstrate that the observed response is indeed due to local changes in the brain induced by forepaw stimulation. In developing and demonstrating the method, algorithms and analysis methods are developed. The results pave the way for longitudinal, nondestructive imaging in preclinical rodent models that can readily be translated to the human brain. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Author Keywords
Blood or tissue constituent monitoring;  Functional monitoring and imaging;  Medical and biological imaging;  Speckle imaging

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Deformable registration of whole brain zebrafish microscopy using an implementation of the flash algorithm within ants” (2019) Proceedings – International Symposium on Biomedical Imaging

Deformable registration of whole brain zebrafish microscopy using an implementation of the flash algorithm within ants
(2019) Proceedings – International Symposium on Biomedical Imaging, 2019-April, art. no. 8759549, pp. 213-217. 

Fleishman, G.M.a , Zhang, M.b , Tustison, N.J.c , Espinosa-Medina, I.a , Mu, Y.a , Khairy, K.a , Ahrens, M.a

a HHMI Janelia Research Campus, Ashburn, VA, United States
b Washington University in St. Louis, St. Louis, MO, United States
c University of Virginia, Charlottesville, VA, United States

Abstract
Recent advancements in microscopy, protein engineering, and genetics have rendered the larval zerbrafish a powerful model system for which whole brain, real time, functional neuroimaging at cellular resolution is accessible. Supplementing functional data with additional modalities in the same fish such as structural connectivity and transcriptomics will enable interpretation of structure-function relationships across the entire brains of individual animals. However, proper identification of corresponding cells in the large image volumes produced depends on accurate and efficient deformable registration. To address this challenge, we implemented the Fourier-approximated Lie Algebras for Shooting (FLASH) algorithm within the well-known Advanced Normalization Tools (ANTs) package. This combines the speed of FLASH with the extensive set of image matching functionals and multi-staging multi-resolution capabilities of ANTs. We registered longitudinal data from nine fish, using a line that uniquely identifies subsets of neurons in an independent channel. We validate our approach by demonstrating accurate cell-to-cell correspondence while requiring significantly less time and memory than the Symmetric Normalization (SyN) implementation in ANTs, and without compromising the theoretical foundations of the Large Deformation Diffeomorphic Metric Mapping (LDDMM) model. © 2019 IEEE.

Author Keywords
Registration diffeomorphism flash ants confocal lightsheet spim microscopy zebrafish

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Self-reported hearing quality of life measures in pediatric cochlear implant recipients with bilateral input” (2019) Cochlear Implants International

Self-reported hearing quality of life measures in pediatric cochlear implant recipients with bilateral input
(2019) Cochlear Implants International, . 

Suneel, D.a , Davidson, L.S.b c , Lieu, J.b

a Department of Communication Sciences and Disorders, University of Texas Austin, Austin, TX, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
c Program in Audiology and Communication Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Self-reported hearing quality of life (QoL) for pediatric cochlear implant (CI) recipients was examined, asking whether 1) children with CIs have similar QoL as those with less severe hearing loss (HL); 2) children with different bilateral CI (BCI) device configurations report different QoL; and 3) do audiological, demographic and spoken language factors affect hearing QoL? Design: One hundred four children (ages 7–11 years) using bimodal devices or BCIs participated. The Hearing Environments and Reflection of Quality of Life (HEAR-QL) questionnaire, receptive language and speech perception tests were administered. HEAR-QL scores of CI recipients were compared to scores of age-mates with normal hearing and mild to profound HL. Results: HEAR-QL scores for CI participants were similar to those of children with less severe HL and did not differ with device configuration. Emotion identification and word recognition in noise correlated significantly with HEAR-QL scores. Discussion: CI recipients reported that HL hinders social participation. Better understanding of speech in noise and emotional content was associated with fewer hearing-related difficulties on the HEAR-QL. Conclusions: Noisy situations encountered in educational settings should be addressed for children with HL. The link between perception of emotion and hearing-related QoL for CI recipients should be further examined. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Bilateral input;  Cochlear implants;  Hearing quality of life;  Pediatric patients;  Speech perception

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency” (2019) Genetics in Medicine

Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency
(2019) Genetics in Medicine, . 

Zawerton, A.a , Mignot, C.b c , Sigafoos, A.d , Blackburn, P.R.e , Haseeb, A.f , McWalter, K.g , Ichikawa, S.h , Nava, C.b c , Keren, B.b c , Charles, P.c , Marey, I.c , Tabet, A.-C.i j , Levy, J.i , Perrin, L.i , Hartmann, A.b k , Lesca, G.l m , Schluth-Bolard, C.l m , Monin, P.l , Dupuis-Girod, S.l n , Guillen Sacoto, M.J.g , Schnur, R.E.g , Zhu, Z.g , Poisson, A.o , El Chehadeh, S.p , Alembik, Y.p , Bruel, A.-L.q r , Lehalle, D.q s , Nambot, S.q s , Moutton, S.q s , Odent, S.t u , Jaillard, S.v , Dubourg, C.u w , Hilhorst-Hofstee, Y.x , Barbaro-Dieber, T.y , Ortega, L.y , Bhoj, E.J.z , Masser-Frye, D.aa , Bird, L.M.aa ab , Lindstrom, K.ac , Ramsey, K.M.ad , Narayanan, V.ad , Fassi, E.ae , Willing, M.ae , Cole, T.af , Salter, C.G.af ag , Akilapa, R.ah , Vandersteen, A.ai , Canham, N.aj ak , Rump, P.al , Gerkes, E.H.al , Wassink-Ruiter, J.S.K.al , Bijlsma, E.al , Hoffer, M.J.V.x , Vargas, M.am an , Wojcik, A.am an , Cherik, F.ao , Francannet, C.ao , Rosenfeld, J.A.ap , Machol, K.ap , Scott, D.A.ap aq , Bacino, C.A.ap , Wang, X.ap , Clark, G.D.ar , Bertoli, M.as , Zwolinski, S.as , Thomas, R.H.at au , Akay, E.au , Chang, R.C.av , Bressi, R.av , Sanchez Russo, R.aw , Srour, M.ax , Russell, L.ay , Goyette, A.-M.E.az , Dupuis, L.ba , Mendoza-Londono, R.ba , Karimov, C.bb , Joseph, M.bc , Nizon, M.bd be , Cogné, B.bd be , Kuechler, A.bf , Piton, A.bg bh , Klee, E.W.e bi , Lefebvre, V.f , Clark, K.J.d , Depienne, C.b bf bh , Deciphering Developmental Disorder Studybj

a Department of Cellular & Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, United States
b INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France
c AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique; Centre de Référence Déficiences Intellectuelles de Causes Rares, GRC UPMC « Déficience Intellectuelle et Autisme », Paris, France
d Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
e Center for Individualized Medicine, Department of Health Science Research, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
f Department of Surgery, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g GeneDx, Gaithersburg, MD, United States
h Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA, United States
i Genetics Department, Robert Debré Hospital, APHP, Paris, France
j Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
k APHP, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France
l Service de Génétique, Hospices Civils de Lyon – GHE, Lyon, France
m CNRS UMR 5292, INSERM U1028, CNRL, and Université Claude Bernard Lyon 1, GHE, Lyon, France
n Centre de référence pour la maladie de Rendu-Osler, Bron, France
o GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier and EDR-Psy Team (CNRS & Lyon 1 Claude Bernard University), Lyon, France
p Département de Génétique Médicale, CHU de Hautepierre, Strasbourg, France
q INSERM 1231 LNC, Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, France
r FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France
s Centre de Génétique et Centre de Référence Maladies Rares «Anomalies du Développement de l’Interrégion Est», Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
t CHU de Rennes, service de génétique clinique, Rennes, France
u Univ Rennes, CNRS, IGDR, UMR 6290, Rennes, France
v Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Rennes, France
w Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
x Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
y Cook Childrens Medical Center, Fort Worth, TX, United States
z Department of Clinical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
aa Rady Children’s Hospital San Diego, Division of Genetics and Dysmorphology, San Diego, CA, United States
ab Department of Pediatrics, University of California–San Diego, San Diego, CA, United States
ac Division of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix, AZ, United States
ad Translational Genomics Research Institute (TGen), Center for Rare Childhood Disorders, Phoenix, AZ, United States
ae Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
af West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom
ag RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
ah North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, London, United Kingdom
ai IWK Health Centre, Dalhousie University, Halifax, NS, Canada
aj North West Thames Regional Genetics Service, Northwick Park Hospital, London, United Kingdom
ak Cheshire & Merseyside Regional Genetics Service, Liverpool Women’s Hospital, Liverpool, United Kingdom
al Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
am Gillette Children’s Specialty Healthcare, St. Paul, MN, United States
an Children’s Minnesota, Minneapolis, MN, United States
ao Service de génétique clinique, Centre de Référence Maladies Rares «Anomalies du Développement et syndromes malformatifs du Sud-Est”, CHU de Clermont-Ferrand, Clermont-Ferrand, France
ap Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States
aq Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States
ar Pediatrics–Neurology, Baylor College of Medicine, Houston, TX, United States
as Northern Genetics Service—Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
at Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom
au Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
av Division of Metabolic Disorders, Children’s Hospital of Orange County (CHOC), Orange, CA, United States
aw Department of Human Genetics, Emory Universit, Atlanta, GA, United States
ax Division of Pediatric Neurology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada
ay Division of Medical Genetics, Department of Specialized Medicine, McGill University, Montreal, QC, Canada
az Child Development Program, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada
ba Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
bb Children’s hospital of Los Angeles, Los Angeles, CA, United States
bc Medical Genetics and Metabolism, Valley Children’s Hospital, Madera, CA, United States
bd CHU Nantes, Service de Génétique Médicale, Nantes, France
be INSERM, CNRS, UNIV Nantes, l’institut du thorax, Nantes, France
bf Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
bg Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
bh IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
bi Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
bj DDD Study, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom

Abstract
Purpose: Lamb–Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated. Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype–phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features. © 2019, American College of Medical Genetics and Genomics.

Author Keywords
autism;  developmental delay;  epilepsy;  intellectual disability;  missense variants

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Prospective Memory: Age related change is influenced by APOE genotype” (2019) Aging, Neuropsychology, and Cognition

Prospective Memory: Age related change is influenced by APOE genotype
(2019) Aging, Neuropsychology, and Cognition, . 

Lancaster, C.a , McDaniel, M.A.b , Tabet, N.c , Rusted, J.a

a School of Psychology, University of Sussex, Brighton, United Kingdom
b Department of Psychological and Brain Sciences, Washington University, St Louis, MI, United States
c Brighton and Sussex Medical School, Centre for Dementia Studies, Brighton, United Kingdom

Abstract
Non-focal prospective memory (PM) is sensitive to age-related decline; an additional impairment in focal PM is characteristic of mild stage Alzheimer’s disease. This research explored whether, by mid-adulthood, the distinct demands of focal and non-focal PM expose differences in carriers of an APOE ε4 allele, a genetic risk factor for Alzheimer’s disease. Thirty-three young and 55 mid-age adults, differentiated by APOE genotype, completed a category-decision task with a concurrent focal or non-focal PM demand. Only mid-age ε4 carriers showed a cost of carrying a focal PM intention. In addition, mid-age ε4 carriers showed a significantly greater cost of carrying a non-focal PM intention than young ε4 carriers, supporting a profile of accelerated aging. Consistency in the profile of cost differences observed in mid-age ε4 carriers and pathological aging may indicate premature vulnerability. Future research correlating a shift in PM performance with early genotype differences in brain-based markers of decline is important. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
aging;  Alzheimer’s disease;  APOE;  mid-adulthood;  prospective memory

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Franz Joseph Gall’s non-cortical faculties and their organs” (2019) Journal of the History of the Behavioral Sciences

Franz Joseph Gall’s non-cortical faculties and their organs
(2019) Journal of the History of the Behavioral Sciences, . 

Eling, P.a , Finger, S.b

a Department of Psychology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands
b Department of Psychological and Brain Sciences, Washington University, Saint Louis, MO, United States

Abstract
Franz Joseph Gall (1758–1828) is remembered for his claims that behavior results from a large number of independent mental faculties, and that these faculties are associated with cortical organs. Apart from the 26 faculties he localized in the cerebrum, he also recognized one faculty (reproductive drive) in the cerebellum. This picture, however, is based on Gall’s presentations in his well-known later works, his four volume Anatomie et Physiologie. These books reflect the outcomes of Gall’s thinking. They were steered by the observations and feedback he received in Vienna and while presenting his theories in the German states and neighboring countries between 1805 and 1807. Examining his lists before what he published in Paris shows how his faculties were changing. Notably, and as shown here, he had previously included several faculties associated with brainstem structures, in addition to the cerebellum, which he would continue to associate with some reproductive behaviors. © 2019 The Authors. Journal of The History of the Behavioral Sciences published by Wiley Periodicals, Inc.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

“Diffusion basis spectrum imaging for identifying pathologies in MS subtypes” (2019) Annals of Clinical and Translational Neurology

Diffusion basis spectrum imaging for identifying pathologies in MS subtypes
(2019) Annals of Clinical and Translational Neurology, . 

Shirani, A.a b , Sun, P.c , Trinkaus, K.d , Perantie, D.C.a , George, A.c , Naismith, R.T.a , Schmidt, R.E.e , Song, S.-K.c , Cross, A.H.a

a The John L. Trotter Multiple Sclerosis Center and Neuroimmunology Section, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Multiple Sclerosis, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, United States
c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Biostatistics Shared Resource and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology. © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

“Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke” (2019) Neuroscience Bulletin

Propofol Attenuates α-Synuclein Aggregation and Neuronal Damage in a Mouse Model of Ischemic Stroke
(2019) Neuroscience Bulletin, . 

Wang, Y.a b , Tian, D.b , Wei, C.a , Cui, V.c , Wang, H.b , Zhu, Y.b , Wu, A.a , Yue, Y.a

a Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
b Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
c Washington University School of Medicine, St. Louis, MI, United States

Abstract
α-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of α-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. α-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute ischemic stroke. While propofol has demonstrated neuroprotective properties following brain injury, the mechanism of protection in the setting of ischemic stroke is unclear. In this study, propofol administration significantly reduced the neurotoxic aggregation of α-synuclein, decreased the infarct area, and attenuated the neurological deficits after ischemic stroke in a mouse model. We then demonstrated that the propofol-induced reduction of α-synuclein aggregation was associated with increased mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 signaling pathway activity and reduction of the excessive autophagy occurring after acute ischemic stroke. © 2019, Shanghai Institutes for Biological Sciences, CAS.

Author Keywords
Autophagy;  Neuroprotection;  Propofol;  Stroke;  α-Synuclein

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Smartphone-based fundus photography for screening of plus-disease retinopathy of prematurity” (2019) Graefe’s Archive for Clinical and Experimental Ophthalmology

Smartphone-based fundus photography for screening of plus-disease retinopathy of prematurity
(2019) Graefe’s Archive for Clinical and Experimental Ophthalmology, . 

Patel, T.P.a , Aaberg, M.T.a , Paulus, Y.M.a b , Lieu, P.a , Dedania, V.S.c , Qian, C.X.d , Besirli, C.G.a , Margolis, T.e , Fletcher, D.A.f g , Kim, T.N.a h

a Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States
b Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
c Department of Ophthalmology, New York University School of Medicine, New York, NY, United States
d Department of Ophthalmology, University of Montreal, Montreal, Canada
e Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Bioengineering and Biophysics Program, University of California, Berkeley, CA, United States
g Chan-Zuckerberg Biohub, San Francisco, CA, United States
h Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, United States

Abstract
Background: Inadequate screening of treatment-warranted retinopathy of prematurity (ROP) can lead to devastating visual outcomes. Especially in resource-poor communities, the use of an affordable, portable, and easy to use smartphone-based non-contact fundus photography device may prove useful for screening for high-risk ROP. This study evaluates the feasibility of screening for high-risk ROP using a novel smartphone-based fundus photography device, RetinaScope. Methods: Retinal images were obtained using RetinaScope on a cohort of prematurely born infants during routine examinations for ROP. Images were reviewed by two masked graders who determined the image quality, the presence or absence of plus disease, and whether there was retinopathy that met predefined criteria for referral. The agreement between image-based assessments was compared to the gold standard indirect ophthalmoscopic assessment. Results: Fifty-four eyes of 27 infants were included. A wide-field fundus photograph was obtained using RetinaScope. Image quality was acceptable or excellent in 98% and 95% of cases. There was substantial agreement between the gold standard and photographic assessment of presence or absence of plus disease (Cohen’s κ = 0.85). Intergrader agreement on the presence of any retinopathy in photographs was also high (κ = 0.92). Conclusions: RetinaScope can capture digital retinal photographs of prematurely born infants with good image quality for grading of plus disease. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Fundus photography;  Plus disease;  Retinopathy of prematurity;  Smartphone;  Telemedicine

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Nerve transfer surgery in cervical spinal cord injury: a qualitative study exploring surgical and caregiver participant experiences” (2019) Disability and Rehabilitation

Nerve transfer surgery in cervical spinal cord injury: a qualitative study exploring surgical and caregiver participant experiences
(2019) Disability and Rehabilitation, . 

Fox, I.a b , Hoben, G.c , Komaie, G.d , Novak, C.e , Hamm, R.f , Kahn, L.g , Whitehead, M.f , Juknis, N.h , Ruvinskaya, R.h , Mackinnon, S.a , James, A.d

a Division of Plastic & Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, United States
b Division of Plastic Surgery, Veterans Administration Saint Louis Health Care System, Saint Louis, United States
c Department of Plastic Surgery, Medical College of Wisconsin, Milwaukee, United States
d Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, United States
e Division of Plastic & Reconstructive Surgery, University of Toronto, Toronto, Canada
f School of Physical Therapy, Washington University School of Medicine, Saint Louis, United States
g Milliken Hand Rehabilitation Center, Department of Occupational Therapy, Washington University School of Medicine, Saint Louis, United States
h Division of Neurorehabilitation, Department of Neurology, Washington University School of Medicine, Saint Louis, United States

Abstract
Purpose: To investigate perceptions of surgical participants and their caregivers regarding novel nerve transfer surgery to restore upper extremity function in cervical level spinal cord injury. Materials and Methods: A qualitative study design was used. A multidisciplinary team developed semi-structured interview guides. Interviews were recorded, transcribed and analyzed using basic text analysis. Results: Participants had limited information about procedures to improve function after spinal cord injury. When discussing their choice to undergo nerve (as compared to traditional tendon) transfer surgery, they describe a desire to avoid post-operative immobilization. Barriers included the pre-operative testing, cost and inconvenience of travel for surgery, and understanding complex health information related to the procedure. While expectations matched descriptions of outcomes among participants and were generally positive, caregivers expressed disappointment. The long time interval for gains in function to be realized and relatively incremental gains achieved were frustrating to all. Conclusions: People with cervical spinal cord injury and their caregivers need more information about options to restore function and about realistic range of improvements with treatment. Further work to mitigate barriers and develop health information materials around nerve transfer surgery may improve medical decision making around and appropriate use of this newer treatment option.IMPLICATIONS FOR REHABILITATION Nerve transfer surgery is a novel and acceptable means of improving upper extremity function in the setting of cervical spinal cord injury. People with cervical spinal cord injury and their caregivers need information about options to restore hand and arm function and mitigation of barriers around these treatment options. © 2019, © 2019 Washington University in Saint Louis.

Author Keywords
caregiver;  education materials;  nerve transfer surgery;  rehabilitation;  spinal cord injury;  tetraplegia;  treatment barriers;  upper extremity function

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Learning to see” (2019) Mind and Language

Learning to see
(2019) Mind and Language, . 

Millar, B.

Department of Philosophy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
It is often assumed that the empirical literature on sight restoration tells us something important about the relationship between visual and haptic representations of shape. However, I maintain that, immediately after having their sight restored, at least some newly sighted individuals undergo visual experiences that instantiate basic shape phenomenology but which do not present the corresponding shape properties. Consequently, the empirical literature on sight restoration tells us something important about the role that perceptual phenomenology plays in our perceptual awareness of an object’s properties—it tells us that the properties presented by perceptual experiences are not “built into” perceptual phenomenology. © 2019 John Wiley & Sons Ltd

Author Keywords
Molyneux’s question;  naïve realism;  perception;  property perception;  representationalism;  sensory phenomenology

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“An image processing algorithm to aid diagnosis of mesial temporal sclerosis in children: a case-control study” (2019) Pediatric Radiology

An image processing algorithm to aid diagnosis of mesial temporal sclerosis in children: a case-control study
(2019) Pediatric Radiology, . 

Strnad, B.S.a , Orlowski, H.L.P.a , Parsons, M.S.a , Salter, A.b , Dahiya, S.c , Sharma, A.a

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S Kingshighway Blvd., St. Louis, MO 63110, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Division of Neuropathology,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Mesial temporal sclerosis (MTS) is an important cause of intractable epilepsy. Early and accurate diagnosis of MTS is essential to providing curative and life-changing therapy but can be challenging in children in whom the impact of diagnosis is particularly high. Magnetic resonance imaging (MRI) plays an important role in the diagnosis of MTS, and image processing of MRI is a recently studied strategy to improve its accuracy. Objective: In a retrospective case-control study, we assessed the performance of an image processing algorithm (Correlative Image Enhancement [CIE]) for detecting MTS-related hippocampal signal abnormality in children. Materials and methods: Twenty-seven pediatric MTS cases (9 males, 18 females; mean age: 16±standard deviation [SD] 6.7 years) were identified from a pathology database of amygdylo-hippocampectomies performed in children with epilepsy. Twenty-seven children with no seizure history (9 males, 18 females; mean age: 13.8±SD 2.8 years), and with normal brain MRI, were identified for the control group. Blinded investigators processed the MRI coronal FLAIR (fluid-attenuated inversion recovery) images with CIE, saved the processed images as a separate series, and made equivalent region of interest measurements on the processed and unprocessed series to calculate contrast-to-noise ratio. Six blinded reviewers then rated the randomized series for hippocampal signal abnormality and MTS disease status. Results: CIE increased signal intensity and contrast-to-noise ratio in 26/27 hippocampi with pathologically confirmed MTS (96.3%) with the mean (SD) contrast-to-noise ratio of cases increasing from 14.9 (11.1) to 77.7 (58.7) after processing (P<0.001). Contrast-to-noise ratio increased in 1/54 normal control hippocampi (1.9%), with no significant change in the mean contrast-to-noise ratio of the control group after processing (P=0.57). Mean (SD) reader sensitivity for detecting abnormal signal intensity increased from 83.3% (14.2) to 94.8% (3.3) after processing. Mean specificity for abnormal signal intensity increased from 94.4% (7.3) to 96.3% (0). While sensitivity improved after processing for detection of MTS disease status in 4/6 readers, the mean reader sensitivity and specificity for MTS detection increased only minimally after processing, from 79.6% to 80.7% and from 95.7% to 96.3%, respectively. Conclusion: The CIE image processing algorithm selectively increased the contrast-to-noise ratio of hippocampi affected by MTS, improved reader performance in detecting MTS-related hippocampal signal abnormality and could have high impact on pediatric patients undergoing work-up for seizures. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Children;  Correlative image enhancement;  Epilepsy;  Image processing;  Magnetic resonance imaging;  Mesial temporal sclerosis;  Seizures

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Circadian regulation of astrocyte function: implications for Alzheimer’s disease” (2019) Cellular and Molecular Life Sciences

Circadian regulation of astrocyte function: implications for Alzheimer’s disease
(2019) Cellular and Molecular Life Sciences, . 

McKee, C.A., Lananna, B.V., Musiek, E.S.

Department of Neurology, Washington University School of Medicine, Box 8111, 425 S. Euclid Ave, St. Louis, MO 63105, United States

Abstract
The circadian clock regulates rhythms in gene transcription that have a profound impact on cellular function, behavior, and disease. Circadian dysfunction is a symptom of aging and neurodegenerative diseases, and recent studies suggest a bidirectional relationship between impaired clock function and neurodegeneration. Glial cells possess functional circadian clocks which may serve to control glial responses to daily oscillations in brain activity, cellular stress, and metabolism. Astrocytes directly support brain function through synaptic interactions, neuronal metabolic support, neuroinflammatory regulation, and control of neurovascular coupling at blood and CSF barriers. Emerging evidence suggests that the astrocyte circadian clock may be involved in many of these processes, and that clock disruption could influence neurodegeneration by disrupting several aspects of astrocyte function. Here we review the literature surrounding circadian control of astrocyte function in health and disease, and discuss the potential implications of astrocyte clocks for neurodegeneration. © 2019, Springer Nature Switzerland AG.

Author Keywords
Alzheimer’s disease;  Astrocyte;  Circadian rhythms;  Neurodegeneration

Document Type: Review
Publication Stage: Article in Press
Source: Scopus

“A curved port delivery system for laser interstitial thermal therapy of brain tumors” (2019) Frontiers in Biomedical Devices, BIOMED – 2019 Design of Medical Devices Conference, DMD 2019

A curved port delivery system for laser interstitial thermal therapy of brain tumors
(2019) Frontiers in Biomedical Devices, BIOMED – 2019 Design of Medical Devices Conference, DMD 2019, . 

Agwu, N.a , Deprow, K.a , Williams, J.E.a , Gorlewicz, J.L.a , Leuthardt, E.C.b

a St. Louis University, St. Louis, MO, United States
b Washington University in St. Louis, St. Louis, MO, United States

Abstract
Laser interstitial thermal therapy (LITT) is a neurosurgical procedure that involves using heat treatment to ablate glioblastomas in the brain. Current methods for placing probes in LITT involve straight trajectory pathways. This limitation often requires surgeons to make multiple trajectories or leave undesired margins. There has been extensive work in steerable needles, concentric tube cannulas, and flexible surgical tools. In this work, we present an approach which focuses on providing steerability to tools that aren’t inherently steerable. To do this, we developed a curved port delivery system that leverages an active cannula for the deployment of a plastic, flexible port that delivers existing surgical tools. We present an initial prototype coupled with feasibility results illustrating that the port can be placed to steer probes to a desired location. Copyright © 2019 ASME

Author Keywords
Active cannula;  Laser ablation;  Steerable devices

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Accelerating Motor Skill Acquisition for Bicycle Riding in Children with ASD: A Pilot Study” (2019) Journal of Autism and Developmental Disorders

Accelerating Motor Skill Acquisition for Bicycle Riding in Children with ASD: A Pilot Study
(2019) Journal of Autism and Developmental Disorders, . 

Hawks, Z.a , Constantino, J.N.b c d , Weichselbaum, C.b , Marrus, N.b d

a Department of Psychological & Brain Sciences, Washington University, St. Louis, MO 63105, United States
b Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
c Department of Pediatrics, Washington University, St. Louis, MO 63110, United States
d Intellectual and Developmental Disabilities Research Center, Washington University, St. Louis, MO 63110, United States

Abstract
Motor impairment is common in autism spectrum disorder (ASD) and, as such, a potential target for interventions to improve adaptive functioning. This study investigated motor skill acquisition in children with ASD (n = 15, 12 males; ages 7–16 years) during iCan Bike Camp, a 1-week, community-based intervention (5 × 75-min sessions) to teach independent bicycle riding. After completing the camp’s task-oriented, individualized training program, all participants demonstrated motor skill acquisition on the bicycle, and nine participants rode independently at least 70 feet. Exploratory analyses showed that motor coordination and social communication correlated with rates of skill acquisition. These findings indicate the feasibility and efficacy of brief, community-based motor interventions to teach bicycle riding—an important developmental skill supporting adaptive functioning—to children with ASD. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Adaptive function;  Autism spectrum disorder (ASD);  Bicycle riding;  Motor coordination;  Motor skill acquisition;  Social communication

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone” (2019) Advances in Radiation Oncology

Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone
(2019) Advances in Radiation Oncology, . 

Miller, S.a , Li, P.b , Schipper, M.b , Junck, L.c , Piert, M.d , Lawrence, T.S.a , Tsien, C.e , Cao, Y.a , Kim, M.M.a

a Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
b Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
c Department of Neurology, University of Michigan, Ann Arbor, MI, United States
d Department of Radiology University of Michigan, Ann Arbor, MI, United States
e Department of Radiation Oncology, Washington University in St Louis, St Louis, MO, United States

Abstract
Purpose: To evaluate whether response assessment of newly diagnosed glioblastoma at 3 months using 11C-methionine-positron emission tomography (MET-PET) is better associated with patient outcome compared with baseline MET-PET or anatomic magnetic resonance imaging alone. Methods and Materials: Patients included were participants in a phase I/II trial of dose-escalated chemoradiation based on anatomic magnetic resonance imaging. Automated segmentation of metabolic tumor volume (MTV) was performed at a threshold of 1.5 times mean cerebellar uptake. Progression-free (PFS) and overall survival were estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariate analysis for PFS and overall survival was performed using Cox proportional hazards, and spatial overlap between imaging and recurrence volumes were analyzed. Results: Among 37 patients, 15 had gross total resection, of whom 10 (67%) had residual MTV, 16 subtotal resection, and 6 biopsy alone. Median radiation therapy dose was 75 Gy (range, 66-81). Median baseline T1 Gd-enhanced tumor volume (GTV-Gd) was 38.0 cm3 (range, 8.0-81.5). Median pre-CRT MTV was 4.9 cm3 (range, 0-43.8). Among 25 patients with 3-month MET-PET, MTV was only 2.4 cm3 (range, 0.004-18.0) in patients with uptake. Patients with MTV = 0 cm3 at 3 months had superior PFS (18.2 vs 10.1 months, P =.03). On multivariate analysis, larger 3-month MTV (hazard ratio [HR] 2.4, 95% confidence interval [CI], 1.4-4.3, P =.03), persistent MET-PET subvolume (overlap of pre-CRT and 3 month MTV; HR 2.0, 95% CI, 1.2-3.4, P =.06), and increase in MTV (HR 1.8, 95% CI, 1.1-3.1, P =.09) were the only imaging factors significant for worse PFS. GTV-Gd at recurrence encompassed 97% of the persistent MET-PET subvolume (interquartile range 72%-100%), versus 71% (interquartile range 39%-93%) of baseline MTV, 54% of baseline GTV-Gd (18%-87%), and 78% of 3-month MTV (47%-95%). Conclusions: The majority of patients with apparent gross total resection of glioblastoma have measurable postoperative MTV. Total and persisting MTV 3 months post-CRT were significant predictors of PFS, and persistent MET-PET subvolume was the strongest predictor for localizing tumor recurrence. © 2019 The Authors

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

“The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology” (2019) Alzheimer’s and Dementia

The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology
(2019) Alzheimer’s and Dementia, . 

Boeve, B.a , Bove, J.b , Brannelly, P.c , Brushaber, D.a , Coppola, G.d , Dever, R.e , Dheel, C.a , Dickerson, B.f , Dickinson, S.g , Faber, K.h , Fields, J.a , Fong, J.e , Foroud, T.h , Forsberg, L.a , Gavrilova, R.a , Gearhart, D.a , Ghoshal, N.i , Goldman, J.j , Graff-Radford, J.a , Graff-Radford, N.k , Grossman, M.b , Haley, D.k , Heuer, H.e , Hsiung, G.-Y.R.l , Huey, E.j , Irwin, D.b , Jones, D.a , Jones, L.i , Kantarci, K.a , Karydas, A.e , Knopman, D.a , Kornak, J.e , Kraft, R.a , Kramer, J.e , Kremers, W.a , Kukull, W.m , Lapid, M.a , Lucente, D.f , Mackenzie, I.l , Manoochehri, M.j , McGinnis, S.f , Miller, B.e , Pearlman, R.n , Petrucelli, L.k , Potter, M.h , Rademakers, R.k , Ramos, E.d , Rankin, K.e , Rascovsky, K.b , Sengdy, P.l , Shaw, L.b , Syrjanen, J.a , Tatton, N.g , Taylor, J.e , Toga, A.o , Trojanowski, J.b , Weintraub, S.p , Wong, B.f , Wszolek, Z.k , Boxer, A.e , Rosen, H.e , LEFFTDS Consortiumq

a Mayo Clinic, Rochester, MN, United States
b University of Pennsylvania, Philadelphia, PA, United States
c Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, United States
d UCLA, Los Angeles, CA, United States
e UCSF, San Francisco, CA, United States
f Harvard University/MGH, Boston, MA, United States
g Association for Frontotemporal Degeneration, Radnor, PA, United States
h National Cell Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Indiana University, Indianapolis, IN, United States
i Washington University, St. Louis, MO, United States
j Columbia University, New York, NY, United States
k Mayo Clinic, Jacksonville, FL, United States
l University of British Columbia, Vancouver, British Columbia, Canada
m National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, United States
n Bluefield Project, San Francisco, CA, United States
o Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, United States
p Northwestern University, Chicago, IL, United States

Abstract
Introduction: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. Methods: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes—microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. Results: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. Discussion: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD. © 2019 The Authors

Author Keywords
C9orf72;  Frontotemporal dementia;  Genetics;  GRN;  MAPT;  Tau;  TDP-43

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

“Social Network Mapping and Functional Recovery Within 6 Months of Ischemic Stroke” (2019) Neurorehabilitation and Neural Repair

Social Network Mapping and Functional Recovery Within 6 Months of Ischemic Stroke
(2019) Neurorehabilitation and Neural Repair, . 

Dhand, A.a b , Lang, C.E.c , Luke, D.A.d , Kim, A.f , Li, K.a , McCafferty, L.a , Mu, Y.e , Rosner, B.e , Feske, S.K.a , Lee, J.-M.c

a Harvard Medical School, Boston, MA, United States
b Northeastern University, Boston, MA, United States
c Washington University School of Medicine, St Louis, MO, United States
d Washington University in St LouisMO, United States
e Harvard T. H. Chan School of Public Health, Boston, MA, United States

Abstract
Objective. Stroke recovery is a multidimensional process influenced by biological and psychosocial factors. To understand the latter, we mapped the social networks of stroke patients, analyzing their changes and effects on physical function at 3 and 6 months after stroke. Methods. We used a quantitative social network assessment tool to map the structure and health habits embedded in patients’ personal social networks. The physical function outcome was determined using the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Scale (0-100, mean 50 for US general population). We used mixed-effects models to assess changes in social network metrics. We used multivariable models to test the association between social networks and physical function, independent of demographics, socioeconomic status, clinical characteristics, comorbidities, cognition, and depression. Results. The cohort consisted of 172 patients, with mostly mild motor-predominant stroke (median NIH Stroke Scale of 2) with retention of 149 at 3 months and 139 at 6 months. An average patient’s network over 6 months contracted by 1.25 people and became denser and family oriented. Network composition also became healthier with pruning of ties with people who smoked or did not exercise. The baseline network size, and not density or health habits in the network, was independently associated with 3- and 6-month physical function PROMIS scores. Patients embedded in small kin-based networks reported more negative social interactions. Conclusions. Despite social networks becoming smaller and close-knit after stroke, they also become healthier. Larger baseline social networks are independently associated with better patient-reported physical function after stroke. © The Author(s) 2019.

Author Keywords
psychosocial support systems;  recovery of function;  social environment;  social networking;  stroke rehabilitation

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Preschool-Onset Major Depressive Disorder is Characterized by Electrocortical Deficits in Processing Pleasant Emotional Pictures” (2019) Journal of Abnormal Child Psychology

Preschool-Onset Major Depressive Disorder is Characterized by Electrocortical Deficits in Processing Pleasant Emotional Pictures
(2019) Journal of Abnormal Child Psychology, . 

Whalen, D.J.a , Gilbert, K.E.a , Kelly, D.a , Hajcak, G.b , Kappenman, E.S.c , Luby, J.L.a , Barch, D.M.a d e f

a Department of Psychiatry, Washington University School of Medicine in St. Louis, 4444 Forest Park, Suite 2100, St. Louis, MO 63108, United States
b Department of Psychology, Florida State University, Tallahassee, FL, United States
c Department of Psychology, San Diego State University, San Diego, CA, United States
d The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Reductions in positive affect are a salient feature of preschool-onset major depressive disorder. Yet, little is known about the psychophysiological correlates of this blunted positive affect and whether reduced physiological responding to pleasant stimuli may differentiate depressed and healthy young children. 120 four-to-seven year old children with current depression and 63 psychiatrically healthy 4-to-7 year old children completed a simple picture-viewing task of pleasant and neutral pictures while event-related potentials (ERPs) were recorded. The early-childhood version of the Kiddie Schedule for Affective Disorders and Depression was used to establish psychiatric diagnoses. A one-way ANCOVA was used to test for group differences in response to pleasant and neutral pictures. Young children with depression showed a reduced response to pleasant vs. neutral pictures (LPP), after controlling for children’s age (F(1,180) = 4.15, p = 0.04, η2 = 0.02). The LPP for the children with preschool-onset depression (M = 0.99, SE = 0.65) was significantly smaller than the LPP in the healthy group of young children (M = 3.27, SE = 0.90). This difference did not vary as a function of depression or anhedonia severity within the group with depression or the healthy children. Similar to older children and adolescents with depression, young children with depression display reductions in responsivity to pleasant stimuli as indexed by the LPP. These findings extend prior findings indicating a blunted response to pleasant stimuli in preschool- onset depression. Given the greater neuroplasticity of emotional response and regulation, these findings suggest clinical attention to emotional response to pleasure is an important target in preschool-onset depression. Clinical trial registration information: A Randomized Control Trial of PCIT-ED for Preschool Depression; http://clinicaltrials.gov/;NCT02076425. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Depression;  Early childhood;  ERP;  Late positive potential (LPP)

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Association between personality and tau-PET binding in cognitively normal older adults” (2019) Brain Imaging and Behavior

Association between personality and tau-PET binding in cognitively normal older adults
(2019) Brain Imaging and Behavior, . 

Schultz, S.A.a b , Gordon, B.A.b c d , Mishra, S.b e , Su, Y.b f , Morris, J.C.c g , Ances, B.M.c g , Duchek, J.M.c d , Balota, D.A.c d , Benzinger, T.L.S.b c h

a Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, United States
c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, United States
d Department of Psychological & Brain Sciences, Washington University, St. Louis, United States
e Department of Radiology, Mass General Hospital, Boston, MA, United States
f Banner Alzheimer’s Institute, Phoenix, AZ, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, United States
h Department of Neurological Surgery, Washington University School of Medicine, St. Louis, United States

Abstract
Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n = 128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and β-amyloid (Aβ)-PET imaging. We utilized linear regression models, adjusting for age, sex, geriatric depression score, and Aβ to evaluate the association between each of the personality traits and regional tau-PET accumulation. Elevated Neuroticism scores were associated with higher tau-PET accumulation in the amygdala (p =.002), entorhinal cortex (p =.012), and inferior temporal cortex (p =.016), as well as with a composite tau-PET measure (p =.002). In contrast, Extroversion, Openness, Agreeableness, and Conscientiousness were not associated with tau deposition in any of these regions (p’s > 0.160). Our results indicate that increased Neuroticism is associated with higher tau pathophysiology in regions known to be vulnerable to AD pathophysiology in CN participants. High Neuroticism scores may therefore serve as a potential risk factor for tau accumulation. Alternatively, personality can change with the onset of AD, thus increased tau levels may affect Neuroticism scores. While future longitudinal studies are needed to determine directionality, our findings suggest early associations between Neuroticism and tau accumulation in CN adults. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alzheimer disease;  Neurodegeneration;  Neuroticism;  Personality;  Tau

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Isolated Axillary Nerve Injury in an Elite High School American Football Player: A Case Report” (2019) Sports Health

Isolated Axillary Nerve Injury in an Elite High School American Football Player: A Case Report
(2019) Sports Health, . 

Probst, D.T.a , Mackinnon, S.E.b , Prather, H.c

a Division of Neurorehabilitation, Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Plastic and Reconstructive Surgery, Washington University School of Medicine, St Louis, MO, United States
c Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
An elite high school American football athlete sustained a traumatic, isolated, axillary nerve injury. Axillary nerve injuries are uncommon, but serious injuries in American football. With the advent of nerve transfers and grafts, these injuries, if diagnosed in a timely manner, are treatable. This case report discusses the multidisciplinary approach necessary for the diagnosis and treatment of an elite high school American football player who presented with marked deltoid atrophy. The athlete’s injury was diagnosed via electrodiagnostic testing and he underwent a medial triceps nerve to axillary nerve transfer. After appropriate postsurgical therapy, the athlete was able to return to American football the subsequent season and continue performing at an elite level. This case report reviews the evaluation and modern treatment for axillary nerve injuries in the athlete including nerve transfers, nerve grafts, and return to play. © 2019 The Author(s).

Author Keywords
axillary nerve palsy;  deltoid atrophy;  nerve transfer

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Use of an experimental language acquisition paradigm for standardized neuropsychological assessment of learning: A pilot study in young and older adults” (2019) Journal of Clinical and Experimental Neuropsychology

Use of an experimental language acquisition paradigm for standardized neuropsychological assessment of learning: A pilot study in young and older adults
(2019) Journal of Clinical and Experimental Neuropsychology, . 

Baker, J.E.a , Bruns Jr, L.b , Hassenstab, J.c d , Masters, C.L.a , Maruff, P.a e , Lim, Y.Y.a

a Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, Parkville, Australia
b School of Computing and Information Systems, The University of Melbourne, Parkville, Australia
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
e Cogstate Ltd, Melbourne, Australia

Abstract
Introduction: Despite the numerous episodic memory tasks used in neuropsychological assessment, relatively few learning tasks are available, with methods lacking the complexity and sophistication to capture very subtle changes in information acquisition. Method: We adapted a previously validated associative learning task for use within an online framework, utilizing real-world stimuli, in which learning of audio-visual pairs of Chinese characters and English words occurs over 5 days. The aim of this study was to validate our adaptation to the task, provide estimates of rates of learning in both young and older adults, as well as provide a methodological framework for further adaptation and development of the paradigm. A total of 30 young adults and 30 older adults completed 5 days of the Chinese Characters Learning Task (CCLT). Results: Results indicated that rates of learning on the adapted task were comparable to the original paradigm and consistent across variations to testing frequency and duration. Our results also indicate the presence of a significant age-related impairment in the rate and accuracy of learning, with young adults aged 18–45 years performing significantly better than older adults aged 65–85 years, that was not due to differences in reaction time. Conclusions: These findings suggest that daily measurement of cognition via an online platform can detect age-related impairments in learning and is therefore applicable for use within the context of age-related disorders of memory and learning. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
acquisition;  associative learning;  impairment;  Learning curves;  repeated assessment

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I” (2019) Molecular Genetics and Metabolism

Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I
(2019) Molecular Genetics and Metabolism, . 

Vera, M.U.a b , Le, S.Q.b c , Victoroff, A.a , Passage, M.B.b , Brown, J.R.d , Crawford, B.E.e , Polgreen, L.E.b , Chen, A.H.b , Dickson, P.I.b c

a Children’s Hospital Los Angeles, Los Angeles, CA, United States
b Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, United States
c Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
d TEGA Therapeutics, Inc., San Diego, CA, United States
e BioMarin Pharmaceutical Inc., San Rafael, CA, United States

Abstract
Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-L-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p &lt; 0.001). Unexpectedly, we also observed a decrease in non-reducing end levels in cerebrospinal fluid in all five subjects for whom samples were collected (mean 41.8% reduction, p = 0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r2 = 0.65, p = 0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I. © 2019 Elsevier Inc.

Author Keywords
Enzyme replacement therapy;  Glycosaminoglycan;  Hurler;  Lysosomal storage disorder;  Mucopolysaccharidosis

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Gender identity and sexual orientation affect health care satisfaction, but not utilization, in persons with Multiple Sclerosis” (2019) Multiple Sclerosis and Related Disorders

Gender identity and sexual orientation affect health care satisfaction, but not utilization, in persons with Multiple Sclerosis
(2019) Multiple Sclerosis and Related Disorders, art. no. 101440, . 

Khayambashi, S.a , Salter, A.b , Tyry, T.c , Cutter, G.R.d , Fox, R.J.e , Marrie, R.A.a f

a Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
b Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
c Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
d Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
e Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
f Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada

Abstract
Objective: We aimed to determine the association between gender identity and sexual orientation on health care utilization in persons with multiple sclerosis (MS), as well as satisfaction with their doctor and comfort discussing sexual health with their doctor. Methods: We surveyed participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their gender identity and sexual orientation in 2017. Participants also reported their sociodemographic characteristics, disability status, health behaviors and health care utilization, including whether any hospitalizations or emergency room (ER) visits occurred or any disease-modifying therapy (DMT) was used within the last six months. We compared the likelihood of hospitalizations, ER visits and DMT use between (i) cisgender and transgender participants; and (ii) heterosexual, homosexual, and “other sexual orientation” participants using multivariable logistic regression models adjusting for potential confounding factors. Results: Of the 5,604 eligible responders, 1168 (20.8%) reported their sex at birth as male and 4436 reported their sex at birth as female (79.2%). Twenty-five (0.45%) participants identified as transgender and 260 (4.6%) as non-heterosexual individuals. As compared to participants who reported their sexual orientation as heterosexual, non-heterosexual participants were younger, with an earlier age at MS symptom onset, more likely to have a post-secondary education, and more likely to be single. The frequency of any ER visits, any hospital admissions, and DMT use did not differ according to gender identity did not differ according to gender identity or sexual orientation. As compared to cisgender participants, transgender participants reported less comfort (p < 0.042) discussing sexual health with their doctor; findings were similar for non-heterosexual participants as compared to heterosexual participants. Participants reporting other sexual orientation also reported lower satisfaction (p < 0.039) with their doctor than other participants. Conclusion: Gender identity and sexual orientation were not associated with differences in healthcare utilization in persons with MS. However, health care experiences and satisfaction with care may be altered by gender identity and sexual orientation. © 2019 Elsevier B.V.

Author Keywords
Gender identity;  Multiple sclerosis;  Sexual orientation

Document Type: Article
Publication Stage: Article in Press
Source: Scopus