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WashU weekly Neuroscience publications

“Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia” (2019) Scientific Reports

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
(2019) Scientific Reports, 9 (1), art. no. 10854, . 

Bonham, L.W.a b , Steele, N.Z.R.a , Karch, C.M.c , Broce, I.b , Geier, E.G.a , Wen, N.L.c , Momeni, P.d , Hardy, J.e , Miller, Z.A.a , Gorno-Tempini, M.L.a , Hess, C.P.b , Lewis, P.e f , Miller, B.L.a , Seeley, W.W.a , Manzoni, C.e f , Desikan, R.S.b , Baranzini, S.E.g , Ferrari, R.e , Yokoyama, J.S.a , Hernandez, D.G.h i , Nalls, M.A.h , Rohrer, J.D.i j , Ramasamy, A.i k l , Kwok, J.B.J.m n , Dobson-Stone, C.m n , Schofield, P.R.m n , Halliday, G.M.m n , Hodges, J.R.m n , Piguet, O.m n , Bartley, L.m n , Thompson, E.o p , Haan, E.o p , Hernández, I.q , Ruiz, A.q , Boada, M.q , Borroni, B.r , Padovani, A.r , Cruchaga, C.s t , Cairns, N.J.u v , Benussi, L.w , Binetti, G.x , Ghidoni, R.w , Forloni, G.y , Albani, D.y , Galimberti, D.z aa , Fenoglio, C.z aa , Serpente, M.z aa , Scarpini, E.z aa , Clarimón, J.ab ac , Lleó, A.ab ac , Blesa, R.ab ac , Landqvist Waldö, M.ad , Nilsson, K.ad , Nilsson, C.ae , Mackenzie, I.R.A.af , Hsiung, G.-Y.R.ag , Mann, D.M.A.ah , Grafman, J.ai aj ak , Morris, C.M.al am an , Attems, J.am , Griffiths, T.D.an , McKeith, I.G.am , Thomas, A.J.am , Pietrini, P.ao , Huey, E.D.ap , Wassermann, E.M.aq , Baborie, A.ar , Jaros, E.am , Tierney, M.C.aq , Pastor, P.ac , Razquin, C.as , Ortega-Cubero, S.ac as , Alonso, E.as at , Perneczky, R.au av aw , Diehl-Schmid, J.aw , Alexopoulos, P.aw , Kurz, A.aw , Rainero, I.ax , Rubino, E.ax , Pinessi, L.ax , Rogaeva, E.ay , St George-Hyslop, P.ay az , Rossi, G.ba , Tagliavini, F.ba , Giaccone, G.ba , Rowe, J.B.bb bc bd , Schlachetzki, J.C.M.be , Uphill, J.bf , Collinge, J.bf , Mead, S.bf , Danek, A.bg , Van Deerlin, V.M.bh , Grossman, M.bi , Trojanowski, J.Q.bj bk , van der Zee, J.bj bk , Cruts, M.bj bk , Van Broeckhoven, C.bj bk , Cappa, S.F.bl , Leber, I.bm bn bo bp , Hannequin, D.bq , Golfier, V.br , Vercelletto, M.bs , Brice, A.bm bn bo bp , Nacmias, B.bt , Sorbi, S.bt , Bagnoli, S.bt , Piaceri, I.bt , Nielsen, J.E.bu bv , Hjermind, L.E.bu bv , Riemenschneider, M.bw bx , Mayhaus, M.bx , Ibach, B.by , Gasparoni, G.bx , Pichler, S.bx , Gu, W.bx bz , Rossor, M.N.j , Fox, N.C.j , Warren, J.D.j , Spillantini, M.G.bb , Morris, H.R.e , Rizzu, P.ca , Heutink, P.ca , Snowden, J.S.ah , Rollinson, S.ah , Richardson, A.cb , Gerhard, A.ah , Bruni, A.C.cc , Maletta, R.cc , Frangipane, F.cc , Cupidi, C.cc , Bernardi, L.cc , Anfossi, M.cc , Gallo, M.cc , Conidi, M.E.cc , Smirne, N.cc , Rademakers, R.cd , Baker, M.cd , Dickson, D.W.cd , Graff-Radford, N.R.cd , Petersen, R.C.ce , Knopman, D.ce , Josephs, K.A.ce , Boeve, B.F.ce , Parisi, J.E.cf , Karydas, A.M.a , Rosen, H.a , van Swieten, J.C.cg ch , Dopper, E.G.P.cg ch , Seelaar, H.cg ch , Pijnenburg, Y.A.L.ci , Scheltens, P.ci , Logroscino, G.cj , Capozzo, R.cj , Novelli, V.ck , Puca, A.A.cl cm , Franceschi, M.cn , Postiglione, A.co , Milan, G.cp , Sorrentino, P.cp , Kristiansen, M.cq , Chiang, H.-H.cr cs , Graff, C.cr cs , Pasquier, F.ct , Rollin, A.ct , Deramecourt, V.ct , Lebouvier, T.ct , Kapogiannis, D.cu , Ferrucci, L.cv , Pickering-Brown, S.ah , Singleton, A.B.h , International FTD-Genomics Consortium (IFGC)cw

a Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
b Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
c Department of Psychiatry, Washington University, St. Louis, MO, United States
d Texas Tech University Health Science Center, Laboratory of Neurogenetics, Lubbock, TX, United States
e Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
f School of Pharmacy, University of Reading, Whiteknights, Reading, United Kingdom
g Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
h Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
i Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
j Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
k Department of Medical and Molecular Genetics, King’s College London Tower Wing, Guy’s Hospital, London, United Kingdom
l The Jenner Institute, University of Oxford, Oxford, United Kingdom
m Neuroscience Research Australia, Sydney, NSW, Australia
n School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
o South Australian Clinical Genetics Service, SA Pathology (at Women’s and Children’s Hospital), North Adelaide, SA, Australia
p Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia
q Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
r Neurology Clinic, University of Brescia, Brescia, Italy
s Department of Psychiatry, Washington University, St. Louis, MO, United States
t Hope Center, Washington University School of Medicine, St. Louis, MO, United States
u Hope Center, Washington University School of Medicine, St. Louis, MO, United States
v Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
w Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
x MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
y Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
z University of Milan, Milan, Italy
aa Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
ab Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
ac Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
ad Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden
ae Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
af Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
ag Division of Neurology, University of British Columbia, Vancouver, Canada
ah Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, United Kingdom
ai Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology & Alzheimer’s Disease Center, Rehabilitation Institute of Chicago, Chicago, United States
aj Feinberg School of Medicine, Northwestern University, Chicago, United States
ak Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, United States
al Newcastle Brain Tissue Resource, Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom
am Institute of Neuroscience and Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom
an Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom
ao IMT School for Advanced Studies, Lucca, Lucca, Italy
ap Taub Institute, Departments of Psychiatry and Neurology, Columbia University, New York, NY, United States
aq Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, National Insititutes of Health, Bethesda, MD, United States
ar Department of Laboratory Medicine & Pathology, University of Alberta EdmontonAB, Canada
as Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
at Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
au Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, United Kingdom
av West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, United Kingdom
aw Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
ax Neurology I, Department of Neuroscience, University of Torino, Italy, A.O. Città della Salute e della Scienza di Torino, Torino, Italy
ay Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
az Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
ba Division of Neurology and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
bb Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, Forvie Site, University of Cambridge, Cambridge, United Kingdom
bc MRC Cognition and Brain Sciences Unit, Cambridge, United Kingdom
bd Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom
be University of California San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA, United States
bf MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square House, Queen Square, London, United Kingdom
bg Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany
bh Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
bi Department of Neurology and Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
bj Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium
bk Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
bl Neurorehabilitation Unit, Department of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy
bm CRICM; UPMC Univ Paris 06, UMR_S975, Paris, France
bn UPMC Univ Paris 06, UMR_S975, Université Pierre et Marie Curie, Paris, France
bo AP-HP, Département de neurologie-centre de références des démences rares, Hôpital de la Salpêtrière, Paris, France
bp CNRS UMR 7225, F-75013, Paris, France
bq Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, Rouen, France
br Service de Neurologie, CH Saint Brieuc, Rouen, France
bs Service de neurologie, CHU de Nantes, Nantes, France
bt Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence, Florence, Italy
bu Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
bv Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
bw Department for Psychiatry & Psychotherapy, Saarland University Hospital, Homburg, Saar, Germany
bx Laboratory for Neurogenetics, Saarland University, Homburg, Saar, Germany
by Department of Psychiatry, Psychotherapy and Psychosomatics, University Regensburg, Regensburg, Germany
bz Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
ca Tübingen Site, German Center for Neurodegenerative Diseases, Tübingen, Germany
cb Salford Royal Foundation Trust, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
cc Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
cd Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, United States
ce Department of Neurology, Mayo Clinic Rochester, Rochester, MN, United States
cf Department of Pathology, Mayo Clinic Rochester, Rochester, MN, United States
cg Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands
ch Department of Medical Genetics, VU university Medical Centre, Amsterdam, Netherlands
ci Alzheimer Centre and Department of Neurology, VU University Medical Centre, Amsterdam, Netherlands
cj Department of Basic Medical Sciences, Neurosciences and Sense Organs, “Aldo Moro” University of Bari, Bari, Italy
ck Medical Genetics Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
cl Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy
cm Department of Medicine and Surgery, University of Salerno, Baronissi, SA, Italy
cn Neurology Department, IRCCS Multimedica, Milan, Italy
co Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
cp Geriatric Center Frullone ASL Napoli 1 Centro, Naples, Italy
cq UCL Genomics, Institute of Child Health (ICH), UCL, London, United Kingdom
cr Dept NVS, Alzheimer Research Center, Karolinska Institutet, Stockholm, Sweden
cs Dept of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden
ct Université des Sciences et Technologies de Lille, Inserm 1171, DISTALZ, CHU 59000, Lille, France
cu National Institute on Aging (NIA/NIH), Baltimore, MD, United States
cv Clinical Research Branch, National Institute on Aging, Baltimore, MD, United States

Abstract
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration. © 2019, The Author(s).

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

“Gabapentin prescribed during substance abuse treatment: The perspective of treatment providers” (2019) Journal of Substance Abuse Treatment

Gabapentin prescribed during substance abuse treatment: The perspective of treatment providers
(2019) Journal of Substance Abuse Treatment, 105, pp. 1-4. 

Buttram, M.E.a , Kurtz, S.P.a , Ellis, M.S.b , Cicero, T.J.b

a Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, 7255 NE 4th Avenue, Suite 112, Miami, FL 33138, United States
b Washington University, Department of Psychiatry, Campus Box 8134, 600 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Background: Gabapentin, a prescription medication approved for the treatment of seizures and neuralgia, is often prescribed off-label for substance use treatment, mental health problems, and pain. Emerging reports also suggest it is misused for the purpose of getting high. The present study examines substance abuse treatment provider key informants’ experiences with gabapentin prescribed to clients in treatment. The focus of this exploratory study is to ascertain how gabapentin is used in these settings and the benefits and risks for clients. Methods: Key informants from South Florida participated in confidential, in-depth interviews (N = 12). Data analyses included descriptive and in vivo coding schemes and employed a descriptive qualitative approach. Results: All key informants recognized the benefits of prescribing gabapentin to clients in treatment for problems related to withdrawal symptoms, mental distress and pain. At the same time, half of participants described gabapentin misuse among clients and four key informants described such misuse as a first marker of relapse. Key informants also stated that more research must be done about how to use gabapentin effectively in treatment settings. Conclusions: These findings illustrate the lack of clarity about the efficacy of administration of gabapentin in treatment settings. Additional research about how to best use gabapentin, for whom it may be beneficial, and the effect of prescribed gabapentin on addiction recovery is needed. © 2019

Author Keywords
Gabapentin;  Misuse;  Qualitative;  Substance abuse treatment

Document Type: Article
Publication Stage: Final
Source: Scopus

“Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma” (2019) Translational Oncology

Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma
(2019) Translational Oncology, 12 (10), pp. 1314-1322. 

Hanaford, A.R.a , Alt, J.b , Rais, R.b c , Wang, S.Z.a , Kaur, H.a , Thorek, D.L.J.d e , Eberhart, C.G.f g , Slusher, B.S.b c , Martin, A.M.a g , Raabe, E.H.a f g

a Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, United States
c Department of Neurology, Johns Hopkins University School of Medicine, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, United States
g Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, United States

Abstract
A subset of poor-prognosis medulloblastoma has genomic amplification of MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. We hypothesized that this prodrug would kill MYC-expressing medulloblastoma. JHU-083 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines. We generated a mouse MYC-driven medulloblastoma model by transforming C57BL/6 mouse cerebellar stem and progenitor cells. When implanted into the brains of C57BL/6 mice, these cells formed large cell/anaplastic tumors that resembled aggressive medulloblastoma. A cell line derived from this model was sensitive to JHU-083 in vitro. Oral administration of JHU-038 led to the accumulation of micromolar concentrations of DON in the mouse brain. JHU-083 treatment significantly increased the survival of immune-competent animals bearing orthotopic tumors formed by the mouse cerebellar stem cell model as well as immune-deficient animals bearing orthotopic tumors formed by a human MYC-amplified medulloblastoma cell line. These data provide pre-clinical justification for the ongoing development and testing of orally bioavailable DON prodrugs for use in medulloblastoma patients. © 2019 The Authors

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

“Potential uses of naltrexone in emergency department patients with opioid use disorder” (2019) Clinical Toxicology

Potential uses of naltrexone in emergency department patients with opioid use disorder
(2019) Clinical Toxicology, 57 (9), pp. 753-759. 

Bradley, E.S.a , Liss, D.b , Carreiro, S.P.a , Brush, D.E.a , Babu, K.a

a Department of Emergency Medicine, Division of Medical Toxicology, University of Massachusetts Medical School and Umass Memorial Medical Center, Worcester, MA, United States
b Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Despite widespread recognition of the opioid crisis, opioid overdose remains a common reason for Emergency Department (ED) utilization. Treatment for these patients after stabilization often involves the provision of information for outpatient treatment options. Ideally, an ED visit for overdose would present an opportunity to start treatment for opioid use disorder (OUD) immediately. Although widely recognized as effective, opioid agonist therapy with methadone and buprenorphine commonly referred to as “medication-assisted therapy” but more correctly as “medication for addiction treatment” (MAT), can be difficult to access even for motivated individuals due to shortages of prescribers and treatment programs. Moreover, opioid agonist therapy may not be appropriate for all patients, as many patients who present after overdose are not opioid dependent. More treatment options are required to successfully match patients with diverse needs to an optimal treatment plan in order to avoid relapse. Naltrexone, a long-acting opioid antagonist, available orally and as a monthly extended-release intramuscular injection, may represent another treatment option. Methods: We conducted a literature search of MEDLINE and PubMed. We aimed to capture references related to naltrexone and is use as MAT for OUD, as well as manuscripts that discussed naltrexone in comparison toother agents used for MAT, opioid detoxification, and naltrexone metabolism. Our initial search logic returned a total of 618 articles. Following individual evaluation for relevance, we selected 65 for in-depthreview. Manuscripts meeting criteria were examined for citations meriting further review, leading to the addition of 30 manuscripts Conclusions: Here, we review the pharmacology of naltrexone as it relates to OUD, its history of use, and highlight recent studies and new approaches for use of the drug as MAT including its potential initiation after ED visit for opioid overdose. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
abstinence;  addiction;  medication-assisted therapy;  Naltrexone;  overdose

Document Type: Review
Publication Stage: Final
Source: Scopus

“Differential impact of physical activity type on depression in adults with congenital heart disease: A multi-center international study” (2019) Journal of Psychosomatic Research

Differential impact of physical activity type on depression in adults with congenital heart disease: A multi-center international study
(2019) Journal of Psychosomatic Research, 124, art. no. 109762, . 

Ko, J.M.a , White, K.S.b , Kovacs, A.H.c d , Tecson, K.M.e , Apers, S.f , Luyckx, K.g , Thomet, C.h , Budts, W.i j , Enomoto, J.k , Sluman, M.A.l , Wang, J.-K.m , Jackson, J.L.n , Khairy, P.o , Cook, S.C.p , Chidambarathanu, S.q , Alday, L.r , Eriksen, K.s , Dellborg, M.t u v , Berghammer, M.v w , Johansson, B.x , Mackie, A.S.y , Menahem, S.z , Caruana, M.aa , Veldtman, G.ab , Soufi, A.ac , Fernandes, S.M.ad , Callus, E.ae af , Kutty, S.ag , Moons, P.f v ah , Cedars, A.M.a , on behalf of the APPROACH-IS consortium and International Society for Adult Congenital Heart Disease (ISACHD)ai

a Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
b Adult Congenital Heart Disease Center, Washington University and Barnes Jewish Heart & Vascular Center, University of Missouri, Saint Louis, MO, United States
c Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada
d Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States
e Baylor Heart and Vascular Institute, Dallas, TX, United States
f KU Leuven Department of Public Health and Primary Care, KU Leuven – University of Leuven, Leuven, Belgium
g School Psychology and Child and Adolescent Development, KU Leuven – University of Leuven, Leuven, Belgium
h Center for Congenital Heart Disease, Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
i Division of Congenital and Structural Cardiology, University Hospitals Leuven, Leuven, Belgium
j KU Leuven Department of Cardiovascular Sciences, KU Leuven – University of Leuven, Leuven, Belgium
k Department of Adult Congenital Heart Disease, Cardiovascular Center, Chiba, Chiba, Japan
l Department of Cardiology, Academic Medical Center, Amsterdam, Netherlands
m Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
n Center for Biobehavioral Health, Nationwide Children’s Hospital, Columbus, OH, United States
o Adult Congenital Heart Center, Montreal Heart Institute, Université de Montréal, Montreal, Canada
p Adult Congenital Heart Disease Center, Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
q Pediatric Cardiology, Frontier Lifeline Hospital (Dr. K. M. Cherian Heart Foundation), Chennai, India
r Division of Cardiology, Hospital de Niños, Córdoba, Argentina
s Department of Cardiology, Oslo University Hospital – Rikshospitalet, Oslo, Norway
t Adult Congenital Heart Unit, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
u Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Sweden
v Centre for Person-Centred Care (GPCC), University of Gothenburg, Gothenburg, Sweden
w Department of Health Sciences, University West, Trollhättan, Sweden
x Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
y Division of Cardiology, Stollery Children’s Hospital, University of Alberta, Edmonton, Canada
z Monash Heart, Monash Medical Centre, Monash University, Melbourne, Australia
aa Department of Cardiology, Mater Dei Hospital, Birkirkara Bypass, Malta
ab Adult Congenital Heart Disease Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
ac Department of Congenital Heart Disease, Louis Pradel Hospital, Hospices civils de Lyon, Lyon, France
ad Department of Pediatrics and Medicine, Divisions of Pediatric Cardiology and Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, United States
ae Clinical Psychology Service, IRCCS Policlinico San Donato, Milan, Italy
af Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
ag Adult Congenital Heart Disease Center, University of Nebraska Medical Center, Children’s Hospital and Medical Center, Omaha, NE, United States
ah Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden

Abstract
Objective: This study aimed to examine the association between physical activity (PA) and depression in a large international cohort of adults with congenital heart disease (ACHD) as data about the differential impact of PA type on depression in this population are lacking. Methods: In 2018, we conducted a cross-sectional assessment of 3908 ACHD recruited from 24 ACHD-specialized centers in 15 countries between April 2013 to March 2015. The Hospital Anxiety and Depression Scale was used to assess self-reported depressive symptoms and the Health-Behavior Scale-Congenital Heart Disease was used to collect PA information. Cochran-Armitage tests were performed to assess trends between depressive symptom levels and PA participation. Chi-Square and Wilcoxon Rank Sum tests were utilized to examine relations between depressive symptom levels and patient characteristics. Stepwise multivariable models were then constructed to understand the independent impact of PA on depressive symptoms. Results: The overall prevalence of elevated depressive symptoms in this sample was 12% with significant differences in rates between countries (p <.001). Physically active individuals were less likely to be depressed than those who were sedentary. Of the 2 PA domains examined, sport participation rather than active commute was significantly associated with reduced symptoms of depression. After adjustment in multivariable analysis, sport participation was still significantly associated with 38% decreased probability of depressive symptoms (p <.001). Conclusions: Sport participation is independently associated with reduced depressive symptoms. The development and promotion of sport-related exercise prescriptions uniquely designed for ACHD may improve depression status in this unique population. © 2019 Elsevier Inc.

Author Keywords
Adult congenital heart disease;  Depression;  Perceived health;  Physical activity;  Prognosis

Document Type: Article
Publication Stage: Final
Source: Scopus

“High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes” (2019) Molecular Biology Reports

High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes
(2019) Molecular Biology Reports, 46 (4), pp. 4369-4375. 

Jang, J.S.a g , Choi, C.-I.b , Yi, J.c , Butters, K.d , Kim, I.e , Bhagwate, A.f , Jen, J.a g , Chang, S.-Y.b h

a Medical Genome Facility, Pomona College, Claremont, United States
b Department of Neurologic Surgery, Mayo Clinic, Rochester, United States
c Division of Biology and Biomedical Science, Washington University in St. Louis, St. Louis, United States
d Department of Anatomical Pathology, Mayo Clinic, Rochester, MN, United States
e Department of Neurology, Mayo Clinic, Rochester, MN, United States
f Bioinformatics Core, Mayo Clinic, Rochester, MN, United States
g Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
h Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, United States

Abstract
Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24 h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time. © 2019, Springer Nature B.V.

Author Keywords
Astrocyte;  Deep brain stimulation;  Extracellular matrix;  Matricellular protein;  Single cell transcriptome

Document Type: Article
Publication Stage: Final
Source: Scopus

“Enduring mental health in the Baltimore epidemiologic catchment area follow-up study” (2019) Social Psychiatry and Psychiatric Epidemiology

Enduring mental health in the Baltimore epidemiologic catchment area follow-up study
(2019) Social Psychiatry and Psychiatric Epidemiology, 54 (8), pp. 997-1006. 

Schneider, K.E.a , Holingue, C.a , Roth, K.B.b , Eaton, W.W.a

a Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Room 886, Baltimore, MD 21205-1999, United States
b Center for Mental Health Services Research, Brown School, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Purpose: To estimate the prevalence of enduring mental health (EMH) and examine important correlates of EMH 23 years later in the Baltimore Epidemiologic Catchment Area Follow-Up study. Methods: We estimated the prevalence of EMH among 964 adults with diagnostic data at all four study waves (1981–2004). Those with EMH were compared to those with any mental or behavioral disorder by demographic, psychosocial, and health characteristics. We used forward selection models to identify the most important predictors of EMH. Results: Twenty-six percent of participants met criteria for enduring mental health across the four waves. Neuroticism, GHQ-20 score, childhood conduct problems, female sex, maternal depression, and poor self-rated health were negatively associated with EMH. Conclusions: We identified several malleable factors associated with a decreased likelihood of enduring mental health. Interventions that target high neuroticism, childhood conduct problems, or maternal depression may increase the likelihood that children achieve EMH later in life. Identifying and treating other factors such as poor self-reported health and greater psychological distress may also keep sub-clinical symptoms from developing into a full mental or behavioral disorder. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Enduring mental health;  Prospective cohort study;  Psychiatric epidemiology;  Resilience

Document Type: Article
Publication Stage: Final
Source: Scopus

“Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice” (2019) Cell Metabolism

Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice
(2019) Cell Metabolism, 30 (2), pp. 329-342.e5. 

Yoshida, M.a f , Satoh, A.g , Lin, J.B.b f , Mills, K.F.a , Sasaki, Y.c , Rensing, N.d , Wong, M.d , Apte, R.S.a b e , Imai, S.-I.a e h

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
f MD-PhD Program, Washington University School of Medicine, St. Louis, MO 63110, United States
g Sleep and Aging Research Regulation Project Team, National Center for Geriatrics and GerontologyAichi, Japan
h Department of Gerontology, Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe, Japan

Abstract
Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD+ availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD+ levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD+ biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans. Yoshida et al. demonstrate that the levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) decline with age in mice and humans. Increasing eNAMPT promotes NAD+, counteracting aging and extending healthspan. eNAMPT is contained in extracellular vesicles (EVs). Supplementing eNAMPT-containing EVs improves physical activity and extends mouse lifespan, suggesting a potential anti-aging intervention. © 2019 Elsevier Inc.

Author Keywords
adipose tissue;  aging;  eNAMPT;  EV;  exosome;  extracellular vesicle;  hypothalamus;  longevity;  metabolism;  NAD+

Document Type: Article
Publication Stage: Final
Source: Scopus

“Adiposity, Hepatic Triglyceride, and Carotid Intima Media Thickness during Behavioral Weight Loss Treatment in Antipsychotic-Treated Youth: A Randomized Pilot Study” (2019) Journal of Child and Adolescent Psychopharmacology

Adiposity, Hepatic Triglyceride, and Carotid Intima Media Thickness during Behavioral Weight Loss Treatment in Antipsychotic-Treated Youth: A Randomized Pilot Study
(2019) Journal of Child and Adolescent Psychopharmacology, 29 (6), pp. 439-447. 

Nicol, G.E.a , Kolko, R.b , Lenze, E.J.a , Yingling, M.D.a , Miller, J.P.a c , Ricchio, A.R.a , Schweiger, J.A.a , Findling, R.L.d , Wilfley, D.a e f , Newcomer, J.W.a g

a Healthy Mind Lab, Department of Psychiatry, Washington University, School of Medicine, 600 S. Taylor Ave., Ste. 121, St. Louis, MO 63110, United States
b Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Medicine, Washington University School of Medicine, St. LouisMO, United States
g Thriving Mind South Florida Behavioral Health Network, Miami, FL, United States

Abstract
Objectives: The purpose of this pilot study was to evaluate changes in adiposity, carotid intima media thickness (CIMT), and hepatic fat content measured via magnetic resonance imaging-estimated hepatic proton density fat fraction (PDFF) in antipsychotic (AP)-treated youth versus nonpsychiatric (NP) participants during participation in a 16-week behavioral weight loss (BWL) intervention. Subjects/Methods: Overweight/obese AP-treated youth (n = 26) were randomized 2:1 to weekly treatment versus recommended care (RC) over 16 weeks. NP controls (n = 21) were assigned to weekly treatment. Dual-energy X-ray absorptiometry (DEXA)-measured adiposity, CIMT, and PDFF were measured at baseline and 16 weeks. Analyses assessed group differences in the effect of BWL on adiposity, CIMT, and PDFF. Results: BWL was well tolerated in both AP-treated and NP groups. DEXA-measured fat decreased significantly in the NP group (F[1,16] = 11.81, p = 0.003), with modest improvements in adiposity and hepatic fat in the AP-treated group, while an increase in adiposity was observed in the RC group. Significant differences in endpoint DEXA total fat (F[2,34] = 4.81, p = 0.01) and PDFF (F[2,30] = 3.60, p = 0.04) occurred across treatment groups, explained by larger improvements in NP versus RC youth in DEXA total fat (p = 0.03) and PDFF (p = 0.04). Conclusions: Intensive, family-based BWL treatment can improve whole-body adiposity and liver fat in obese youth, with decreases or attenuation of additional fat gain observed in AP-treated youth. © 2019, Mary Ann Liebert, Inc.

Author Keywords
antipsychotic;  child psychiatry;  obesity;  weight loss

Document Type: Article
Publication Stage: Final
Source: Scopus

“Posterior Reversible Encephalopathy Syndrome as a Complication of Induced Hypertension in Subarachnoid Hemorrhage: A Case-Control Study” (2019) Neurosurgery

Posterior Reversible Encephalopathy Syndrome as a Complication of Induced Hypertension in Subarachnoid Hemorrhage: A Case-Control Study
(2019) Neurosurgery, 85 (2), pp. 223-230. Cited 2 times.

Allen, M.L., Kulik, T., Keyrouz, S.G., Dhar, R.

Department of Neurology (Division of Neurocritical Care), Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Induced hypertension (IH) remains the mainstay of medical management for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). However, raising blood pressure above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (PRES) has been increasingly recognized. OBJECTIVE: To ascertain the frequency and predisposing factors for PRES during IH therapy. METHODS: We identified 68 patients treated with IH from 345 SAH patients over a 3-yr period. PRES was diagnosed based on clinical suspicion, confirmed by imaging. We extracted additional data on IH, including baseline and highest target mean arterial pressure (MAP), comparing PRES to IH-treated controls. RESULTS: Five patients were diagnosed with PRES at median 6.6 d (range 1-8 d) from vasopressor initiation. All presented with lethargy, 3 had new focal deficits, and 1 had a seizure. Although baseline MAP (prior to DCI) did not differ between cases and controls, both MAP immediately prior to IH (112 vs 90) and highest MAP targeted were greater (140 vs 120 mm Hg, both P < .01). Magnitude of MAP elevation was greater (54 vs 34 above baseline, P = .004) while degree of IH was not (37 vs 38 above pre-IH MAP). All 4 surviving PRES patients had complete resolution with IH discontinuation. CONCLUSION: PRES was diagnosed in 7% of SAH patients undergoing IH therapy, most often when MAP was raised well above baseline to levels that exceed traditional autoregulatory thresholds. High suspicion for this reversible disorder appears warranted in the face of unexplained neurological deterioration during aggressive IH. Copyright © 2018 by the Congress of Neurological Surgeons.

Author Keywords
Delayed cerebral ischemia;  Induced hypertension;  Posterior reversible encephalopathy syndrome;  Subarachnoid hemorrhage;  Vasopressor complication

Document Type: Article
Publication Stage: Final
Source: Scopus

“Evaluation of Tung et al.: Mir-17∼92 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration” (2019) Cell Stem Cell

Evaluation of Tung et al.: Mir-1792 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration
(2019) Cell Stem Cell, 25 (2), pp. 165-166. 

Liu, Y.a b , Yoo, A.S.a b

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
An example of the peer review process for “Mir-1792 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration” (Tung et al., 2019) is presented here. © 2019 Elsevier Inc.

Document Type: Short Survey
Publication Stage: Final
Source: Scopus

“Division of labor in honey bees is associated with transcriptional regulatory plasticity in the brain” (2019) The Journal of Experimental Biology

Division of labor in honey bees is associated with transcriptional regulatory plasticity in the brain
(2019) The Journal of Experimental Biology, 222, . 

Hamilton, A.R.a , Traniello, I.M.a , Ray, A.M.b , Caldwell, A.S.b , Wickline, S.A.c , Robinson, G.E.b d e

a Neuroscience Program, University of Illinois at Champaign-Urbana, Urbana, IL 61801, United States
b Carl R. Woese Institute for Genomic Biology, University of Illinois at Champaign-Urbana, Urbana, IL 61801, United States
c Department of Computation and Molecular Biophysics, School of Medicine, Washington University, St. Louis, MO 63110, United States
d Neuroscience Program, University of Illinois at Champaign-Urbana, Urbana, IL 61801, United States
e Department of Entomology, University of Illinois at Champaign-Urbana, Urbana, IL 61801, United States

Abstract
Studies in evolutionary and developmental biology show that relationships between transcription factors (TFs) and their target genes can be altered to result in novel regulatory relationships that generate phenotypic plasticity. We hypothesized that context-dependent shifts in the nervous system associated with behavior may also be linked to changes in TF-target relationships over physiological time scales. We tested this hypothesis using honey bee (Apis mellifera) division of labor as a model system by performing bioinformatic analyses of previously published brain transcriptomic profiles together with new RNAi and behavioral experiments. The bioinformatic analyses identified five TFs that exhibited strong signatures of regulatory plasticity as a function of division of labor. RNAi targeting of one of these TFs (broad complex) and a related TF that did not exhibit plasticity (fushi tarazu transcription factor 1) was administered in conjunction with automated analyses of foraging behavior in the field, laboratory assays of aggression and brood care behavior, and endocrine treatments. The results showed that changes in the regulatory relationships of these TFs were associated with behavioral state, social context and endocrine state. These findings provide the first empirical evidence that TF-target relationships in the brain are altered in conjunction with behavior and social context. They also suggest that one mechanism for this plasticity involves pleiotropic TFs high up in regulatory hierarchies producing behavior-specific transcriptional responses by activating different downstream TFs to induce discrete context-dependent transcriptional cascades. These findings provide new insights into the dynamic nature of the transcriptional regulatory architecture underlying behavior in the brain. © 2019. Published by The Company of Biologists Ltd.

Author Keywords
Behavioral endocrinology;  Gene regulatory networks;  Social behavior;  Social insects;  Transcriptomic plasticity

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

“Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls” (2019) Circulation. Genomic and Precision Medicine

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls
(2019) Circulation. Genomic and Precision Medicine, 12 (7), p. e002338. 

Traylor, M.a b , Anderson, C.D.c d e f , Rutten-Jacobs, L.C.A.g , Falcone, G.J.h , Comeau, M.E.i , Ay, H.j k , Sudlow, C.L.M.l m , Xu, H.n , Mitchell, B.D.n o , Cole, J.W.p q , Rexrode, K.r , Jimenez-Conde, J.s t , Schmidt, R.u , Grewal, R.P.v , Sacco, R.w , Ribases, M.x y z , Rundek, T.w , Rosand, J.c d e f , Dichgans, M.aa ab , Lee, J.-M.ac , Langefeld, C.D.i , Kittner, S.J.p q , Markus, H.S.a , Woo, D.ad , Malik, R.aa , NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)ae

a Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge (M.T.
b William Harvey Research Institute, Queen Mary University of London (M.T.), Barts and The London School of Medicine and Dentistry
c Center for Genomic Medicine (C.D.A., Massachusetts General Hospital, Boston, United Kingdom
d J. Philip Kistler Stroke Research Center, Department of Neurology (C.D.A., Massachusetts General Hospital, Boston, United Kingdom
e Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., Massachusetts General Hospital, Boston, United Kingdom
f Program in Medical and Population Genetics, Broad Inst, Cambridge, Canada
g German Center for Neurodegenerative Diseases, Population Health Sciences, Germany (L.C.A.R.-J.), Bonn, Germany
h Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, CT (G.J.F.), New Haven
i Department of Biostatistical Sciences, Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, Italy
j Stroke Service (H.A.), Massachusetts General Hospital, Boston, United Kingdom
k A.A. Martinos Center for Biomedical Imaging, Department of Radiology (H.A.), Massachusetts General Hospital, Boston, United Kingdom
l Center for Clinical Brain Sciences, University of Edinburgh (C.L.M.S.)
m Usher Institute of Population Health Sciences and Informatics, Nine Bioquarter, United Kingdom (C.L.M.S.), Edinburgh, United Kingdom
n Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X., University of Maryland School of Medicine, United Kingdom
o Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center (B.D.M.)
p Department of Neurology (S.J.K., University of Maryland School of Medicine, United Kingdom
q Department of Neurology, Veterans Affairs Medical Center, Baltimore, Canada
r Channing Division of Network Medicine and Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, Boston, United Kingdom
s Neurovascular Research Unit, Department of Neurology (J.J.-C.), Institut Municipal d’Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain
t Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d’Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain
u Department of Neurology, Medical University of Graz, Australia
v Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, United States
w Department of Neurology, Miller School of Medicine, University of Miami, FL (R. Sacco
x Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (M.R.)
y Department of Psychiatry, Hospital Universitari Vall d’Hebron (M.R.)
z Biomedical Network Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain
aa Institute for Stroke and Dementia Research, Klinikum der Universität München
ab Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.)
ac Department of Neurology, Radiology, Biomedical Engineering, Washington University School of Medicine, St Louis, United States
ad Department of Neurology and Rehabilitation Medicine and Comprehensive Stroke Center, University of Cincinnati, Bulgaria

Abstract
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

Author Keywords
atherosclerosis;  cerebral hemorrhage;  chromosome;  dementia;  haplotype

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

“Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome” (2019) The Journal of Craniofacial Surgery

Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome
(2019) The Journal of Craniofacial Surgery, 30 (5), pp. 1484-1487. 

Kitchin, S.a , Grames, L.b , Naidoo, S.D.d , Skolnick, G.a , Schoenborn, A.c , Snyder-Warwick, A.a , Patel, K.a

a Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, United States
b Department of Therapy Services
c Department of Audiology, St Louis Children’s Hospital, St Louis, MO, United States

Abstract
OBJECTIVE: The purpose of this study was to investigate the surgical, speech, and audiologic outcomes in patients with Van der Woude syndrome (VWS) and compare them to patients with nonsyndromic cleft palate with or without cleft lip (NS-CP ± L) treated at the same institution. DESIGN: Retrospective chart review. SETTING: A single children’s hospital at a major academic institution. PATIENTS: The records of 18 patients with VWS who had been treated at a single institution from 1989 to 2017 have been retrospectively examined. Thirty-eight patients with NS-CP ± L who were also treated at the same institution during that same time frame were selected to closely match sex and date of birth. MAIN OUTCOME MEASURES: Demographic, clinical, surgical, and speech pathology data were gathered from medical charts. RESULT: By age 4, 88% of subjects with VWS and 76% of subjects with NS-CP ± L (P = 0.732) had been, or were actively involved in, speech therapy. By age 10, 100% of remaining subjects with VWS and 58% of remaining subjects with NS-CP ± L remained involved in speech therapy (P = 0.027).About 33% of patients with VWS and 16% of patients with NS-CP ± L had a secondary procedure for velopharyngeal dysfunction (VPD) (P = 0.171). CONCLUSION: The VWS group had more than twice the rate of secondary procedures for VPD repair, and a higher rate of continuing involvement for speech therapy at age 10. No differences were found in the rate of participation in speech therapy at or by age 4.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Delayed cord clamping is associated with improved dynamic cerebral autoregulation and decreased incidence of intraventricular hemorrhage in preterm infants” (2019) Journal of Applied Physiology (Bethesda, Md. : 1985)

Delayed cord clamping is associated with improved dynamic cerebral autoregulation and decreased incidence of intraventricular hemorrhage in preterm infants
(2019) Journal of Applied Physiology (Bethesda, Md. : 1985), 127 (1), pp. 103-110. 

Vesoulis, Z.A., Liao, S.M., Mathur, A.M.

Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Delayed cord clamping (DCC) improves neurologic outcomes in preterm infants through a reduction in intraventricular hemorrhage (IVH) incidence. The mechanism behind this neuroprotective effect is not known. Infants born <28 wk gestation were recruited for longitudinal monitoring. All infants underwent 72 h of synchronized near-infrared spectroscopy (NIRS) and mean arterial blood pressure (MABP) recording within 24 h of birth. Infants with DCC were compared with control infants with immediate cord clamping (ICC), controlling for severity of illness [clinical risk index for babies (CRIB-II) score], chorioamnionitis, antenatal steroids, sedation, inotropes, and delivery mode. Autoregulatory dampening was calculated as the transfer function gain coefficient between the MABP and NIRS signals. Forty-five infants were included (DCC; n = 15, paired 2:1 with ICC controls n = 30). ICC and DCC groups were similar including gestational age (25.5 vs. 25.2 wk, P = 0.48), birth weight (852.3 vs. 816.6 g, P = 0.73), percent female (40 vs. 40%, P = 0.75), and dopamine usage (27 vs. 23%, P = 1.00). There was a significant difference in IVH incidence between the DCC and ICC groups (20 vs. 50%, P = 0.04). Mean MABP was not different (35.9 vs. 35.1 mmHg, P = 0.44). Compared with the DCC group, the ICC group had diminished autoregulatory dampening capacity (-12.96 vs. -15.06 dB, P = 0.01), which remained significant when controlling for confounders. Dampening capacity was, in turn, strongly associated with decreased risk of IVH (odds ratio = 0.14, P < 0.01). The results of this pilot study demonstrate that DCC is associated with improved dynamic cerebral autoregulatory function and may be the mechanism behind the decreased incidence of IVH. NEW & NOTEWORTHY The neuroprotective mechanism of delayed cord clamping in premature infants is unclear. Delayed cord clamping was associated with improved cerebral autoregulatory function and a marked decrease in intraventricular hemorrhage (IVH). Improved dynamic cerebral autoregulation may decrease arterial baroreceptor sensitivity, thereby reducing the risk of IVH.

Author Keywords
autoregulation;  blood pressure;  delayed cord clamping;  near-infrared spectroscopy;  prematurity

Document Type: Article
Publication Stage: Final
Source: Scopus

“Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer’s disease” (2019) Alzheimer’s and Dementia

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer’s disease
(2019) Alzheimer’s and Dementia, . 

Bos, I.a , Vos, S.J.B.a , Schindler, S.E.b c , Hassenstab, J.b c , Xiong, C.c d , Grant, E.c d , Verhey, F.a , Morris, J.C.b c , Visser, P.J.a e , Fagan, A.M.b c

a Department of Psychiatry & Neuropsychology, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
e Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands

Abstract
Introduction: Vascular factors increase the risk of Alzheimer’s disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition. Methods: 433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/−) and tau status (T+/−). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition. Results: The absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline. Discussion: Our results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD. © 2019 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  Amyloid-β;  Biomarkers;  Cardiovascular disorders;  Cerebrospinal fluid;  Dementia;  Depression;  Framingham Risk Score;  Hypercholesterolemia;  Hypertension;  Neurodegeneration;  Obesity;  Tau;  Vascular risk factors

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

“Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma” (2019) Journal of Biological Chemistry

Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma
(2019) Journal of Biological Chemistry, 294 (29), pp. 11286-11296. 

Ryan, J.J.a , Sprunger, M.L.a , Holthaus, K.a , Shorter, J.b , Jackrel, M.E.a

a Department of Chemistry, Washington University, St. Louis, MO 63130, United States
b Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
FUS and EWSR1 are RNA-binding proteins with prion-like domains (PrLDs) that aggregate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The FUS and EWSR1 genes are also prone to chromosomal translocation events, which result in aberrant fusions between portions of the PrLDs of FUS and EWSR1 and the transcription factors CHOP and FLI. The resulting fusion proteins, FUS-CHOP and EWSFLI, drive aberrant transcriptional programs that underpin liposarcoma and Ewing’s sarcoma, respectively. The translocated PrLDs alter the expression profiles of these proteins and promote their phase separation and aggregation. Here, we report the development of yeast models of FUS-CHOP and EWS-FLI toxicity and aggregation. These models recapitulated several salient features of sarcoma patient cells harboring the FUSCHOP and EWS-FLI translocations. To reverse FUS and EWSR1 aggregation, we have explored Hsp104, a hexameric AAA+ protein disaggregase from yeast. Previously, we engineered potentiated Hsp104 variants to suppress the proteotoxicity, aggregation, and mislocalization ofFUSand other proteins that aggregate in ALS/FTD and Parkinson’s disease. Potentiated Hsp104 variants that robustly suppressed FUS toxicity and aggregation also suppressed the toxicity and aggregation of FUS-CHOP and EWS-FLI. We suggest that these new yeast models are powerful platforms for screening for modulators of FUS-CHOP and EWS-FLI phase separation. Moreover, Hsp104 variants might be employed to combat the toxicity and phase separation of aberrant fusion proteins involved in sarcoma. © 2019 American Society for Biochemistry and Molecular Biology Inc. All rights reserved.

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

“The fetal origins of mental illness” (2019) American Journal of Obstetrics and Gynecology

The fetal origins of mental illness
(2019) American Journal of Obstetrics and Gynecology, . 

al-Haddad, B.J.S.a , Oler, E.b , Armistead, B.c d , Elsayed, N.A.e , Weinberger, D.R.f , Bernier, R.g , Burd, I.e h , Kapur, R.i , Jacobsson, B.j k l , Wang, C.m , Mysorekar, I.n , Rajagopal, L.d o , Adams Waldorf, K.M.p q

a Department of Pediatrics, University of Washington, Seattle, WA, United States
b Department of Obstetrics & Gynecology, University of Washington, Seattle, WA, United States
c Department of Global Health, University of Washington SeattleWA, United States
d Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, United States
e Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
f Lieber Institute for Brain Development, Departments of Psychiatry, Neurology, Neuroscience, and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine BaltimoreMD, United States
g Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
h Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
i Department of Pediatrics, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
j Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
k Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
l Department of Genetics and Bioinformatics, Domain of Health Data and Digitalization, Institute of Public Health, Oslo, Norway
m Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
n Departments of Obstetrics and Gynecology and Pathology and Immunology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
o Center for Innate Immunity and Immune Disease, Department of Pediatrics, University of Washington, Seattle, WA, United States
p Department of Obstetrics & Gynecology and Global Health, Center for Innate Immunity and Immune Disease, Center for Emerging and Reemerging Infectious Diseases, University of Washington, Seattle, WA, United States
q Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Abstract
The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections—or simply inflammation—may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain. © 2019 Elsevier Inc.

Author Keywords
autism;  brain;  depression;  fetus;  infection;  inflammation;  influenza virus;  microglia;  neuronal injury;  pregnancy;  schizophrenia;  seasonality of birth hypothesis;  TORCH;  urinary tract infection

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

“Arterial Ischemic Stroke Secondary to Cardiac Disease in Neonates and Children” (2019) Pediatric Neurology

Arterial Ischemic Stroke Secondary to Cardiac Disease in Neonates and Children
(2019) Pediatric Neurology, . 

Chung, M.G.a , Guilliams, K.P.b , Wilson, J.L.c , Beslow, L.A.d , Dowling, M.M.e , Friedman, N.R.f , Hassanein, S.M.A.g , Ichord, R.d , Jordan, L.C.h , Mackay, M.T.i , Rafay, M.F.j , Rivkin, M.k , Torres, M.l , Zafeiriou, D.m , deVeber, G.n , Fox, C.K.o , International Pediatric Stroke Study Investigatorsp

a Divisions of Critical Care Medicine and Neurology, Department of Pediatrics, The Ohio State University and Nationwide Children’s Hospital, Columbus, OH, United States
b Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Division of Neurology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States
d Division of Neurology, Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
e Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas and Children’s Health Dallas, Dallas, TX, United States
f Center for Pediatric Neurosciences, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
g Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
h Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
i Department of Neurology, Royal Children’s Hospital Melbourne, Murdoch Children’s Research Institute Melbourne, Parkville, Victoria, Australia
j Section of Pediatric Neurology, Department of Pediatrics and Child Health, University of Manitoba, Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
k Departments of Neurology, Psychiatry, and Radiology, and the Stroke and Cerebrovascular Center, Boston Children’s Hospital, Boston, MA, United States
l Pediatric Hematology and Oncology, Cook Children’s Medical Center, Fort Worth, TX, United States
m 1<sup>st</sup> Department of Pediatrics, Aristotle University, “Hippokratio” General Hospital, Thessaloniki, Greece
n Department of Neurology, The Hospital for Sick Children, Toronto, Canada
o Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, United States

Abstract
Objective: We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease. Methods: We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared. Results: We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS. Conclusions: Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population. © 2019 Elsevier Inc.

Author Keywords
Cardiac disease;  Cardiac procedure;  Embolism;  Pediatric arterial ischemic stroke;  Pediatric stroke;  Stroke

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

“Limb-girdle muscular dystrophy: A perspective from adult patients on what matters most” (2019) Muscle and Nerve

Limb-girdle muscular dystrophy: A perspective from adult patients on what matters most
(2019) Muscle and Nerve, . 

Hunter, M.a , Heatwole, C.b , Wicklund, M.c , Weihl, C.C.d , Mozaffar, T.e , Statland, J.M.f , Johnson, N.E.g

a Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, United States
b Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
c Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
e UC Irvine-MDA ALS and Neuromuscular Center, University of California Irvine, Orange, CA, United States
f Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
g Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Introduction: Limb-girdle muscular dystrophy (LGMD) consists of over 30 genetic conditions with varying clinical phenotypes primarily affecting pelvic girdle, shoulder girdle, and other proximal limb muscles. Studies focusing on the physical, mental, and social effects of this disease from the patient’s perspective are limited. Methods: Adults with LGMD were interviewed and asked to identify issues that have the greatest impact on their quality of life. Each interview was recorded, transcribed, coded, and analyzed. Results: Participants provided 1385 direct quotes. One hundred sixty-five potential symptoms of importance were identified and grouped into 15 larger themes. The most frequently reported themes included limitations with mobility, difficulty performing activities, social role limitations, and emotional distress. Discussion: There are multiple symptoms that alter the lives of adults with LGMD. These affect their physical, emotional, and social health, and may be amenable to medical intervention. © 2019 Wiley Periodicals, Inc.

Author Keywords
disease burden;  limb-girdle muscular dystrophy;  neuromuscular diseases;  rare diseases;  signs and symptoms

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

“Jackhammer esophagus with and without esophagogastric junction outflow obstruction demonstrates altered neural control resembling type 3 achalasia” (2019) Neurogastroenterology and Motility

Jackhammer esophagus with and without esophagogastric junction outflow obstruction demonstrates altered neural control resembling type 3 achalasia
(2019) Neurogastroenterology and Motility, art. no. e13678, . 

Quader, F.a , Mauro, A.b c , Savarino, E.d , Tolone, S.e , de Bortoli, N.f , Franchina, M.b c , Ghisa, M.d , Edelman, K.g h , Jha, L.K.i , Penagini, R.b c , Gyawali, C.P.a

a Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
c Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
d Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
e General, Mini-Invasive and Bariatric Surgery Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy
f Division of Gastroenterology, Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Cisanello Hospital, Pisa, Italy
g Division of Gastroenterology, Duke University, Durham, NC, United States
h Richmond Gastroenterology Associates, Richmond, VA, United States
i Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States

Abstract
Background: Esophageal hypercontractility can manifest with and without esophagogastric junction (EGJ) outflow obstruction. We investigated clinical presentations and motility patterns in patients with esophageal hypercontractile disorders. Methods: Esophageal HRM studies fulfilling Chicago Classification 3.0 criteria for jackhammer esophagus (distal contractile integral, DCI >8000 mmHg.cm.s in ≥ 20% swallows) with (n = 30) and without (n = 83) EGJ obstruction (integrated relaxation pressure, IRP > 15 mm Hg) were retrospectively reviewed from five centers (4 in Europe, 1 in US). Single swallows (SS) and multiple rapid swallows (MRS) were analyzed using HRM software tools (IRP, DCI, distal latency, DL); MRS: SS DCI ratio >1 defined contraction reserve. Comparison groups were achalasia type 3 (n = 72, positive control for abnormal inhibition and EGJ obstruction) and healthy controls (n = 18). Symptoms, HRM metrics, and MRS contraction reserve were analyzed within jackhammer subgroups and comparison groups. Key Results: The esophageal smooth muscle was excessively stimulated at baseline in jackhammer subgroups, with lack of augmentation following MRS identified more often compared with controls (P =.003) and type 3 achalasia (P =.07). Consistently abnormal inhibition was identified in type 3 achalasia (47%), and to a lower extent in jackhammer with obstruction (37%, P =.33), jackhammer esophagus (28%, P =.01), and controls (11%, P <.01 compared with type 3 achalasia). Perceptive symptoms (heartburn, chest pain) were common in jackhammer esophagus (P <.01 compared with type 3 achalasia), while transit symptoms (dysphagia) were more frequent with presence of EGJ obstruction (P ≤.01 compared with jackhammer without obstruction). Conclusions and inferences: The balance of excessive excitation and abnormal inhibition defines clinical and manometric manifestations in esophageal hypercontractile disorders. © 2019 John Wiley & Sons Ltd

Author Keywords
dysphagia;  high-resolution manometry;  hypercontractile disorders;  jackhammer esophagus;  multiple rapid swallows;  type 3 achalasia

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

“Scope of hearing loss in Beckwith–Wiedemann syndrome and hemihypertrophy” (2019) American Journal of Medical Genetics, Part A

Scope of hearing loss in Beckwith–Wiedemann syndrome and hemihypertrophy
(2019) American Journal of Medical Genetics, Part A, . 

Camet, M.L.a , Hayashi, S.S.b , Druley, T.a , Henry, J.a , Gettinger, K.a , Stacy, A.a , Hayashi, R.J.a

a Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
b St. Louis Children’s Hospital, BJC HealthCare, St. Louis, MO, United States

Author Keywords
Beckwith–Wiedmann syndrome;  cancer predisposition;  hearing loss;  hemihypertrophy;  pediatrics

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

“Acute Disseminated Encephalomyelitis in Children: An Updated Review Based on Current Diagnostic Criteria” (2019) Pediatric Neurology

Acute Disseminated Encephalomyelitis in Children: An Updated Review Based on Current Diagnostic Criteria
(2019) Pediatric Neurology, . 

Cole, J., Evans, E., Mwangi, M., Mar, S.

Pediatric Multiple Sclerosis and Demyelinating Diseases Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Acute disseminated encephalomyelitis is an inflammatory disorder of the central nervous system. Uniform diagnostic criteria for acute disseminated encephalomyelitis did not exist until publication of expert-defined consensus definitions by the International Pediatric Multiple Sclerosis Society Group in 2007, with updates in 2013. In the expanding field of pediatric neuroimmunology, consistent diagnostic criteria are essential to correctly categorize patients as increasing information regarding prognosis and management becomes available. Scientific literature is relatively lacking in review articles on International Pediatric Multiple Sclerosis Society Group-defined acute disseminated encephalomyelitis. This review focuses primarily on references applying the International Pediatric Multiple Sclerosis Society Group criteria for acute disseminated encephalomyelitis presenting specific, up-to-date, and translatable information regarding the epidemiology, pathophysiology, clinical features, diagnosis, management, and prognosis of acute disseminated encephalomyelitis in the pediatric population. © 2019 Elsevier Inc.

Author Keywords
Acute disseminated encephalomyelitis;  International Pediatric Multiple Sclerosis Society Group diagnostic criteria;  Pediatric demyelinating disease;  Topical review

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

“New persistent opioid use among older patients following surgery: A Medicare claims analysis” (2019) Surgery (United States)

New persistent opioid use among older patients following surgery: A Medicare claims analysis
(2019) Surgery (United States), . 

Santosa, K.B.a , Hu, H.-M.a , Brummett, C.M.b , Olsen, M.A.c , Englesbe, M.J.d , Williams, E.A.e , Waljee, J.F.a

a Section of Plastic Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States
b Division of Pain Medicine, Department of Anesthesia, University of Michigan Health System, Ann Arbor, MI, United States
c Division of Infectious Diseases, Department of Medicine, and Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Section of Transplantation, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States
e Miller School of Medicine, University of Miami, Coral Gables, FL, United States

Abstract
Background: Although new persistent opioid use and high-risk prescribing have been recognized as important postoperative complications among younger patients (18–64 years of age), little is known about the incidence for postoperative opioid use among older patients (>65 years of age). Methods: We analyzed a 20% national sample of Medicare Part D claims among beneficiaries >65 years of age who underwent a major or minor surgical procedure between January 1, 2009, and June 30, 2015. We identified patients without an opioid prescription fill in the year before surgery and examined their perioperative and 6-month postoperative opioid prescription fills to examine the incidence of new persistent opioid use and high-risk prescribing. Results: We identified 81,839 opioid naïve patients who underwent surgery and filled an opioid prescription perioperatively. Overall, 9.8% developed new persistent opioid use. Risk factors for new persistent opioid use included major surgery (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.17–1.31), more comorbid conditions (aOR 1.71, 95% CI 1.58–1.84), mood disorders (aOR 1.16, 95% CI 1.09–1.24), suicide or self-harm (aOR 1.60, 95% CI 1.05–2.44), substance abuse disorders (aOR 1.38, 95% CI 1.20–1.59), filling an opioid prescription before surgery (aOR 1.67, 95% CI 1.58–1.77), higher amounts of opioids filled (aOR 1.44, 95% CI 1.37–1.52), black race (aOR 1.23, 95% CI 1.12–1.36), and Medicaid eligibility (aOR 1.45, 95% CI 1.35–1.55). Conclusion: About 10% of Medicare beneficiaries who were previously opioid naïve continue to fill opioids past 3 months after surgery. In addition to comorbidities and mental health conditions, new persistent opioid use is associated with surgery type, preoperative opioid fill, high-risk prescribing practices, and sociodemographic factors. © 2019

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

“Sensory Neurons Drive Anticipatory Immunity” (2019) Cell

Sensory Neurons Drive Anticipatory Immunity
(2019) Cell, . 

Trier, A.M.a b , Kim, B.S.a b c d

a Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
b Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Sensory neurons have recently emerged as critical mediators of immunity. Cohen et al. (2019) demonstrate that peripheral neurons utilize reflex arcs in order to rapidly condition the immune response in skin adjacent to the site of infection. This nerve reflex arc generates anticipatory immunity for more effective elimination of the pathogen if later exposed. © 2019 Elsevier Inc.

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

Genetic diversity underlying behavioral plasticity in human adaptation” (2019) Progress in Brain Research

Genetic diversity underlying behavioral plasticity in human adaptation
(2019) Progress in Brain Research, . 

Bauernfeind, A.L.a b , Babbitt, C.C.c

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anthropology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biology, University of Massachusetts Amherst, Amherst, MA, United States

Abstract
The human brain is notably different from that of other primate species by its size and structure, in addition to its behavioral output. As we seek to understand how the human brain has evolved, many researchers have turned to genomics to help elucidate the biological basis for uniqueness of the human brain. When considering the molecular evolution of the human brain, a common misconception is that molecular evolution should be “unidirectional”—progressing along a single trajectory with the human brain as the ultimate goal. This outlook fails to acknowledge the importance of variability in the evolutionary process. In this review, we review what we know about inter- and intraspecific molecular diversity in the human brain arising from heritable and non-heritable sources. We note that genetic substitutions may not be optimal in brain evolution due to pleiotropic effects. Instead, we focus on other sources of molecular diversity including gene duplications, copy number variations, and transcriptional regulation. With recent advancements in the field of single-cell genomics, we explore what is currently known about gene expression at the cellular level and highlight opportunities to advance our understanding of human uniqueness at the neuronal level. © 2019 Elsevier B.V.

Author Keywords
Chimpanzee;  Copy number variations;  Duplication;  Gene expression;  Pleiotropy;  Transcription

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

“Measuring Adaptive Control in Conflict Tasks” (2019) Trends in Cognitive Sciences

Measuring Adaptive Control in Conflict Tasks
(2019) Trends in Cognitive Sciences, . 

Braem, S.a , Bugg, J.M.b , Schmidt, J.R.c , Crump, M.J.C.d , Weissman, D.H.e , Notebaert, W.f , Egner, T.g

a Vrije Universiteit Brussel, Brussels, Belgium
b Washington University in St. Louis, St. Louis, MO, United States
c Université Bourgogne Franche-Comté (UBFC), Dijon, France
d Brooklyn College of the City University of New York (CUNY), Brooklyn, NY, United States
e University of Michigan, Ann Arbor, MI, United States
f Ghent University, Ghent, Belgium
g Duke University, Durham, NC, United States

Abstract
The past two decades have witnessed an explosion of interest in the cognitive and neural mechanisms of adaptive control processes that operate in selective attention tasks. This has spawned not only a large empirical literature and several theories but also the recurring identification of potential confounds and corresponding adjustments in task design to create confound-minimized metrics of adaptive control. The resulting complexity of this literature can be difficult to navigate for new researchers entering the field, leading to suboptimal study designs. To remediate this problem, we present here a consensus view among opposing theorists that specifies how researchers can measure four hallmark indices of adaptive control (the congruency sequence effect, and list-wide, context-specific, and item-specific proportion congruency effects) while minimizing easy-to-overlook confounds. © 2019 Elsevier Ltd

Author Keywords
cognitive control;  conflict adaptation;  executive function;  interference effects

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

“Stem cell-based approaches to enhance nerve regeneration and improve functional outcomes in vascularized composite allotransplantation” (2018) Current Opinion in Organ Transplantation

Stem cell-based approaches to enhance nerve regeneration and improve functional outcomes in vascularized composite allotransplantation
(2018) Current Opinion in Organ Transplantation, 23 (5), pp. 577-581. 

Tung, T.H., Mackinnon, S.E.

Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
PURPOSE OF REVIEW: The current review will discuss the current understanding of nerve regeneration in vascularized composite allotransplantation (VCA). The success of proximal arm and leg transplants has been hampered by the limitations of nerve regrowth across long distances resulting in poor regeneration and functional recovery. Relevant research in stem-cell therapies to overcome these issues will be reviewed. RECENT FINDINGS: The effect of rejection on nerve regeneration in the VCA may be unpredictable and may be quite different for the nerve allograft. The issues that limit functional outcome are likely common to both VCA and proximal nerve injuries or replantation. Stem-cell therapies have focused on augmenting Schwann cell function and appear promising. SUMMARY: A better understanding of the effects of transplant rejection on nerve regeneration and function, as well as the factors that affect regeneration over long distances may inform further therapeutic approaches for improvement.

Document Type: Article
Publication Stage: Final
Source: Scopus