Arts & Sciences Brown School Law McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease” (2019) Stroke

Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease
(2019) Stroke, 50 (2), pp. 266-273. 

Guilliams, K.P.a b , Fields, M.E.b , Dowling, M.M.c

a From the Department of Neurology (K.P.G.), Washington University School of Medicine, St Louis, MO, United States
b Department of Pediatrics (K.P.G., Washington University School of Medicine, St Louis, MO, United States
c Department of Pediatrics and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, United States

Author Keywords
anemia;  cerebrovascular circulation;  hemolysis;  hydroxyurea;  oxygen consumption;  stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

“Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke” (2019) Stroke

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke
(2019) Stroke, 50 (2), pp. 298-304. 

Pfeiffer, D.a , Chen, B.b , Schlicht, K.c , Ginsbach, P.d , Abboud, S.e , Bersano, A.f , Bevan, S.g , Brandt, T.a h , Caso, V.i , Debette, S.j k , Erhart, P.l , Freitag-Wolf, S.c , Giacalone, G.m , Grau, A.J.n , Hayani, E.a , Jern, C.o p , Jiménez-Conde, J.q , Kloss, M.a , Krawczak, M.c , Lee, J.-M.r , Lemmens, R.s t u , Leys, D.v , Lichy, C.w , Maguire, J.M.x y , Martin, J.J.z , Metso, A.J.aa , Metso, T.M.aa , Mitchell, B.D.ab ac , Pezzini, A.ad , Rosand, J.ae , Rost, N.S.af , Stenman, M.ag ah , Tatlisumak, T.aa ai aj , Thijs, V.ak al , Touzé, E.am an , Traenka, C.ao , Werner, I.a , Woo, D.ap , Del Zotto, E.ad , Engelter, S.T.ao aq ar , Kittner, S.J.as , Cole, J.W.as , Grond-Ginsbach, C.a , Lyrer, P.A.ao , Lindgren, A.ag ah , CADISP; GISCOME; SiGN studies; and ISGCat

a From the Department of Neurology, Heidelberg University Hospital, Germany (D.P., T.B., M. Kloss
b Department of Biology, Southern University of Science and Technology, China (B.C.), Shenzhen, China
c Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany (K.S., M. Krawczak)
d School of Informatics, University of Edinburgh, United Kingdom (P.G.)
e Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
f Cerebrovascular Unit IRCCS Foundation C. Besta Neurological Institute, Milan, United States
g School of Life Science, University of Lincoln, United Kingdom (S.B.)
h Suva/Swiss National Accident Insurance Fund, Lucerne, Switzerland
i Stroke Unit, Perugia University Hospital, Italy
j Inserm, Bordeaux Population Health Research Center, University of Bordeaux
k Department of Neurology, Bordeaux University Hospital, United States
l Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Germany (P.E.)
m Department of Neurology, San Raffaele University Hospital, Milan, United States
n Department of Neurology, Klinikum Ludwigshafen, Germany (A.J.G.)
o Sahlgrenska Academy, University of Gothenburg, Czech Republic
p Sahlgrenska University Hospital, Australia
q IMIM-Parc de Salut Mar, Universitat Autonoma de Barcelona, Switzerland
r Department of Neurology, Washington University School of Medicine, St Louis, United States
s Department of Neurosciences, Experimental Neurology, Leuven Brain Institute, KU Leuven, University of Leuven, Belgium
t VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium
u Department of Neurology, University Hospitals Leuven, Netherlands
v Department of Neurology, University of Lille, United Kingdom
w Department of Neurology, Germany (C.L.), Klinikum Memmingen
x Faculty of Health, University of Technology Sydney, Australia
y Hunter Medical Research Institute, Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Austria
z Department of Neurology, Sanatorio AllendeCordoba, Argentina
aa Department of Neurology, Helsinki University Central Hospital, Finland (A.J.M.
ab Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, United Kingdom
ac Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Canada
ad Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Sweden
ae Center for Genomic Medicine (J.R.), Massachusetts General Hospital, Boston, United Kingdom
af Department of Neurology (N.S.R.), Massachusetts General Hospital, Boston, United Kingdom
ag Department of Clinical Sciences Lund, Neurology, Lund University, Denmark
ah Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
ai Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Czech Republic
aj Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Germany
ak Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia (V.T.)
al Department of Neurology, Austin Health, Heidelberg, Victoria, Australia (V.T.)
am Paris Descartes University, INSERM UMR S894, Department of Neurology, Sainte-Anne Hospital, Paris, Canada
an Université Caen-Normandie, CHU Côte de Nacre, Service de Neurologie, Normandie Université, Caen, France
ao Department of Neurology and Stroke Center, University Hospital Basel, S.T.E.
ap Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Bulgaria
aq Neurorehabilitation Unit, University of Basel, Austria
ar University Center for Medicine of Aging, Felix Platter Hospital, Basel, Switzerland
as Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (S.J.K., J.W.C.); and Department of Neurology University of Maryland School of Medicine, Baltimore (S.J.K., J.W.C.)

Abstract
Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Author Keywords
DNA copy number variations;  genetics;  polymorphism, single nucleotide;  prognosis;  stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

“Hypoperfusion Symptoms Poorly Predict Hemodynamic Compromise and Stroke Risk in Vertebrobasilar Disease” (2019) Stroke

Hypoperfusion Symptoms Poorly Predict Hemodynamic Compromise and Stroke Risk in Vertebrobasilar Disease
(2019) Stroke, 50 (2), pp. 495-497. 

Amin-Hanjani, S.a , Stapleton, C.J.a , Du, X.a , Rose-Finnell, L.a , Pandey, D.K.b , Elkind, M.S.V.c , Zipfel, G.J.d , Liebeskind, D.S.e , Silver, F.L.f , Kasner, S.E.g , Caplan, L.R.h , Derdeyn, C.P.i , Gorelick, P.B.j k l , Charbel, F.T.a , VERiTAS Study Groupm

a From the Department of Neurosurgery (S.A.-H., F.T.C.), University of Illinois at Chicago, Uganda
b Department of Neurology and Rehabilitation (D.K.P.), University of Illinois at Chicago, Uganda
c Departments of Neurology and Epidemiology, Columbia UniversityNY, United States
d Departments of Neurosurgery and Neurology, Washington University in St Louis, United States
e Neurovascular Imaging and Research Core and Department of Neurology, University of California at Los Angeles (D.S.L.)
f Division of Neurology, Department of Medicine, University of Toronto, Canada
g Department of Neurology, University of Pennsylvania, Australia
h Department of Neurology, Beth Israel Deaconess Medical Center, Boston, United Kingdom
i Department of Radiology, University of Iowa Hospitals and Clinics, United States
j Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States
k Population Health Research Institute affiliated with McMaster University Faculty of Health Sciences and Hamilton University Health SciencesON, Canada
l Departments of Translational Science and Molecular Medicine, Michigan State University College of Human Medicine and Mercy Health Hauenstein Neurosciences, Grand Rapids, United States

Abstract
Background and Purpose- Cerebral hypoperfusion symptoms (defined as symptoms related to change in position, effort or exertion, or recent change in antihypertensive medication) have been used in stroke studies as a surrogate for detecting hemodynamic compromise. However, the validity of these symptoms in identifying flow compromise in patients has not been well established. We examined whether hypoperfusion symptoms correlated with quantitative measurements of flow compromise in the prospective, observational VERiTAS study (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke). Methods- VERiTAS enrolled patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis or occlusion in vertebral or basilar arteries. Hemodynamic status using vertebrobasilar large vessel flow was measured using quantitative magnetic resonance angiography, and patients were designated as low, borderline, or normal flow based on distal territory regional flow, incorporating collateral capacity. The presence of qualifying event hypoperfusion symptoms was assessed relative to the quantitatively determined flow status (normal versus borderline/low) and also examined as a predictor of subsequent stroke risk. Results- Of the 72 enrolled subjects, 66 had data on hypoperfusion symptoms available. On initial quantitative magnetic resonance angiography designation, 43 subjects were designated as normal flow versus 23 subjects designated as low flow (n=16) or borderline flow (n=7). Of these, 5 (11.6%) normal flow and 3 (13.0%) low/borderline flow subjects reported at least one qualifying event hypoperfusion symptom ( P=0.99, Fisher exact test). Hypoperfusion symptoms had a positive predictive value of 37.5% and negative predictive value of 65.5% for low/borderline flow status. Compared with flow status, which strongly predicted subsequent stroke risk, hypoperfusion symptoms were not associated with stroke outcome ( P=0.87, log-rank test). Conclusions- These results suggest that hypoperfusion symptoms alone correlate poorly with actual hemodynamic compromise as assessed by quantitative magnetic resonance angiography and subsequent stroke risk in vertebrobasilar disease, and are not a reliable surrogate for flow measurement. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00590980.

Author Keywords
hemodynamics;  magnetic resonance angiography;  magnetic resonance imaging;  risk;  stroke;  vertebrobasilar ischemia

Document Type: Article
Publication Stage: Final
Source: Scopus

“De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms” (2019) European Journal of Human Genetics

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms
(2019) European Journal of Human Genetics, . Article in Press. 

Jansen, S.a , van der Werf, I.M.b , Innes, A.M.c , Afenjar, A.d e , Agrawal, P.B.f , Anderson, I.J.g , Atwal, P.S.h , van Binsbergen, E.i , van den Boogaard, M.-J.i , Castiglia, L.j , Coban-Akdemir, Z.H.k l , van Dijck, A.b , Doummar, D.m n o , van Eerde, A.M.i , van Essen, A.J.p , van Gassen, K.L.i , Guillen Sacoto, M.J.q , van Haelst, M.M.r , Iossifov, I.s t , Jackson, J.L.h , Judd, E.u , Kaiwar, C.v ai , Keren, B.w , Klee, E.W.x , Klein Wassink-Ruiter, J.S.p , Meuwissen, M.E.b , Monaghan, K.G.q , de Munnik, S.A.a , Nava, C.w y , Ockeloen, C.W.a , Pettinato, R.z , Racher, H.c aj , Rinne, T.a , Romano, C.z , Sanders, V.R.aa , Schnur, R.E.q , Smeets, E.J.ab , Stegmann, A.P.A.ab , Stray-Pedersen, A.k ac ad , Sweetser, D.A.ae , Terhal, P.A.i , Tveten, K.af , VanNoy, G.E.f , de Vries, P.F.a , Waxler, J.L.ae , Willing, M.ag , Pfundt, R.a , Veltman, J.A.a ah , Kooy, R.F.b , Vissers, L.E.L.M.a , de Vries, B.B.A.a

a Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, Netherlands
b Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, Antwerp, 2610, Belgium
c Alberta Children’s Hospital Research Institute and Department of Medical Genetics, Cumming School of Medicine, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada
d Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, 75013, France
e APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence ′Malformations et maladies congénitales du cervelet′, Paris, 75012, France
f Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, United States
g The University of Tennessee Genetics Center, Knoxville, TN 37920, United States
h Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, United States
i Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, Utrecht, 3508 GA, Netherlands
j Laboratory of Medical Genetics, Oasi Research Institute, Troina, 94018, Italy
k Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX 77030, United States
l Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
m APHP, Service de Neurologie pédiatrique, Hôpital Armand Trousseau, Paris, France
n Sorbonne Université,GRC ConCer-LD, AP-HP, Hôpital Trousseau, Paris, France
o Service de neuropediatrie, Hôpital Trousseau, 26 avenue du dr Arnold Netter, Paris, 75012, France
p Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), Groningen, 9700 RB, Netherlands
q GeneDx, Gaithersburg, MD 20877, United States
r Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081 HV, Netherlands
s Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, United States
t New York Genome Center, New York, NY 10013, United States
u Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, United States
v Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ 85259, United States
w Département de Génétique, APHP, GH Pitié-Salpêtrière, Paris, 75013, France
x Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, United States
y INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Université de Paris 06, Paris, 75013, France
z Pediatrics and Medical Genetics, Oasi Research Institute – IRCCS, Troina, 94018, Italy
aa Department of Pediatrics, Division of Genetics, Birth Defects and Metabolism, Ann and Robert H Lurie Children’s Hospital of Chicago, 225 East Chicago Avenue, Chicago, IL 60611, United States
ab Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, Maastricht, 9229 ER, Netherlands
ac Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950 Nydalen, Oslo, 0424, Norway
ad Institute of Clinical Medicine, University of Oslo, Oslo, 0318, Norway
ae Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, MA 02114, United States
af Department of Medical Genetics, Telemark Hospital Trust, Skien, 3710, Norway
ag Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, United States
ah Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, United Kingdom
ai Invitae, 1400 16th Street, San Francisco, CA 94103, United States
aj Impact Genetics, 1100 Bennett Road, BowmanvilleON L1C 3K5, Canada

Abstract
Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild–moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype. © 2019, European Society of Human Genetics.

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

“The E3 ligase Highwire promotes synaptic transmission by targeting the NAD-synthesizing enzyme dNmnat” (2019) EMBO Reports

The E3 ligase Highwire promotes synaptic transmission by targeting the NAD-synthesizing enzyme dNmnat
(2019) EMBO Reports, art. no. e46975, . 

Russo, A.a , Goel, P.b , Brace, E.J.a , Buser, C.c , Dickman, D.b , DiAntonio, A.a

a Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurobiology, University of Southern California, Los Angeles, CA, United States
c Oak Crest Institute of Science, Monrovia, CA, United States

Abstract
The ubiquitin ligase Highwire restrains synaptic growth and promotes evoked neurotransmission at NMJ synapses in Drosophila. Highwire regulates synaptic morphology by downregulating the MAP3K Wallenda, but excess Wallenda signaling does not account for the decreased presynaptic release observed in highwire mutants. Hence, Highwire likely has a second substrate that inhibits neurotransmission. Highwire targets the NAD+ biosynthetic and axoprotective enzyme dNmnat to regulate axonal injury responses. dNmnat localizes to synapses and interacts with the active zone protein Bruchpilot, leading us to hypothesize that Highwire promotes evoked release by downregulating dNmnat. Here, we show that excess dNmnat is necessary in highwire mutants and sufficient in wild-type larvae to reduce quantal content, likely via disruption of active zone ultrastructure. Catalytically active dNmnat is required to drive defects in evoked release, and depletion of a second NAD+ synthesizing enzyme is sufficient to suppress these defects in highwire mutants, suggesting that excess NAD+ biosynthesis is the mechanism inhibiting neurotransmission. Thus, Highwire downregulates dNmnat to promote evoked synaptic release, suggesting that Highwire balances the axoprotective and synapse-inhibitory functions of dNmnat. © 2019 The Authors

Author Keywords
DLK;  NAD+ biosynthesis;  Nmnat;  synaptic development;  synaptic transmission

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

“State emotional clarity and attention to emotion: a naturalistic examination of their associations with each other, affect, and context” (2019) Cognition and Emotion

State emotional clarity and attention to emotion: a naturalistic examination of their associations with each other, affect, and context
(2019) Cognition and Emotion, . 

Thompson, R.J.a , Boden, M.T.b

a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Center for Innovation to Implementation, VA Palo Alto Health Care System, Palo Alto, CA, United States

Abstract
Despite emotional clarity and attention to emotion being dynamic in nature, research has largely focused on their trait forms. We examined the association between state and trait forms of these two constructs, and how they are related to affect intensity and two contextual variables: Social context and significant event occurrence. Seventy-nine adults recruited from the community reported eight times a day for a week on the extent to which they were clear about their emotions, attended to their emotions, levels of affect intensity, the number of people with whom they were interacting, and whether a significant event had occurred. State clarity and attention were positively associated, demonstrating a moderate relation similar to that of their trait forms. Trait and state attention, but not trait and state clarity, were significantly positively associated. Positive and negative affect were quadratically associated with clarity and attention, with the highest levels of affect intensity reported at high levels of clarity and attention. Clarity and attention were positively associated with increasing numbers of people with whom people were interacting. Attention and clarity were elevated when significant events occurred–especially during positive events. We discuss the findings in the context of functional adaptation theories of emotion. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
attention to emotion;  context;  Emotional awareness;  emotional clarity;  social

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

“Cross-Palm Nerve Grafts to Enhance Sensory Recovery in Severe Ulnar Neuropathy” (2019) Hand

Cross-Palm Nerve Grafts to Enhance Sensory Recovery in Severe Ulnar Neuropathy
(2019) Hand

Felder, J.M., Hill, E.J.R., Power, H.A., Hasak, J., Mackinnon, S.E.. 

Washington University School of Medicine in St. Louis MO, United States

Abstract
Background: Intrinsic atrophy and debilitating sensory loss are prominent features of severe ulnar neuropathy with limited surgical options to reliably improve recovery. Restoration of sensation is important to provide protection for the vulnerable ulnar border of the hand. Here, we report our experience with side-to-side sensory nerve grafting from the median to ulnar nerve in the palm to enhance ulnar sensory recovery. Methods: A retrospective chart review identified patients with severe ulnar neuropathy who underwent cross-palm nerve grafting. Included patients had objective loss of protective sensation in the ulnar distribution with 2-point discrimination >8 mm, Semmes-Weinstein monofilament testing (SWMT) >4.56, or no sensory response on nerve conduction testing. Cross-palm side-to-side tension-free grafting from median to ulnar sensory components was performed using short-segment allograft or autografts. Analysis included patient etiology, procedures, nerve conduction studies, objective sensory testing, and Disabilities of the Arm, Shoulder, and Hand Disability score. Results: Forty-eight patients with severe ulnar neuropathy underwent cross-palm nerve grafting between 2014 and 2017. Twenty-four patients had adequate follow-up for inclusion. Of the 24 patients, 21 (87%) had return of protective sensation, 16 (66.7%) had return of diminished light touch sensation, and 6 (25%) had return to normal range sensation within 1 year as assessed by SWMT and/or 2-point discrimination. Patients treated with autograft demonstrated referred sensation to the median nerve distribution. Conclusions: Cross-palm nerve grafting may be a useful adjunct to enhance sensory recovery in severe ulnar neuropathy. Further study to quantify differences in sensory recovery between traditional operative techniques and cross-palm nerve grafting is required. © The Author(s) 2019.

Author Keywords
cubital tunnel syndrome;  nerve compression;  nerve graft;  nerve injury;  nerve reconstruction;  nerve regeneration;  outcomes;  research and health outcomes;  side-to-side nerve graft;  surgery;  treatment;  ulnar nerve

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

“Sex-specific contribution of DHEA-cortisol ratio to prefrontal-hippocampal structural development, cognitive abilities and personality traits” (2019) Journal of Neuroendocrinology

Sex-specific contribution of DHEA-cortisol ratio to prefrontal-hippocampal structural development, cognitive abilities and personality traits
(2019) Journal of Neuroendocrinology, art. no. e12682, . Article in Press. 

Farooqi, N.A.I.a , Scotti, M.a , Yu, A.b , Lew, J.b , Monnier, P.c d , Botteron, K.N.e f , Campbell, B.C.g , Booij, L.a h i , Herba, C.M.i j , Séguin, J.R.i k , Castellanos-Ryan, N.i m , McCracken, J.T.f l , Nguyen, T.-V.a c d

a Department of Psychiatry, McGill University, Montreal, QC, Canada
b Department of Psychology, McGill University, Montreal, QC, Canada
c Department of Obstetrics-Gynecology, McGill University Health Center, Montreal, QC, Canada
d Research Institute of the McGill University Health Center, Montreal, QC, Canada
e Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
f Brain Development Cooperative Group, United States
g Department of Anthropology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
h Department of Psychology, Concordia University, Montreal, QC, Canada
i CHU Sainte Justine Hospital Research Centre, University of Montreal, Montreal, QC, Canada
j Department of Psychology, Université du Québec à Montréal, Montreal, QC, Canada
k Department of Psychiatry and Addiction, University of Montreal, Montreal, QC, Canada
l Department of Child and Adolescent Psychiatry, University of California in Los Angeles, Los Angeles, CA, United States
m School of Psychoeducation, University of Montreal, Montreal, QC, Canada

Abstract
Although dehydroepiandrosterone (DHEA) may exert neuroprotective effects in the developing brain, prolonged or excessive elevations in cortisol may exert neurotoxic effects. The ratio between DHEA and cortisol (DC ratio) has been linked to internalising and externalising disorders, as well as cognitive performance, supporting the clinical relevance of this hormonal ratio during development. However, the brain mechanisms by which these effects may be mediated have not yet been identified. Furthermore, although there is evidence that the effects of cortisol in the central nervous system may be sexually dimorphic in humans, the opposite is true for DHEA, with human studies showing no sex-specific associations in cortical thickness, cortico-amygdalar or cortico-hippocampal structural covariance. Therefore, it remains unclear whether sex moderates the developmental associations between DC ratio, brain structure, cognition and behaviour. In the present study, we examined the associations between DC ratio, structural covariance of the hippocampus with whole-brain cortical thickness, and measures of personality, behaviour and cognition in a longitudinal sample of typically developing children, adolescents and young adults aged 6-22 years (N = 225 participants [F = 128]; 355 scans [F = 208]), using mixed effects models that accounted for both within- and between-subject variances. We found sex-specific interactions between DC ratio and anterior cingulate cortex-hippocampal structural covariance, with higher DC ratios being associated with a more negative covariance between these structures in girls, and a more positive covariance in boys. Furthermore, the negative prefrontal-hippocampal structural covariance found in girls was associated with higher verbal memory and mathematical ability, whereas the positive covariance found in boys was associated with lower cooperativeness and reward dependence personality traits. These findings support the notion that the ratio between DHEA and cortisol levels may contribute, at least in part, to the development of sex differences in cognitive abilities, as well as risk for internalising/externalising disorders, via an alteration in prefrontal-hippocampal structure during the transition from childhood to adulthood. © 2018 British Society for Neuroendocrinology

Author Keywords
adolescence;  adrenarche;  androgens;  cognition;  puberty

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

“Perceptions Among Child Welfare Staff when Modifying A Child Mental Health Intervention to be Implemented in Child Welfare Services” (2019) American Journal of Community Psychology

Perceptions Among Child Welfare Staff when Modifying A Child Mental Health Intervention to be Implemented in Child Welfare Services
(2019) American Journal of Community Psychology, . 

Gopalan, G.a , Hooley, C.b , Winters, A.c , Stephens, T.a

a Hunter College – Silberman School of Social Work, New York, NY, United States
b Brown School, Washington University in St. Louis, St. Louis, MO, United States
c Kent School of Social Work, University of Louisville, Louisville, KY, United States

Abstract
In order to increase access to child mental health evidence-based interventions (EBIs) for vulnerable and hard-to-engage families involved in the child welfare (CW) system, innovative approaches coupled with input from service providers are needed. One potential solution involves utilizing task-shifting strategies and implementation science theoretical frameworks to implement such EBIs in CW settings. This study examined perceptions among CW staff who were members of a collaborative advisory board involved in the implementation of the 4Rs and 2Ss Strengthening Families Program (4R2S) in CW placement prevention settings, utilizing task-shifting strategies and the Practical, Robust, Implementation, and Sustainability Model. Advisory board members reported difficulties in engaging families, heavy workloads, and conflicting implementation initiatives. While 4R2S was perceived as generally aligned with their organization’s mission, modifications to the intervention and to agency procedures were recommended to promote implementation success. Suggested modifications to the existing 4R2S training and supervision are discussed. Findings underscore the importance of understanding the experiences of CW service providers, which can inform future efforts to implement child mental health EBIs in CW services. © 2019 Society for Community Research and Action

Author Keywords
4R2S;  Child mental health;  Child welfare;  Implementation;  Multiple family groups;  PRISM;  Task-shifting

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

“Reduction of Computed Tomography Use for Pediatric Closed Head Injury Evaluation at a Nonpediatric Community Emergency Department” (2019) Academic Emergency Medicine

Reduction of Computed Tomography Use for Pediatric Closed Head Injury Evaluation at a Nonpediatric Community Emergency Department
(2019) Academic Emergency Medicine, . 

Puffenbarger, M.S.a , Ahmad, F.A.b , Argent, M.f , Gu, H.c , Samson, C.b , Quayle, K.S.e , Saito, J.M.d

a Mercy St. Louis Emergency Medicine, St. Louis, MO, United States
b Department of Pediatrics, St. Louis, MO, United States
c Department of Biostatistics, St. Louis, MO, United States
d Department of Pediatric Surgery, St. Louis, MO, United States
e Washington University School of Medicine, St. Louis, MO, United States
f Center for Clinical Excellence, St. Louis, MO, United States

Abstract
Objective: The purpose of this study was to determine if implementation of a Pediatric Emergency Care Applied Research Network (PECARN)-based Closed Head Injury Assessment Tool could safely decrease computed tomography (CT) use for pediatric head injury evaluation at a nonpediatric community emergency department (ED). Methods: A quality improvement project was initiated at a nonpediatric community ED to implement an institution-specific, PECARN-based Pediatric Closed Head Injury Assessment Tool. Baseline head CT use at the participating ED was determined for children with closed head injury through retrospective chart review from March 2014 through November 2015. Head injury patients were identified using International Classification of Disease (ICD)-9 codes for head injury, unspecified (959.01) and concussion with and without loss of consciousness (850–850.9) until October 2015, after which ICD-9 was no longer used. To identify eligible patients after October 2015, lists of all pediatric patients evaluated at the participating ED were reviewed, and patients were included in the analysis if they had a physician-assigned discharge diagnosis of head injury or concussion. Exclusion criteria were age ≥ 18 years, penetrating head trauma, history of brain tumor, ventriculoperitoneal shunt, bleeding disorder, or presentation > 24 hours postinjury. Medical history, injury mechanism, symptoms, head CT use, and disposition were recorded. Implementation of the Pediatric Closed Head Injury Assessment Tool was achieved through provider education sessions beginning in December 2015 and ending in August 2016. Head CT use was monitored for 12 months postimplementation, from September 2016 through August 2017. Patients were classified into low, intermediate, or high risk for clinically important traumatic brain injury (ciTBI) by chart review. ED length of stay (LOS), disposition, and ED returns within 72 hours were recorded. Categorical variables were compared using chi-square test or Fisher’s exact test, and continuous variables, using Kruskal-Wallis test. Results: A total of 252 children with closed head injury were evaluated preimplementation (March 2014 through November 2015), 132 children were evaluated during implementation (December 2015 through August 2016), and 172 children were evaluated postimplementation (September 2016 through August 2017). Overall CT use decreased from 37.7% (95% confidence interval [CI] = 31.7–43.7) preimplementation to 16.9% (95% CI = 11.3–22.5) postimplementation (p < 0.001). Only 1% (95% CI = 0%–2.9%) of low-risk patients received a head CT postimplementation compared to 22.6% (95% CI = 16.1%–29.1%) preimplementation (p < 0.001). CT use among patients ≥ 24 months decreased from 42.9% (95% CI = 36.5%–49.6%) to 19.6% (95% CI = 13.1%–26.1%; p < 0.001) and remained low and unchanged for patients < 24 months. Transfers to a pediatric trauma center and ED returns within 72 hours were unchanged, while median ED LOS improved from 1.5 to 1.3 hours (p = 0.03). There were no missed ciTBIs after implementation of the guideline. Conclusion: Implementation of the PECARN-based Pediatric Closed Head Injury Assessment Tool reduced head CT use in a nonpediatric ED. The greatest impact was seen among children aged ≥ 24 months at very low risk for ciTBI. © 2018 by the Society for Academic Emergency Medicine

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

“Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma” (2019) OncoImmunology

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma
(2019) OncoImmunology, . Article in Press. 

Johanns, T.M.a b , Miller, C.A.c , Liu, C.J.b d , Perrin, R.J.e , Bender, D.b , Kobayashi, D.K.b , Campian, J.L.a , Chicoine, M.R.d , Dacey, R.G.d , Huang, J.f , Fritsch, E.F.g , Gillanders, W.E.b h , Artyomov, M.N.b e , Mardis, E.R.i , Schreiber, R.D.b e , Dunn, G.P.b d

a Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States
b Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
c The McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurological Surgery, 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
f Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, United States
g Neon Therapeutics, Cambridge, MA, United States
h Department of Surgery, Section of Endocrine and Oncologic Surgery, Washington University School of Medicine, St. Louis, MO, United States
i Institute for Genomic Medicine, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, United States

Abstract
Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We have previously reported the use of an immunogenomics pipeline to identify candidate neoantigens in preclinical models of GBM. Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I- and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood. A similar pattern of reactivity was observed among isolated post-treatment tumor-infiltrating lymphocytes. Genomic analysis of pre- and post-treatment GBM reflected clonal remodeling. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors. © 2019, © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

Author Keywords
clonal evolution;  glioblastoma;  immunogenomics;  Neoantigen;  personalized vaccine

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

“Pseudobulbar affect prevalence and association with symptoms inmultiple sclerosis” (2018) Neurology: Clinical Practice

Pseudobulbar affect prevalence and association with symptoms inmultiple sclerosis
(2018) Neurology: Clinical Practice, 8 (6), pp. 472-481.

Fitzgerald, K.C.a g , Salter, A.b g g , Tyry, T.c g g , Fox, R.J.d g g , Cutter, G.e g g , Marrie, R.A.f g g  

a Department of Neurology, United States
b Division of Biostatistics, Johns Hopkins School of Medicine, Baltimore, MD, United States
c Washington University in St. Louis School of Medicine, Dignity Health, MO, United States
d St.Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
e Department of Biostatistics, Cleveland Clinic FoundationOH, United States
f Departments of Internal Medicine and Community Health Sciences, University of Alabama in Birmingham School of Public HealthAL, United States
g Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada

Abstract
Background We sought to determine the prevalence of pseudobulbar affect (PBA) in a large MS population and assess its association with disability and symptom severity. Methods North American Research Committee on MS (NARCOMS) registry participants completed the Center for Neurologic Study-Lability Scale (CNS-LS), a validated 7- question self-report measure of PBA. A composite PBA score was derived from the sum of responses to the 7 questions. We categorized individuals as PBA-positive (PBA[+]) if they had a composite score ≥17 without current depression. Participants also reported their demographic characteristics and their clinical characteristics using Patient-Determined Disease Steps and Performance Scales. We compared clinical and disease characteristics for PBA(+) responders with those without PBA using descriptive statistics and multivariable multinomial logistic regression. Results Of the 8,136 responders, 574 (7%) had scores ≥17 on the CNS-LS; however, only 200 (2.5%) individuals had scores ≥17 without comorbid depression, of whom only 22 (11%) reported a diagnosis of PBA. PBA(+) individuals tended to be younger (mean [SD] 53.4 [11.0] vs 57.2 [10.3] years), non-white (13% vs 9%), and have lower socioeconomic status (≤$30,000 annual income: 28% vs 22%). In multivariable models, PBA(+) was associated with increased odds of more severe cognitive impairment (moderate vs mild disability OR: 1.37; 95% CI: 1.01, 1.84). Conclusions Our findings suggest that the prevalence of PBA in MS is low, but similar symptoms may cooccur or overlap with depression, highlighting the importance of concomitant assessment of mood when evaluating potential PBA. PBA may be associated with cognitive impairment in people with MS. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Independent NF1 mutations underlie café-au-lait macule development in a woman with segmental NF1” (2018) Neurology: Genetics

Independent NF1 mutations underlie café-au-lait macule development in a woman with segmental NF1
(2018) Neurology: Genetics, 4 (4), art. no. e261, . 

Freret, M.E.a b , Anastasaki, C.a , Gutmann, D.H.a

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
b Harvard Medical School, Boston, MA, United States

Abstract
Segmental neurofibromatosis type 1 (NF1) is an under-recognized form of NF1 caused by postzygotic somatic loss-of-function NF1 gene mutations that affect a subset of cells in the body.1 This is in contrast to classic or generalized NF1, in which a germline NF1 gene mutation affects all diploid cells in the body. In the segmental NF1 variant, individuals typically exhibit clinical features characteristic of generalized NF1, such as café-au-lait macules (CALMs), skinfold freckling, and neurofibromas, restricted to one segment of the body. For this reason, establishing the diagnosis can be challenging because the underlying NF1 gene mutation is often not detected in the blood. Underscoring the challenges of caring for individuals with this variant of NF1, we describe a woman with segmental NF1 referred to us at 22 years of age for evaluation. © 2018 American Academy of Neurology.

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