WashU weekly Neuroscience publications | Office of Neuroscience Research

“Toxic effects of endoplasmic reticulum stress transducer BBF2H7-derived small peptide fragments on neuronal cells” (2020) Brain Research

Toxic effects of endoplasmic reticulum stress transducer BBF2H7-derived small peptide fragments on neuronal cells
(2020) Brain Research, 1749, art. no. 147139, .

Matsuhisa, K.^a ^b , Cai, L.^a , Saito, A.^a ^b , Sakaue, F.^b , Kamikawa, Y.^b , Fujiwara, S.^b , Asada, R.^c , Kudo, Y.^d , Imaizumi, K.^a

^a Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
^b Department of Stress Protein Processing, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
^c Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Gerontology and Geriatrics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan

Abstract
Aggregation, fibril formation, and deposition of amyloid β (Aβ) protein are believed to be the central pathogeneses of Alzheimer’s disease (AD). Numerous studies have shown that fibril formation is promoted by preformed seeds at the beginning of the aggregation process. Therefore, aggregated molecules that promote fibrillization of Aβ protein as seeds could affect the pathology. We recently found that approximately 40 amino acid hydrophobic peptides, BBF2H7-derived small peptide (BSP) fragments, are generated via intramembranous cleavage under endoplasmic reticulum (ER) stress conditions. Interestingly, similar to Aβ protein, the fragments exhibit a high aggregation propensity and form fibril structures. It has been noted that ER stress is involved in the pathogenesis of AD. In this study, we examined the effect of BSP fragments on aggregation and cytotoxicity of Aβ1–40 protein, which is generated as a major species of Aβ protein, but has a lower aggregative property than Aβ1–42 protein. We demonstrated that BSP fragments promote aggregation of Aβ1–40 protein. Aggregates of Aβ1–40 protein mediated by BSP fragments also exhibited potent neurotoxicity. Our findings suggest the possibility that BSP fragments affect accumulation of Aβ proteins and are involved in the pathogenesis of AD. © 2020 The Author(s)

Author Keywords
Alzheimer’s disease; BBF2H7; Endoplasmic reticulum stress

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

“Robust deep learning classification of adamantinomatous craniopharyngioma from limited preoperative radiographic images” (2020) Scientific Reports

Robust deep learning classification of adamantinomatous craniopharyngioma from limited preoperative radiographic images
(2020) Scientific Reports, 10 (1), art. no. 16885, .

Prince, E.W.^a ^b ^c , Whelan, R.^b , Mirsky, D.M.^d , Stence, N.^d , Staulcup, S.^b , Klimo, P.^e ^f , Anderson, R.C.E.^g , Niazi, T.N.^h , Grant, G.ⁱ , Souweidane, M.^j ^k , Johnston, J.M.^l , Jackson, E.M.^m , Limbrick, D.D., Jr.ⁿ , Smith, A.^o , Drapeau, A.^p , Chern, J.J.^q , Kilburn, L.^r , Ginn, K.^s , Naftel, R.^t , Dudley, R.^u , Tyler-Kabara, E.^v , Jallo, G.^w , Handler, M.H.^a ^b , Jones, K.^x , Donson, A.M.^c ^y , Foreman, N.K.^c ^y , Hankinson, T.C.^a ^b ^c

^a Division of Pediatric Neurosurgery, Children’s Hospital Colorado, Aurora, 80045, United States
^b Department of Neurosurgery, University of Colorado School of Medicine, Aurora, 80045, United States
^c Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, 80045, United States
^d Division of Pediatric Radiology, Children’s Hospital Colorado, Aurora, 80045, United States
^e Department of Neurosurgery, University of Tennessee Health and Sciences Center, Memphis, 38163, United States
^f Semmes Murphy Clinic, St. Jude Children’s Research Hospital, Memphis, 38105, United States
^g Neurosurgical Associates of New Jersey, Ridgewood, NJ 07450, United States
^h Department of Pediatric Neurosurgery, Nicklaus Children’s Hospital, Miami, 33155, United States
ⁱ Department of Pediatric Neurosurgery, Lucile Packard Children’s Hospital at Stanford University, Palo Alto, 94305, United States
^j Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, 10065, United States
^k Department of Neurological Surgery, Weill Cornell Medical College, New York, 10065, United States
^l Division of Pediatric Neurosurgery, University of Alabama at Birmingham, Birmingham, 35233, United States
^m Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, 21205, United States
ⁿ Department of Pediatrics, Washington University School of Medicine, St. Louis, 63110, United States
^o Department of Pediatric Hematology-Oncology, Arnold Palmer Hospital, Orlando, 32806, United States
^p Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, 43205, United States
^q Departments of Pediatrics and Neurosurgery, Emory University School of Medicine, Atlanta, 30322, United States
^r Children’s National Health System, Brain Tumor Institute, Washington, DC 20010, United States
^s Division of Pediatric Hematology and Oncology, Children’s Mercy Hospital, Kansas City, 64108, United States
^t Department of Neurological Surgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, 37212, United States
^u Department of Neurosurgery, McGill University, Montreal, H3A 2B4, Canada
^v Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, 15213, United States
^w Institute of Brain Protection Sciences, Johns Hopkins All Children’s Hospital, St Petersburg, 33701, United States
^x University of Oklahoma Health Sciences Center, Oklahoma City, 73104, United States
^y Division of Pediatric Neurooncology, Children’s Hospital Colorado, Aurora, 80045, United States

Abstract
Deep learning (DL) is a widely applied mathematical modeling technique. Classically, DL models utilize large volumes of training data, which are not available in many healthcare contexts. For patients with brain tumors, non-invasive diagnosis would represent a substantial clinical advance, potentially sparing patients from the risks associated with surgical intervention on the brain. Such an approach will depend upon highly accurate models built using the limited datasets that are available. Herein, we present a novel genetic algorithm (GA) that identifies optimal architecture parameters using feature embeddings from state-of-the-art image classification networks to identify the pediatric brain tumor, adamantinomatous craniopharyngioma (ACP). We optimized classification models for preoperative Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and combined CT and MRI datasets with demonstrated test accuracies of 85.3%, 83.3%, and 87.8%, respectively. Notably, our GA improved baseline model performance by up to 38%. This work advances DL and its applications within healthcare by identifying optimized networks in small-scale data contexts. The proposed system is easily implementable and scalable for non-invasive computer-aided diagnosis, even for uncommon diseases. © 2020, The Author(s).

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

“A spinal neural circuitry for converting touch to itch sensation” (2020) Nature Communications

A spinal neural circuitry for converting touch to itch sensation
(2020) Nature Communications, 11 (1), art. no. 5074, .

Chen, S.^a ^b ^c , Gao, X.-F.^a ^b ^d , Zhou, Y.^a ^b ^c , Liu, B.-L.^a ^b , Liu, X.-Y.^a ^b , Zhang, Y.^a ^e , Barry, D.M.^a ^b , Liu, K.^a ^b , Jiao, Y.^c , Bardoni, R.^f , Yu, W.^c , Chen, Z.-F.^a ^b ^g ^h

^a Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
^d Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200434, China
^e Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
^f Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^h Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2Cre) receive direct Aβ low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2Cre neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch. © 2020, The Author(s).

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

“SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage” (2020) Experimental Neurology

SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage
(2020) Experimental Neurology, 334, art. no. 113484, .

Vellimana, A.K.^a , Aum, D.J.^a , Diwan, D.^a , Clarke, J.V.^a , Nelson, J.W.^a , Lawrence, M.^a , Han, B.H.^b , Gidday, J.M.^c , Zipfel, G.J.^a ^d

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Pharmacology, A.T. Still University of Health Sciences, Kirksville College of Osteopathic Medicine, Kirksville, MO 63501, United States
^c Departments of Ophthalmology, Physiology, Biochemistry, and Neuroscience, Louisiana State University, New Orleans, LA, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background and purpose: Vasospasm and delayed cerebral ischemia (DCI) contribute significantly to the morbidity/mortality associated with aneurysmal subarachnoid hemorrhage (SAH). While considerable research effort has focused on preventing or reversing vasospasm, SAH-induced brain injury occurs in response to a multitude of concomitantly acting pathophysiologic mechanisms. In this regard, the pleiotropic epigenetic responses to conditioning-based therapeutics may provide an ideal SAH therapeutic strategy. We previously documented the ability of hypoxic preconditioning (PC) to attenuate vasospasm and neurological deficits after SAH, in a manner that depends on the activity of endothelial nitric oxide synthase. The present study was undertaken to elucidate whether the NAD-dependent protein deacetylase sirtuin isoform SIRT1 is an upstream mediator of hypoxic PC-induced protection, and to assess the efficacy of the SIRT1-activating polyphenol Resveratrol as a pharmacologic preconditioning therapy. Methods: Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxic PC. Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator). Results: Hypoxic PC leads to rapid and sustained increase in cerebral SIRT1 mRNA and protein expression. SIRT1 inhibition blocks the protective effects of hypoxic PC on vasospasm and neurological deficits. Resveratrol pretreatment dose-dependently abrogates vasospasm and attenuates neurological deficits following SAH – beneficial effects that were similarly blocked by pharmacologic inhibition of SIRT1. Conclusion: SIRT1 mediates hypoxic preconditioning-induced protection against neurovascular dysfunction after SAH. Resveratrol mimics this neurovascular protection, at least in part, via SIRT1. Activation of SIRT1 is a promising, novel, pleiotropic therapeutic strategy to combat DCI after SAH. © 2020

Author Keywords
Delayed cerebral ischemia; Resveratrol; SIRT1; Sirtuin; Subarachnoid hemorrhage; Vasospasm

Document Type: Article
Publication Stage: Final
Source: Scopus

“Evaluating resting-state BOLD variability in relation to biomarkers of preclinical Alzheimer’s disease” (2020) Neurobiology of Aging

Evaluating resting-state BOLD variability in relation to biomarkers of preclinical Alzheimer’s disease
(2020) Neurobiology of Aging, 96, pp. 233-245.

Millar, P.R.^a ^b , Ances, B.M.^b ^c , Gordon, B.A.^a ^c , Benzinger, T.L.S.^c , Fagan, A.M.^b , Morris, J.C.^b , Balota, D.A.^a ^b

^a Department of Psychological & Brain Sciences, St. Louis, MO, United States
^b Department of Neurology, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Recent functional magnetic resonance imaging studies have demonstrated that moment-to-moment variability in the blood oxygen level–dependent (BOLD) signal is related to age differences, cognition, and symptomatic Alzheimer’s disease (AD). However, no studies have examined BOLD variability in the context of preclinical AD. We tested relationships between resting-state BOLD variability and biomarkers of amyloidosis, tauopathy, and neurodegeneration in a large (N = 321), well-characterized sample of cognitively normal adults (age = 39–93), using multivariate machine learning techniques. Furthermore, we controlled for cardiovascular health factors, which may contaminate resting-state BOLD variability estimates. BOLD variability, particularly in the default mode network, was related to cerebrospinal fluid (CSF) amyloid-β42 but was not related to CSF phosphorylated tau-181. Furthermore, BOLD variability estimates were also related to markers of neurodegeneration, including CSF neurofilament light protein, hippocampal volume, and a cortical thickness composite. Notably, relationships with hippocampal volume and cortical thickness survived correction for cardiovascular health and also contributed to age-related differences in BOLD variability. Thus, BOLD variability may be sensitive to preclinical pathology, including amyloidosis and neurodegeneration in AD-sensitive areas. © 2020 Elsevier Inc.

Author Keywords
Alzheimer’s disease; Amyloid; BOLD variability; Neurodegeneration; Resting-state fMRI

Document Type: Article
Publication Stage: Final
Source: Scopus

“Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia” (2020) iScience

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia
(2020) iScience, 23 (10), art. no. 101552, .

Dong, W.^a ^b , Jin, S.C.^c , Allocco, A.^d , Zeng, X.^a ^b , Sheth, A.H.^d , Panchagnula, S.^d , Castonguay, A.^e , Lorenzo, L.-É.^e , Islam, B.^f , Brindle, G.^e , Bachand, K.^e , Hu, J.^d , Sularz, A.^d , Gaillard, J.^d , Choi, J.^a ^b ^g , Dunbar, A.^d , Nelson-Williams, C.^a , Kiziltug, E.^d , Furey, C.G.^d , Conine, S.^d , Duy, P.Q.^d , Kundishora, A.J.^d , Loring, E.^a , Li, B.^h , Lu, Q.ⁱ , Zhou, G.^z , Liu, W.^z , Li, X.^y , Sierant, M.C.^a ^b , Mane, S.^j , Castaldi, C.^j , López-Giráldez, F.^j , Knight, J.R.^j , Sekula, R.F., Jr.^k , Simard, J.M.^l , Eskandar, E.N.^m , Gottschalk, C.ⁿ , Moliterno, J.^d , Günel, M.^d , Gerrard, J.L.^d , Dib-Hajj, S.^o ^p , Waxman, S.G.^o ^p , Barker, F.G., II^q ^r ^s , Alper, S.L.^t , Chahine, M.^e ^u , Haider, S.^f , De Koninck, Y.^e ^v , Lifton, R.P.^a ^b , Kahle, K.T.^d ^w ^x

^a Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^b Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^e CERVO Brain Research Centre, Université Laval, Québec, QC, Canada
^f University College London, School of Pharmacy, London, United Kingdom
^g Department of Biomedical Sciences, Korea University College of Medicine, Seoul, 02841, South Korea
^h Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States
ⁱ Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States
^j Yale Center for Genome Analysis, West Haven, CT, United States
^k Department of Neurological Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^l Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, United States
^m Department of Neurological Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York, United States
ⁿ Headache Medicine, Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^o Center for Neuroscience & Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, United States
^p Department of Neurology; Yale University, New Haven, CT, United States
^q Harvard Medical School, Boston, MA, United States
^r Cancer Center, Massachusetts General Hospital, Boston, MA, United States
^s Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
^t Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, United States
^u Department of Medicine, Université Laval, Québec, QC, Canada
^v Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada
^w Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
^x Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, United States
^y School of Data Science, City University of Hong Kong, Hong Kong, Hong Kong
^z Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, United States

Abstract
Neuroscience; Structural Biology; Genomics © 2020 The Authors

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis. © 2020 The Authors

Author Keywords
Genomics; Neuroscience; Structural Biology

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

“Surgical resource utilization after initial treatment of infant hydrocephalus: Comparing etv, early experience of etv with choroid plexus cauterization, and shunt insertion in the hydrocephalus clinical research network” (2020) Journal of Neurosurgery: Pediatrics

Surgical resource utilization after initial treatment of infant hydrocephalus: Comparing etv, early experience of etv with choroid plexus cauterization, and shunt insertion in the hydrocephalus clinical research network
(2020) Journal of Neurosurgery: Pediatrics, 26 (4), pp. 337-345.

Pindrik, J.^a , Riva-Cambrin, J.^b , Kulkarni, A.V.^c , Alvey, J.S.^d , Reeder, R.W.^d , Pollack, I.F.^e , Wellons, J.C., III^f , Jackson, E.M.^g , Rozzelle, C.J.^h , Whitehead, W.E.ⁱ , Limbrick, D.D., Jr.^j , Naftel, R.P.^f , Shannon, C.^f , McDonald, P.J.^k , Tamber, M.S.^k , Hankinson, T.C.^l , Hauptman, J.S.^m , Simon, T.D.^m , Krieger, M.D.ⁿ , Holubkov, R.^o , Kestle, J.R.W.^d , Hydrocephalus Clinical Research Network^p

^a Division of Pediatric Neurosurgery, Department of Neurological Surgery, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, United States
^b Section of Pediatric Neurosurgery, Division of Neurosurgery, Alberta Children’s Hospital, University of Calgary, Alberta, Canada
^c Division of Neurosurgery, Hospital for Sick Children, University of TorontoON, Canada
^d Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
^e Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^f Division of Pediatric Neurosurgery, Department of Neurosurgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, United States
^g Department of Neurosurgery, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Division of Pediatric Neurosurgery, Department of Neurosurgery, Children’s of Alabama, University of Alabama School of Medicine, Birmingham, AL, United States
ⁱ Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^j Division of Pediatric Neurosurgery, Departments of Neurological Surgery and Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine in, St. Louis, MO, United States
^k Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
^l Departments of Neurosurgery and Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
^m Division of Pediatric Neurosurgery, Department of Neurosurgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
ⁿ Department of Surgery, Children’s Hospital of Los AngelesCA, United States
^o Hydrocephalus Clinical Research Network Data Coordinating Center, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States

Abstract
OBJECTIVE Few studies have addressed surgical resource utilization-surgical revisions and associated hospital admission days-following shunt insertion or endoscopic third ventriculostomy (ETV) with or without choroid plexus cauterization (CPC) for CSF diversion in hydrocephalus. Study members of the Hydrocephalus Clinical Research Network (HCRN) investigated differences in surgical resource utilization between CSF diversion strategies in hydrocephalus in infants. METHODS Patients up to corrected age 24 months undergoing initial definitive treatment of hydrocephalus were reviewed from the prospectively maintained HCRN Core Data Project (Hydrocephalus Registry). Postoperative courses (at 1, 3, and 5 years) were studied for hydrocephalus-related surgeries (primary outcome) and hospital admission days related to surgical revision (secondary outcome). Data were summarized using descriptive statistics and compared using negative binomial regression, controlling for age, hydrocephalus etiology, and HCRN center. The study population was organized into 3 groups (ETV alone, ETV with CPC, and CSF shunt insertion) during the 1st postoperative year and 2 groups (ETV alone and CSF shunt insertion) during subsequent years due to limited long-term follow-up data. RESULTS Among 1090 patients, the majority underwent CSF shunt insertion (CSF shunt, 83.5%; ETV with CPC, 10.0%; and ETV alone, 6.5%). Patients undergoing ETV with CPC had a higher mean number of revision surgeries (1.2 ± 1.6) than those undergoing ETV alone (0.6 ± 0.8) or CSF shunt insertion (0.7 ± 1.3) over the 1st year after surgery (p = 0.005). At long-term follow-up, patients undergoing ETV alone experienced a nonsignificant lower mean number of revision surgeries (0.7 ± 0.9 at 3 years and 0.8 ± 1.3 at 5 years) than those undergoing CSF shunt insertion (1.1 ± 1.9 at 3 years and 1.4 ± 2.6 at 5 years) and exhibited a lower mean number of hospital admission days related to revision surgery (3.8 ± 10.3 vs 9.9 ± 27.0, p = 0.042). CONCLUSIONS Among initial treatment strategies for hydrocephalus, ETV with CPC yielded a higher surgical revision rate within 1 year after surgery. Patients undergoing ETV alone exhibited a nonsignificant lower mean number of surgical revisions than CSF shunt insertion at 3 and 5 years postoperatively. Additionally, the ETV-alone cohort demonstrated significantly fewer hospital admission days related to surgical management of hydrocephalus within 3 years after surgery. These findings suggest a time-dependent benefit of ETV over CSF shunt insertion regarding surgical resource utilization. © AANS 2020, except where prohibited by US copyright law

Author Keywords
Cerebrospinal fluid; Choroid plexus cauterization; Endoscopic third ventriculostomy; HCRN; Hydrocephalus Clinical Research Network; Resource utilization; Shunt

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

“Establishing the minimum clinically important difference in neck disability index and modified japanese orthopaedic association scores for adult cervical deformity” (2020) Journal of Neurosurgery: Spine

Establishing the minimum clinically important difference in neck disability index and modified japanese orthopaedic association scores for adult cervical deformity
(2020) Journal of Neurosurgery: Spine, 33 (4), pp. 441-445.

Soroceanu, A.^a , Smith, J.S.^b , Lau, D.^c , Kelly, M.P.^d , Passias, P.G.^e , Protopsaltis, T.S.^e , Gum, J.L.^f , Lafage, V.^g , Kim, H.-J.^g , Scheer, J.K.^c , Gupta, M.^d , Mundis, G.M., Jr.^h , Klineberg, E.O.ⁱ , Burton, D.^j , Bess, S.^k , Ames, C.P.^c , International Spine Study Group^l

^a Department of Orthopaedic Surgery, University of Calgary, Alberta, Canada
^b Department of Neurosurgery, University of Virginia Health System, Charlottesville, VA, United States
^c Department of Neurological Surgery, University of California, San Francisco, CA, United States
^d Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
^e Department of Orthopaedic Surgery, New York University, New York, NY, United States
^f Department of Orthopaedic Surgery, Norton Leatherman Spine Center, Louisville, KY, United States
^g Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, NY, United States
^h Department of Orthopaedic Surgery, Scripps, San Diego, CA, United States
ⁱ Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA, United States
^j Department of Orthopaedic Surgery, University of Kansas, Kansas City, KS, United States
^k Department of Orthopaedic Surgery, Denver International Spine Center, Denver, CO, United States

Abstract
OBJECTIVE It is being increasingly recognized that adult cervical deformity (ACD) is correlated with significant pain, myelopathy, and disability, and that patients who undergo deformity correction gain significant benefit. However, there are no defined thresholds of minimum clinically important difference (MCID) in Neck Disability Index (NDI) and modified Japanese Orthopaedic Association (mJOA) scores. METHODS Patients of interest were consecutive patients with ACD who underwent cervical deformity correction. ACD was defined as C2-7 sagittal Cobb angle ≥ 10° (kyphosis), C2-7 coronal Cobb angle ≥ 10° (cervical scoliosis), C2-7 sagittal vertical axis ≥ 4 cm, and/or chin-brow vertical angle ≥ 25°. Data were obtained from a consecutive cohort of patients from a multiinstitutional prospective database maintained across 13 sites. Distribution-based MCID, anchor-based MCID, and minimally detectable measurement difference (MDMD) were calculated. RESULTS A total of 73 patients met inclusion criteria and had sufficient 1-year follow-up. In the cohort, 42 patients (57.5%) were female. The mean age at the time of surgery was 62.23 years, and average body mass index was 29.28. The mean preoperative NDI was 46.49 and mJOA was 13.17. There was significant improvement in NDI at 1 year (46.49 vs 37.04; p = 0.0001). There was no significant difference in preoperative and 1-year mJOA (13.17 vs 13.7; p = 0.12). Using multiple techniques to yield MCID thresholds specific to the ACD population, the authors obtained values of 5.42 to 7.48 for the NDI, and 1.00 to 1.39 for the mJOA. The MDMD was 6.4 for the NDI, and 1.8 for the mJOA. Therefore, based on their results, the authors recommend using an MCID threshold of 1.8 for the mJOA, and 7.0 for the NDI in patients with ACD. CONCLUSIONS The ACD-specific MCID thresholds for NDI and mJOA are similar to the reported MCID following surgery for degenerative cervical disease. Additional studies are needed to verify these findings. Nonetheless, the findings here will be useful for future studies evaluating the success of surgery for patients with ACD undergoing deformity correction. © AANS 2020, except where prohibited by US copyright law

Author Keywords
Cervical deformity; Minimum clinically importance difference; Modified Japanese Orthopaedic Association; Neck Disability Index

Document Type: Article
Publication Stage: Final
Source: Scopus

“National institute of neurological disorders and stroke: Current funding status, opportunities, challenges, emerging scientific advances, and recommendations for neurosurgery” (2020) Journal of Neurosurgery

National institute of neurological disorders and stroke: Current funding status, opportunities, challenges, emerging scientific advances, and recommendations for neurosurgery
(2020) Journal of Neurosurgery, 133 (4), pp. 1264-1269.

Lonser, R.R.^a , Zipfel, G.J.^b , Antonio Chiocca, E.^c

^a Department of Neurological Surgery, Ohio State University Wexner Medical Center, Columbus, OH, United States
^b Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurological Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Document Type: Review
Publication Stage: Final
Source: Scopus

“Factors Associated With Participation in the Chronic Disease Self-Management Program: Findings From the SUCCEED Trial” (2020) Stroke

Factors Associated With Participation in the Chronic Disease Self-Management Program: Findings From the SUCCEED Trial
(2020) Stroke, 51 (10), pp. 2910-2917.

Lin, A.M.^a ^b , Vickrey, B.G.^c , Barry, F.^d , Lee, M.L.^d ^e , Ayala-Rivera, M.^a ^f ^g , Cheng, E.^e , Montoya, A.V.^h , Mojarro-Huang, E.^f , Gomez, P.^g , Castro, M.^f ^g , Corrales, M.^g , Sivers-Teixeira, T.^a ^g , Tran, J.L.^h , Johnson, R.^g , Ediss, C.^g , Shaby, B.ⁱ , Willis, P.^j , Sanossian, N.^a ^f , Mehta, B.^d ^h , Dutta, T.^g ^k , Razmara, A.^g ^l , Bryg, R.^m ⁿ , Song, S.^o , Towfighi, A.^a ^f ^g

^a Department of Neurology, University of Southern California (A.M.L., M.A.-R., T.S.-T., Los Angeles, Mexico
^b Department of Neurology, Washington University in St. Louis
^c Department of Neurology, Icahn School of Medicine at Mount Sinai
^d Department of Neurology (F.B., M.L.L., University of California, Los Angeles, Mexico
^e VA Greater Los Angeles Healthcare System
^f Department of Neurology, LAC+USC Medical Center (M.A.-R., Los Angeles, Mexico
^g Department of Neurology, Rancho Los Amigos National Rehabilitation Center, T.S.-T., R.J., C.E., A.T., T.D., Downey, United States
^h Department of Neurology, Harbor-UCLA Medical Center, Torrance
ⁱ Department of Neurology (B.S.), Olive View-UCLA Medical Center, CA, Italy
^j Watts Labor Community Action Committee, Los Angeles, Mexico
^k Department of Neurology, University of Maryland
^l Department of Neurology, Kaiser Permanente, Irvine
^m Department of Medicine (R.B.), University of California, Los Angeles, Mexico
ⁿ Department of Medicine (R.B.), Olive View-UCLA Medical Center, CA, Italy
^o Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, Mexico

Abstract
BACKGROUND AND PURPOSE: Self-management programs may improve quality of life and self-efficacy for stroke survivors, but participation is low. In a randomized controlled trial of a complex, multidisciplinary, team-based secondary stroke prevention intervention, we offered participants Chronic Disease Self-Management Program (CDSMP) workshops in addition to clinic visits and home visits. To enhance participation, workshops were facilitated by community health workers who were culturally and linguistically concordant with most participants and scheduled CDSMP sessions at convenient venues and times. Over time, we implemented additional strategies such as free transportation and financial incentives. In this study, we aimed to determine factors associated with CDSMP participation and attendance. METHODS: From 2014 to 2018, 18 CDSMP workshop series were offered to 241 English and Spanish-speaking individuals (age ≥40 years) with recent stroke or transient ischemic attack. Zero-inflated Poisson regression was used to identify factors associated with participation and attendance (ie, number of sessions attended) in CDSMP. Missing values were imputed using multiple imputation methods. RESULTS: Nearly one-third (29%) of intervention subjects participated in CDSMP. Moderate disability and more clinic/home visits were associated with participation. Participants with higher numbers of clinic and home visits (incidence rate ratio [IRR], 1.06 [95% CI, 1.01-1.12]), severe (IRR, 2.34 [95% CI, 1.65-3.31]), and moderately severe disability (IRR, 1.55 [95% CI, 1.07-2.23]), and who enrolled later in the study (IRR, 1.12 [95% CI, 1.08-1.16]) attended more sessions. Individuals with higher chaos scores attended fewer sessions (IRR, 0.97 [95% CI, 0.95-0.99]). CONCLUSIONS: Less than one-third of subjects enrolled in the SUCCEED (Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities) intervention participated in CDSMP; however, participation improved as transportation and financial barriers were addressed. Strategies to address social determinants of health contributing to chaos and engage individuals in healthcare may facilitate attendance. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01763203.

Author Keywords
quality of life; secondary prevention; self-efficacy; self-management

Document Type: Article
Publication Stage: Final
Source: Scopus

“Stepwise Regression and Latent Profile Analyses of Locomotor Outcomes Poststroke” (2020) Stroke

Stepwise Regression and Latent Profile Analyses of Locomotor Outcomes Poststroke
(2020) Stroke, 51 (10), pp. 3074-3082.

Hornby, T.G.^a ^b ^c , Henderson, C.E.^a ^b , Holleran, C.L.^c ^d , Lovell, L.^c ^e , Roth, E.J.^c ^e , Jang, J.H.^f

^a Department of Physical Medicine and Rehabilitation, Indiana University School of Medicine
^b Rehabilitation Hospital of Indiana
^c Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Mexico
^d Division of Physical Therapy, Department of Neurology, Washington University School of Medicine, St. Louis, United States
^e Shirley Ryan Ability Lab, Chicago, Mexico
^f Department of Biostatistics, Indiana University School of Medicine

Abstract
BACKGROUND AND PURPOSE: Previous data suggest patient demographics and clinical presentation are primary predictors of motor recovery poststroke, with minimal contributions of physical interventions. Other studies indicate consistent associations between the amount and intensity of stepping practice with locomotor outcomes. The goal of this study was to determine the relative contributions of these combined variables to locomotor outcomes poststroke across a range of patient demographics and baseline function. METHODS: Data were pooled from 3 separate trials evaluating the efficacy of high-intensity training, low-intensity training, and conventional interventions. Demographics, clinical characteristics, and training activities from 144 participants >1-month poststroke were included in stepwise regression analyses to determine their relative contributions to locomotor outcomes. Subsequent latent profile analyses evaluated differences in classes of participants based on their responses to interventions. RESULTS: Stepwise regressions indicate primary contributions of stepping activity on locomotor outcomes, with additional influences of age, duration poststroke, and baseline function. Latent profile analyses revealed 2 main classes of outcomes, with the largest gains in those who received high-intensity training and achieved the greatest amounts of stepping practice. Regression and latent profile analyses of only high-intensity training participants indicated age, baseline function, and training activities were primary determinants of locomotor gains. Participants with the smallest gains were older (≈60 years), presented with slower gait speeds (<0.40 m/s), and performed 600 to 1000 less steps/session. CONCLUSIONS: Regression and cluster analyses reveal primary contributions of training interventions on mobility outcomes in patients >1-month poststroke. Age, duration poststroke, and baseline impairments were secondary predictors. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02507466 and NCT01789853.

Author Keywords
cluster analyses; demography; heart rate; regression analysis; walk test

Document Type: Article
Publication Stage: Final
Source: Scopus

“Local Anesthesia Without Sedation During Thrombectomy for Anterior Circulation Stroke Is Associated With Worse Outcome” (2020) Stroke

Local Anesthesia Without Sedation During Thrombectomy for Anterior Circulation Stroke Is Associated With Worse Outcome
(2020) Stroke, 51 (10), pp. 2951-2959.

Benvegnù, F.^a , Richard, S.^b ^c , Marnat, G.^d , Bourcier, R.^e , Labreuche, J.^f , Anadani, M.^g , Sibon, I.^h , Dargazanli, C.ⁱ , Arquizan, C.^j , Anxionnat, R.^k ^l , Audibert, G.^m , Zhu, F.^k , Mazighi, M.ⁿ , Blanc, R.ⁿ , Lapergue, B.^o , Consoli, A.^p , Gory, B.^k ^l , ETIS Registry Investigators^q

^a University of Padova
^b Department of Neurology, Stroke Unit, CHRU-Nancy, Université de Lorraine, Nancy, F-54000, France
^c INSERM U1116, CHRU-Nancy, Nancy, F-54000, France
^d Department of Diagnostic and Interventional Neuroradiology, University Hospital of Bordeaux
^e Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nantes, L’institut du thorax, CNRS, UNIV Nantes
^f University Lille, Santé Publique: épidémiologie et Qualité des Soins, CHU Lille, EA 2694
^g Department of Neurology, Washington University School of Medicine, St Louis, United States
^h Department of Neurology, Stroke Center, University Hospital of Bordeaux
ⁱ Department of Interventional Neuroradiology, CHRU Gui de Chauliac, Montpellier, France
^j Department of Neurology, CHRU Gui de Chauliac, Montpellier, France
^k CHRU-Nancy, Department of Diagnostic and Therapeutic Neuroradiology, Université de Lorraine, Nancy, F-54000, France
^l IADI, Université de Lorraine, Nancy, F-54000, France
^m CHRU-Nancy, Department of Anesthesiology and Surgical Intensive Care, Université de Lorraine, Nancy, F-54000, France
ⁿ Department of Interventional Neuroradiology, Rothschild Foundation, Paris, United States
^o Department of Neurology, Foch Hospital, Versailles Saint-Quentin en Yvelines University, Suresnes, France
^p Department of Diagnostic and Interventional Neuroradiology, Foch Hospital, Versailles Saint-Quentin en Yvelines University, Suresnes, France

Abstract
BACKGROUND AND PURPOSE: The best anesthetic management for mechanical thrombectomy of large vessel occlusion strokes is still uncertain and could impact the quality of reperfusion and clinical outcome. We aimed to compare the efficacy and safety outcomes between local anesthesia (LA) and conscious sedation in a large cohort of acute ischemic stroke patients with anterior circulation large vessel occlusion strokes treated with mechanical thrombectomy in current, everyday clinical practice. METHODS: Patients undergoing mechanical thrombectomy for anterior large vessel occlusion strokes at 4 comprehensive stroke centers in France between January 1, 2018, and December 31, 2018, were pooled from the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France. Intention-to-treat and per-protocol analyses were used. RESULTS: Among the included 1034 patients, 762 were included in the conscious sedation group and 272 were included in the LA group. In the propensity score matched cohort, the rate of favorable outcome (90-day modified Rankin Scale score 0-2) was significantly lower in the LA group than in the conscious sedation group (40.0% versus 52.0%, matched relative risk=0.76 [95% CI, 0.60-0.97]), as well as the rate of successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3; 76.6% versus 87.1%; matched relative risk=0.88 [95% CI, 0.79-0.98]). There was no difference in procedure time between the 2 groups. In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar significant differences were found for favorable outcomes and successful reperfusion. In inverse probability of treatment weighting-propensity score-adjusted cohort, a higher rate of 90-day mortality and a lower parenchymal hematoma were observed after LA. The sensitivity analysis restricted to our per-protocol sample provided similar results in the matched- and inverse probability of treatment weighting-propensity cohorts. CONCLUSIONS: In the Endovascular Treatment in Ischemic Stroke registry mainly included patients in early time window (<6 hours), LA was associated with lower odds of favorable outcome, successful reperfusion, and higher odds of mortality compared with conscious sedation for mechanical thrombectomy of large vessel occlusion.

Author Keywords
anesthesia; conscious sedation; propensity score; reperfusion; stroke; thrombectomy

Document Type: Article
Publication Stage: Final
Source: Scopus

“Homeostatic mechanisms regulate distinct aspects of cortical circuit dynamics” (2020) Proceedings of the National Academy of Sciences of the United States of America

Homeostatic mechanisms regulate distinct aspects of cortical circuit dynamics
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (39), pp. 24514-24525.

Wu, Y.K.^a , Hengen, K.B.^b ^c , Turrigiano, G.G.^d , Gjorgjieva, J.^e ^f

^a Computation in Neural Circuits Group, Max Planck Institute for Brain Research, Germany
^b Department of Biology, Brandeis University, Waltham, United States
^c Department of Biology, Washington University in St. Louis, St. Louis, MO 63130
^d Department of Biology, Brandeis University, Waltham, MA 02454; gjorgjieva@brain.mpg.de
^e Computation in Neural Circuits Group, Max Planck Institute for Brain Research, 60438 Frankfurt, Germany; turrigiano@brandeis.edu gjorgjieva@brain.mpg.de
^f School of Life Sciences, Technical University of Munich, Freising, 85354, Germany

Abstract
Homeostasis is indispensable to counteract the destabilizing effects of Hebbian plasticity. Although it is commonly assumed that homeostasis modulates synaptic strength, membrane excitability, and firing rates, its role at the neural circuit and network level is unknown. Here, we identify changes in higher-order network properties of freely behaving rodents during prolonged visual deprivation. Strikingly, our data reveal that functional pairwise correlations and their structure are subject to homeostatic regulation. Using a computational model, we demonstrate that the interplay of different plasticity and homeostatic mechanisms can capture the initial drop and delayed recovery of firing rates and correlations observed experimentally. Moreover, our model indicates that synaptic scaling is crucial for the recovery of correlations and network structure, while intrinsic plasticity is essential for the rebound of firing rates, suggesting that synaptic scaling and intrinsic plasticity can serve distinct functions in homeostatically regulating network dynamics. Copyright © 2020 the Author(s). Published by PNAS.

Author Keywords
cortical circuits; functional correlation; homeostasis; intrinsic plasticity; synaptic scaling

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

“Treatment of an aggressive orthotopic murine glioblastoma model with combination checkpoint blockade and a multivalent neoantigen vaccine” (2020) Neuro-oncology

Treatment of an aggressive orthotopic murine glioblastoma model with combination checkpoint blockade and a multivalent neoantigen vaccine
(2020) Neuro-oncology, 22 (9), pp. 1276-1288. Cited 1 time.

Liu, C.J.^a ^b , Schaettler, M.^a ^b , Blaha, D.T.^c , Bowman-Kirigin, J.A.^a ^b , Kobayashi, D.K.^a ^b , Livingstone, A.J.^d , Bender, D.^e , Miller, C.A.^f , Kranz, D.M.^c , Johanns, T.M.^d ^e ^g , Dunn, G.P.^b ^g

^a Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Biochemistry, University of Illinois, Urbana, IL, United States
^d Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^e rew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, United States
^f McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, United States
^g Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, United States

Abstract
BACKGROUND: Although clinical trials testing immunotherapies in glioblastoma (GBM) have yielded mixed results, new strategies targeting tumor-specific somatic coding mutations, termed “neoantigens,” represent promising therapeutic approaches. We characterized the microenvironment and neoantigen landscape of the aggressive CT2A GBM model in order to develop a platform to test combination checkpoint blockade and neoantigen vaccination. METHODS: Flow cytometric analysis was performed on intracranial CT2A and GL261 tumor-infiltrating lymphocytes (TILs). Whole-exome DNA and RNA sequencing of the CT2A murine GBM was employed to identify expressed, somatic mutations. Predicted neoantigens were identified using the pVAC-seq software suite, and top-ranking candidates were screened for reactivity by interferon-gamma enzyme linked immunospot assays. Survival analysis was performed comparing neoantigen vaccination, anti-programmed cell death ligand 1 (αPD-L1), or combination therapy. RESULTS: Compared with the GL261 model, CT2A exhibited immunologic features consistent with human GBM including reduced αPD-L1 sensitivity and hypofunctional TILs. Of the 29 CT2A neoantigens screened, we identified neoantigen-specific CD8+ T-cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted (Epb4H471L and Pomgnt1R497L) and one H2-Db restricted neoantigen (Plin2G332R). Survival analysis showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with αPD-L1 treatment was superior to αPD-L1 alone. CONCLUSIONS: We identified endogenous neoantigen specific CD8+ T cells within an αPD-L1 resistant murine GBM and show that neoantigen vaccination significantly augments survival benefit in combination with αPD-L1 treatment. These observations provide important preclinical correlates for GBM immunotherapy trials and support further investigation into the effects of multimodal immunotherapeutic interventions on antiglioma immunity. KEY POINTS: 1. Neoantigen vaccines combined with checkpoint blockade may be promising treatments.2. CT2A tumors exhibit features of human GBM microenvironments.3. Differential scanning fluorimetry assays may complement in silico neoantigen prediction tools. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
glioblastoma; immunogenomics; neoantigen; personalized vaccination

Document Type: Article
Publication Stage: Final
Source: Scopus

“Phenotypic diversity in an international Cure VCP Disease registry” (2020) Orphanet Journal of Rare Diseases

Phenotypic diversity in an international Cure VCP Disease registry
(2020) Orphanet Journal of Rare Diseases, 15 (1), art. no. 267, .

Ikenaga, C.^a , Findlay, A.R.^a , Seiffert, M.^a , Peck, A.^b , Peck, N.^b , Johnson, N.E.^c , Statland, J.M.^d , Weihl, C.C.^a

^a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO 63110, United States
^b Cure VCP Disease, Inc., Americus, GA, United States
^c Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
^d Department of Neurology, University of Kansas, Medical Center, Kansas City, KS, United States

Abstract
Background: Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry. Methods: Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients’ disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019. Results: In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget’s disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness. Conclusions: The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries. © 2020 The Author(s).

Author Keywords
Cure VCP disease patient registry; Multisystem proteinopathy; Valosin-containing protein

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

“Site-specific effects of neurosteroids on gabaa receptor activation and desensitization” (2020) eLife

Site-specific effects of neurosteroids on gabaa receptor activation and desensitization
(2020) eLife, 9, art. no. e55331, pp. 1-32.

Sugasawa, Y.^a , Cheng, W.W.L.^a , Bracamontes, J.R.^a , Chen, Z.-W.^a ^b , Wang, L.^a , Germann, A.L.^a , Pierce, S.R.^a , Senneff, T.C.^a , Krishnan, K.^c , Reichert, D.E.^b ^d , Covey, D.F.^a ^b ^c ^e , Akk, G.^a ^b , Evers, A.S.^a ^b ^c

^a Department of Anesthesiology, Washington University in St. Louis, St. Louis, United States
^b Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, United States
^c Department of Developmental Biology, Washington University in St. Louis, St. Louis, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, United States
^e Department of Psychiatry, Washington University in St. Louis, St. Louis, United States

Abstract
This study examines how site-specific binding to three identified neurosteroid-binding sites in the α1β3 GABAA receptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β3(+)–α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β3 subunit, promoting receptor desensitization and the α1 subunit promoting effects that vary between neurosteroids. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid-binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs. © Sugasawa et al.

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

“Steroid Nomenclature in Inner Ear Therapy” (2020) Otology and Neurotology

Steroid Nomenclature in Inner Ear Therapy
(2020) Otology and Neurotology, 41 (6), pp. 722-726.

Salt, A.N.^a , Plontke, S.K.^b

^a Department of Otolaryngology, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, MO 63110, United States
^b Department of Otorhinolaryngology, Head and Neck Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

Abstract
Local glucocorticosteroid (“steroid”) therapy is widely used to treat the inner ears of patients with Menière’s disease, idiopathic sudden sensorineural hearing loss and in combination with cochlear implants. Applied steroids have included dexamethasone, methylprednisolone, and triamcinolone. In reality, however, this is often not true and the steroid forms commonly applied are dexamethasone-phosphate, methylprednisolone-hemisuccinate, or triamcinolone-Acetonide. In each case, the additional component is not a counter-ion but is covalently bound to the molecule to increase aqueous solubility or potency. These drug forms are approved for intravenous or intramuscular delivery and are used “off-label” in the ear. When given systemically, the molecular form of the drug is of minor importance as the drugs are rapidly metabolized. In contrast, when administered intratympanically, the exact form of the drug has a major influence on entry into perilymph and elimination from perilymph, which in turn influences distribution along the cochlear scalae. Dexamethasone-phosphate has completely different molecular properties to dexamethasone and has different pharmacokinetic properties entering and leaving perilymph. Molecular properties and perilymph pharmacokinetics also differ markedly for triamcinolone and triamcinolone-Acetonide. Methylprednisolone-hemisuccinate has completely different molecular properties to methylprednisolone. In the ear, different steroid forms cannot therefore be regarded as equivalent in terms of pharmacokinetics or efficacy. This presents a terminology problem, where in many cases the drug stated in publications may not be the form actually administered. The lack of precision in nomenclature is a serious problem for the inner ear drug delivery field and needs to be recognized. © 2020 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
Inner ear drug delivery; Intratympanic therapy; Round window membrane; Steroid

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

“Assessment of Speech Understanding after Cochlear Implantation in Adult Hearing Aid Users: A Nonrandomized Controlled Trial” (2020) JAMA Otolaryngology – Head and Neck Surgery

Assessment of Speech Understanding after Cochlear Implantation in Adult Hearing Aid Users: A Nonrandomized Controlled Trial
(2020) JAMA Otolaryngology – Head and Neck Surgery, pp. E1-E9. Cited 1 time.

Buchman, C.A.^a , Herzog, J.A.^a , McJunkin, J.L.^a , Wick, C.C.^a , Durakovic, N.^a , Firszt, J.B.^a , Kallogjeri, D.^a ^b

^a Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis, School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8115, St Louis, MO 63110, United States
^b JAMA Otolaryngology-Head and Neck Surgery

Abstract
Importance: Cochlear implants were approved for use in adults in the 1980s, but use remains low owing to a lack of awareness regarding cochlear implantation candidacy criteria and expected outcomes. There have been limited, small series examining the safety and effectiveness of cochlear implantation in adult hearing aid (HA) users with and without mild cognitive impairment (MCI). Objective: To investigate the safety and effectiveness of a single-ear cochlear implant in a group of optimized adult HA users with and without MCI across a variety of domains. Design, Setting, and Participants: In this nonrandomized controlled trial, a multicenter, prospective, repeated-measures investigation was conducted at 13 US institutions. The setting was academic and community-based cochlear implant programs. Eligible participants were 100 adults (aged >18 years) with postlinguistic onset of bilateral moderate sloping to profound or worse sensorineural hearing loss (≤20 years’ duration). Fluent English speakers underwent an optimized bilateral HA trial for at least 30 days. Individuals with aided Consonant-Vowel Nucleus-Consonant (CNC) word score in quiet of 40% or less correct in the ear to be implanted and 50% or less correct in the contralateral ear were offered cochlear implants. The first participant was enrolled on February 20, 2017, and the last participant was enrolled on May 3, 2018. The final follow-up was on December 21, 2018. Interventions: Participants received the same cochlear implant system and contralateral HA. Main Outcomes and Measures: The primary outcome measure was speech understanding in quiet (CNC word score) using both the cochlear implant and opposite ear HA. Secondary outcome measures included the following: adverse events; speech understanding in noise (AzBio signal-to-noise ratio of +10 db [+10 SNR]) Health Utilities Index Mark 3 (HUI3); Speech, Spatial, and Qualities of Hearing Questionnaire 49 (SSQ49); and Montreal Cognitive Assessment (MoCA). Results: The median age at cochlear implantation of the 96 patients included in the trial was 71 years (range, 23-91 years), and 62 patients (65%) were male. Three serious adverse events requiring revision surgery occurred, and all resolved without sequelae. By 6 months after activation, the absolute marginal mean change in CNC word score and AzBio +10 SNR was 40.5% (95% CI, 35.9%-45.0%) and 24.1% (95% CI, 18.9%-29.4%), respectively. Ninety-one percent (87 of 96) of participants had a clinically important improvement (>15%) in the CNC word score in the implant ear. Mild cognitive impairment (MoCA total score ≤25) was observed in 48 of 81 study participants (59%) at baseline. Speech perception marginal mean improvements were similar between individuals with and without baseline MCI, with values of 40.9% (95% CI, 35.2%-46.6%) and 39.6% (95% CI, 31.8%-47.4%), respectively, for CNC word score and 27.5% (95% CI, 21.0%-33.9%) and 17.8% (95% CI, 9.0%-26.6%), respectively, for AzBio +10 SNR. Statistically significant and clinically important improvements in the HUI3 and SSQ49 were evident at 6 months. Conclusions and Relevance: The findings of this nonrandomized controlled trial seem to indicate that cochlear implants are safe and effective in restoring speech understanding in both quiet and noise and improve quality of life in individuals with and without MCI. Trial Registration: ClinicalTrials.gov Identifier: NCT03007472. © 2020 Lippincott Williams and Wilkins. All rights reserved.

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

“Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs” (2020) Cell Stem Cell

Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs
(2020) Cell Stem Cell, .

Cates, K.^a ^e , McCoy, M.J.^a ^e , Kwon, J.-S.^a ^g , Liu, Y.^a , Abernathy, D.G.^a ^f , Zhang, B.^a ^b , Liu, S.^a ^b , Gontarz, P.^a ^b , Kim, W.K.^a , Chen, S.^a , Kong, W.^a ^c ^g , Ho, J.N.^a ^f , Burbach, K.F.^a ^e , Gabel, H.W.^d , Morris, S.A.^a ^b ^c , 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
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Cell-fate conversion generally requires reprogramming effectors to both introduce fate programs of the target cell type and erase the identity of starting cell population. Here, we reveal insights into the activity of microRNAs miR-9/9∗ and miR-124 (miR-9/9∗-124) as reprogramming agents that orchestrate direct conversion of human fibroblasts into motor neurons by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. We identify KLF-family transcription factors as direct target genes for miR-9/9∗-124 and show their repression is critical for erasing fibroblast fate. Subsequent gain of neuronal identity requires upregulation of a small nuclear RNA, RN7SK, which induces accessibilities of chromatin regions and neuronal gene activation to push cells to a neuronal state. Our study defines deterministic components in the microRNA-mediated reprogramming cascade. © 2020 Elsevier Inc.

Direct cell conversion generally requires reprogramming effectors to simultaneously induce target cell-type-specific fate programs and suppress starting cell identity. Yoo and colleagues reveal that microRNAs 9/9∗ and 124 direct uniform conversion of human fibroblasts by first erasing fibroblast identity and then inducing transition to a neuronal state. © 2020 Elsevier Inc.

Author Keywords
cell fate; chromatin regulation; direct conversion; epigenetics; microRNA; neuronal reprogramming; non-coding RNA; single-cell RNA-sequencing

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

“Affording autism an early brain development re-definition” (2020) Development and Psychopathology

Affording autism an early brain development re-definition
(2020) Development and Psychopathology, .

Klin, A.^a ^b ^c ^d , Micheletti, M.^e , Klaiman, C.^a ^b ^c , Shultz, S.^a ^b ^c , Constantino, J.N.^f , Jones, W.^a ^b ^c ^d

^a Marcus Autism Center, Atlanta, GA, United States
^b Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
^c Children’s Healthcare of Atlanta, Atlanta, GA, United States
^d Emory Center for Translational Social Neuroscience, Atlanta, GA, United States
^e Department of Psychology, University of Texas at Austin, Austin, TX, United States
^f Departments of Psychiatry and Pediatrics, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St Louis, MO, United States

Abstract
The national priority to advance early detection and intervention for children with autism spectrum disorder (ASD) has not reduced the late age of ASD diagnosis in the US over several consecutive Centers for Disease Control and Prevention (CDC) surveillance cohorts, with traditionally under-served populations accessing diagnosis later still. In this review, we explore a potential perceptual barrier to this enterprise which views ASD in terms that are contradicted by current science, and which may have its origins in the current definition of the condition and in its historical associations. To address this perceptual barrier, we propose a re-definition of ASD in early brain development terms, with a view to revisit the world of opportunities afforded by current science to optimize children’s outcomes despite the risks that they are born with. This view is presented here to counter outdated notions that potentially devastating disability is determined the moment a child is born, and that these burdens are inevitable, with opportunities for improvement being constrained to only alleviation of symptoms or limited improvements in adaptive skills. The impetus for this piece is the concern that such views of complex neurodevelopmental conditions, such as ASD, can become self-fulfilling science and policy, in ways that are diametrically opposed to what we currently know, and are learning every day, of how genetic risk becomes, or not, instantiated as lifetime disabilities. Copyright © The Author(s), 2020. Published by Cambridge University Press.

Author Keywords
Autism spectrum disorder; Brain development; Definition; Early diagnosis; Early intervention

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

“A Simple Brochure Improves Disposal of Unused Opioids: An Observational Cross-Sectional Study” (2020) Hand

A Simple Brochure Improves Disposal of Unused Opioids: An Observational Cross-Sectional Study
(2020) Hand, .

Bettlach, C.L.R., Hasak, J.M., Santosa, K.B., Larson, E.L., Tung, T.H., Fox, I.K., Moore, A.M., Mackinnon, S.E.

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

Abstract
Background: We evaluated the effectiveness of a simple, low-cost educational brochure in improving disposal rates of unused opioids after outpatient upper extremity surgery. Methods: This cross-sectional study enrolled eligible adult patients from a peripheral nerve clinic between November 2017 and September 2018. Patients either received or did not receive the educational brochure, which outlined a simple method to dispose of unused opioids and completed a survey at 2 weeks after surgery. We compared the proportion of patients who disposed of unused opioids after surgery between the group that had received the brochure and the group that had not. Categorical data were analyzed with χ2 test, proportions data with binomial tests, and numerical data with Mann-Whitney U test, all with a significance level of P <.05. Results: There were 339 survey respondents. Nineteen patients who did not meet inclusion criteria were excluded. Of the 320 remaining patients, 139 received the brochure and 181 did not. An additional 55 patients were excluded due to preoperative opioid use. Overall, 35.3% of recipients and 38.3% of those who did not receive the brochure used all of their prescribed opioid medication (P =.625; confidence interval = −14.6%-8.8%). Among patients with unused opioid medication, a significantly higher proportion of brochure recipients disposed of the medicine compared with those who did not receive the brochure (46.7% vs 19.6%, P <.001). Conclusions: Distribution of an educational brochure significantly improved disposal of unused opioids after surgery. This easily implemented intervention can improve disposal of unused opioids and ultimately decrease excess opioids available for diverted use in the community. © The Author(s) 2020.

Author Keywords
brochure; diagnosis; disposal; education; opioid; pain

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

“Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum” (2020) American Journal of Medical Genetics, Part A

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum
(2020) American Journal of Medical Genetics, Part A, .

Crow, Y.J.^a ^b , Marshall, H.^a , Rice, G.I.^c , Seabra, L.^b , Jenkinson, E.M.^c , Baranano, K.^d , Battini, R.^e ^f , Berger, A.^g , Blair, E.^h , Blauwblomme, T.ⁱ , Bolduc, F.^j , Boddaert, N.^k , Buckard, J.^l , Burnett, H.^m , Calvert, S.ⁿ , Caumes, R.^o , Ng, A.C.-H.^j , Chiang, D.^j , Clifford, D.B.^p , Cordelli, D.M.^q , de Burca, A.^h , Demic, N.^r , Desguerre, I.^s , De Waele, L.^t ^u , Di Fonzo, A.^v ^w , Dunham, S.R.^p , Dyack, S.^x , Elmslie, F.^y , Ferrand, M.^z , Fisher, G.^aa , Karimiani, E.G.^ab ^ac , Ghoumid, J.^o , Gibbon, F.^aa , Goel, H.^ad ^ae , Hilmarsen, H.T.^af , Hughes, I.^ag , Jacob, A.^ah ^ai , Jones, E.A.^c ^aj , Kumar, R.^ak , Leventer, R.J.^al ^am , MacDonald, S.^an , Maroofian, R.^ao , Mehta, S.G.^ap , Metz, I.^aq , Monfrini, E.^v ^w , Neumann, D.^ar , Noetzel, M.^p ^as , O’Driscoll, M.^at , Õunap, K.^au ^av , Panzer, A.^aw , Parikh, S.^ax , Prabhakar, P.^ay , Ramond, F.^az , Sandford, R.^ba , Saneto, R.^bb ^bc , Soh, C.^bd , Stutterd, C.A.^be , Subramanian, G.M.^bf , Talbot, K.^bg , Thomas, R.H.^bh , Toro, C.^bi , Touraine, R.^bb , Wakeling, E.^bj , Wassmer, E.^bk , Whitney, A.^bl , Livingston, J.H.^bm , O’Keefe, R.T.^c , Badrock, A.P.^a

^a Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
^b Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France
^c Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
^d Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^e Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
^f Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy
^g Department of Neuropediatrics, Kliniken Nordoberpfalz AG, Germany
^h Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
ⁱ Paediatric Neurosurgery Department, Necker-Enfants Malades Hospital, APHP, Université de Paris, Paris, France
^j Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
^k Paediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HP, University de Paris, INSERM U1163, Institut Imagine, Paris, France
^l Department of Neuropediatrics, Sozialpädiatrisches Zentrum am EVK Düsseldorf, Düsseldorf, Germany
^m HNEkidsRehab, Newcastle, NSW, Australia
ⁿ Neurosciences Department, Queensland Children’s Hospital, Brisbane, QLD, Australia
^o Clinique de Génétique Guy Fontaine, CHU Lille, Lille, France
^p Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^q Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Italy
^r Department of Neurology, Vestfold Hospital, Tønsberg, Norway
^s Department of Paediatric Neurology, Université de Paris, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
^t Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium
^u Department of Development and Regeneration, KU Leuven, Leuven, Belgium
^v Foundation IRCCS Ca ‘Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
^w Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
^x Division of Medical Genetics, Dalhousie University, Halifax, NS, Canada
^y South West Thames Regional Genetics Service, St George’s, University of London, London, United Kingdom
^z Department of Neurology, CHRU Nancy, Nancy, France
^aa Department of Paediatric Neurology, University Hospital of Wales, Cardiff, United Kingdom
^ab Molecular and Clinical Sciences Institute, St. George’s University of London, London, United Kingdom
^ac Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
^ad Hunter Genetics, Hunter New England Local Health District, Waratah, Australia
^ae School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
^af Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway
^ag Department of Paediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
^ah Department of Neurology, The Walton Centre NHS Trust, Liverpool, United Kingdom
^ai Department of Neurology, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
^aj Clinical Genetic Service, Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
^ak Department of Paediatric Neurology, Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom
^al Department of Neurology Royal Children’s Hospital, Murdoch Children’s Research Institute, Melbourne, Australia
^am Department of Paediatrics, University of Melbourne, Melbourne, Australia
^an Maritime Medical Genetics, IWK Health Centre, Halifax, NS, Canada
^ao Department of Neuromuscular Disorders, University College London Queen Square Institute of Neurology, London, United Kingdom
^ap East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom
^aq Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany
^ar Klinikum Wilhelmshaven, Department of Neuropediatrics, Germany
^as Department of Pediatrics, Washington University School of Medicine, St. Louis, WA, United States
^at West Midlands Regional Clinical Genetics Service, Birmingham Health Partners, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, United Kingdom
^au Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
^av Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
^aw Paediatric Neurology, DRK Kliniken Berlin-Westend, Berlin, Germany
^ax Neurogenetics Program, Center for Pediatric Neurology, Neurosciences Institute, Cleveland Clinic, Cleveland, OH, United States
^ay Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
^az Service de Génétique, CHU-Hôpital Nord, Saint Etienne, France
^ba Academic Department of Medical Genetics, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
^bb Neuroscience Institute, Division of Paediatric Neurology, Seattle Children’s Hospital and University of Washington, Seattle, WA, United States
^bc Department of Neurology, Seattle Children’s Hospital and University of Washington, Seattle, WA, United States
^bd Radiology Department, Manchester University Foundation NHS Trust, Manchester, United Kingdom
^be Victorian Clinical Genetics Service, Parkville, Australia
^bf Department of Paediatric Neurology, John Hunter Children’s Hospital, New Lambton Heights, NSW, Australia
^bg Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom
^bh Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
^bi NIH Undiagnosed Diseases Program (UDP), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
^bj North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
^bk Department of Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, United Kingdom
^bl University Hospital Southampton NHS Foundation Trust, Department of Paediatric Neurology, Southampton, United Kingdom
^bm Department of Paediatric Neurology, Leeds General Infirmary, Leeds, United Kingdom

Abstract
Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5′ end and 3′ extension of precursor-U8. There was no obvious genotype–phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3′ end processing of precursor-U8. © 2020 Wiley Periodicals LLC

Author Keywords
C/D box snoRNA U8; coats plus; Labrune syndrome; leukoencephalopathy with calcifications and cysts; ribosomopathy; SNORD118

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

“Associations between Prenatal Cannabis Exposure and Childhood Outcomes: Results from the ABCD Study” (2020) JAMA Psychiatry

Associations between Prenatal Cannabis Exposure and Childhood Outcomes: Results from the ABCD Study
(2020) JAMA Psychiatry, .

Paul, S.E.^a , Hatoum, A.S.^b , Fine, J.D.^a , Johnson, E.C.^b , Hansen, I.^a , Karcher, N.R.^a , Moreau, A.L.^a , Bondy, E.^a , Qu, Y.^a , Carter, E.B.^c , Rogers, C.E.^b , Agrawal, A.^b , Barch, D.M.^a ^b , Bogdan, R.^a

^a Department of Psychological and Brain Sciences, Washington University in St Louis, One Brookings Drive, CB 1125 Psychological and Brain Sciences Bldg, St Louis, MO 63130, United States
^b Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, United States
^c Department of Obstetrics and Gynecology, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy. Objective: To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring. Design, Setting, and Participants: In this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018. Exposure: Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy. Main Outcomes and Measures: Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables. Results: Among 11489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |β| > 0.02; all false discovery rate [FDR]-corrected P <.03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |β| > 0.02; all FDR-corrected P <.04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all β > 0.02; FDR-corrected P <.02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |β| < 0.02; FDR-corrected P >.70). Conclusions and Relevance: This study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged. © 2020 American Medical Association. All rights reserved.

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

“Physical Therapy for Iatrogenic Facial Paralysis: A Systematic Review” (2020) JAMA Otolaryngology – Head and Neck Surgery

Physical Therapy for Iatrogenic Facial Paralysis: A Systematic Review
(2020) JAMA Otolaryngology – Head and Neck Surgery, .

Wamkpah, N.S.^a , Jeanpierre, L.^b , Lieu, J.E.C.^a , Del Toro, D.^c , Simon, L.E.^d , Chi, J.J.^e

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Graduate of Wayne State University School of Medicine, Detroit, MI, United States
^c Currently A Medical Student at Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Bernard Becker Medical Library, Washington University School of Medicine in St Louis, St Louis, MO, United States
^e Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8115, St Louis, MO 63110, United States

Abstract
Importance: Facial paralysis (FP) after surgery has substantial functional, emotional, and financial consequences. Most iatrogenic FP is managed by watchful waiting, with the expectation of facial function recovery. A potential treatment is physical therapy (PT). Objective: To investigate whether noninvasive PT compared with no PT or other intervention improves facial nerve outcomes in adults with iatrogenic FP. Evidence Review: Patients with noniatrogenic FP, facial reanimation surgery, and invasive adjunctive treatments (acupuncture or botulinum toxin injection) were excluded. A systematic review was conducted for records discussing iatrogenic FP and PT; a search for these records was performed using Ovid MEDLINE (1946-2019), Embase (1947-2019), Scopus (1823-2019), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform (2004-2019), and ClinicalTrials.gov (1997-2019). The references of all the included articles were also assessed for eligible studies. All human participant, English-language study designs with at least 2 cases were included. Quality assessment was performed using the Methodological Index for Non-randomized Studies (MINORS) and the revised Cochrane Risk of Bias 2 (RoB 2) tool for randomized controlled trials. All search strategies were completed on May 16, 2019, and again on October 1, 2019. Findings: Fifteen studies (7 of which were retrospective cohort studies) and 313 patients with iatrogenic FP were included in the systematic review. Most iatrogenic FP (166 patients [53%]) was associated with parotidectomy; traditional PT (ie, facial massage) was the most common intervention (196 patients [63%]). The use of various facial grading systems and inconsistent reporting of outcomes prevented direct comparison of PT types. Conclusions and Relevance: Because of heterogeneity in reported outcomes of facial nerve recovery, definitive conclusions were unable to be made regarding the association between PT and outcomes of iatrogenic FP. Physical therapy probably has benefit and is associated with no harm in patients with iatrogenic FP. © 2020 American Medical Association. All rights reserved.

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

“Functional insights from biophysical study of TREM2 interactions with apoE and Aβ1-42” (2020) Alzheimer’s and Dementia

Functional insights from biophysical study of TREM2 interactions with apoE and Aβ1-42
(2020) Alzheimer’s and Dementia, .

Kober, D.L.^a ^b , Stuchell-Brereton, M.D.^c , Kluender, C.E.^b ^d , Dean, H.B.^e ^f , Strickland, M.R.^g , Steinberg, D.F.^b , Nelson, S.S.^b , Baban, B.^c , Holtzman, D.M.^g ^h ⁱ , Frieden, C.^c ⁱ , Alexander-Brett, J.^b ^j , Roberson, E.D.^e , Song, Y.^f , Brett, T.J.^b ^c ⁱ ^k

^a Molecular Microbiology and Microbial Pathogenesis Program, United States
^b Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, United States
^c Department of Biochemistry and Molecular Biophysics, United States
^d Biochemistry, Biophysics, and Structural Biology Program, Washington University School of Medicine, St. Louis, MO, United States
^e Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Departments of Neurology and Neurobiology, University of Alabama at BirminghamAL, United States
^f Department of Biomedical Engineering, University of Alabama at BirminghamAL, United States
^g Department of Neurology, United States
^h Charles F. and Joanne Knight Alzheimer’s Disease Research Center, United States
ⁱ Hope Center for Neurological Disorders, United States
^j Department of Pathology and Immunology, United States
^k Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on microglia that also can become soluble (sTREM2). How TREM2 engages different ligands remains poorly understood. Methods: We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 and sTREM2 interactions with apolipoprotein E (apoE) and monomeric amyloid beta (Aβ) (mAβ42). Results: TREM2 engagement of apoE was protein mediated with little effect of lipidation, showing slight affinity differences between isoforms (E4 > E3 > E2). Another family member, TREML2, did not bind apoE. Disease-linked TREM2 variants within a “basic patch” minimally impact apoE binding. Instead, TREM2 uses a unique hydrophobic surface to bind apoE, which requires the apoE hinge region. TREM2 and sTREM2 directly bind mAβ42 and potently inhibit Aβ42 polymerization, suggesting a potential role for soluble sTREM2 in preventing AD pathogenesis. Discussion: These findings demonstrate that TREM2 has at least two ligand-binding surfaces that might be therapeutic targets and uncovers a potential function for sTREM2 in directly inhibiting Aβ polymerization. © 2020 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease; amyloid beta; apolipoprotein E; microglia; neurodegeneration; neuroinflammation; TREM2

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

“The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi-tensor model vs. diffusion orientation distribution function” (2020) NMR in Biomedicine

The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi-tensor model vs. diffusion orientation distribution function
(2020) NMR in Biomedicine, .

Ye, Z.^a , Gary, S.E.^b , Sun, P.^a , Mustafi, S.M.^c , Glenn, G.R.^d , Yeh, F.-C.^e , Merisaari, H.^f , Song, C.^g , Yang, R.^h , Huang, G.-S.ⁱ , Kao, H.-W.ⁱ , Lin, C.-Y.^j , Wu, Y.-C.^c , Jensen, J.H.^k ^l ^m , Song, S.-K.^a

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, United States
^c Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States
^d Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, United States
^e Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^f Department of Diagnostic Radiology, University of Turku, Turku, Finland
^g Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^h Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
ⁱ Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
^j GE Healthcare, Taipei, Taiwan
^k Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, United States
^l Department of Neuroscience, Medical University of South Carolina, Charleston, SC, United States
^m Center for Biomedical Imaging, Medical University of South Carolina, Charleston, SC, United States

Abstract
Diffusion tensor imaging (DTI) has been employed for over 2 decades to noninvasively quantify central nervous system diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of coexisting inflammation, edema and crossing nerve fibers. We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Furthermore, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI) and neurite orientation dispersion and density imaging to resolve fiber crossing, in reference to the gold standard angles measured from structural images. DTI-computed diffusivities and fractional anisotropy were significantly confounded by gel-mimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionally, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when compared with the gold standard (r2 = 0.92, P = 1.9 × 10−9, bias = 3.9°). Small crossing angles and edema significantly impact the diffusion orientation distribution function, making DKI, GQI and QBI less accurate in detecting and estimating fiber crossing angles. Lastly, we used diffusion tensor ellipsoids to demonstrate that DBSI resolves the confounds of edema and crossing fibers in the peritumoral edema region from a patient with lung cancer metastasis, while DTI failed. In summary, DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution compared with DKI, QBI and GQI. © 2020 John Wiley & Sons, Ltd.

Author Keywords
angular resolution; brain tumor; diffusion basis spectrum imaging; diffusion MRI; diffusion orientation distribution function; white matter tractography

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

“Association between delivering live-born twins and acute psychiatric illness within 1 year of delivery” (2020) American Journal of Obstetrics and Gynecology

Association between delivering live-born twins and acute psychiatric illness within 1 year of delivery
(2020) American Journal of Obstetrics and Gynecology, .

Lewkowitz, A.K.^a , López, J.D.^b , Keller, M.^b , Rosenbloom, J.I.^c , Macones, G.A.^e , Olsen, M.A.^c ^d , Cahill, A.G.^e

^a Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI, United States
^b Departments of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States
^d Surgery, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Women’s Health, Dell Medical School, The University of Texas at Austin, Austin, TX, United States

Abstract
Background: Having twins is associated with more depressive symptoms than having singletons. However, the association between having twins and psychiatric morbidity requiring emergency department visit or inpatient hospitalization is less well known. Objective: This study aimed to determine whether women have higher risk of having a psychiatric diagnosis at an emergency department visit or inpatient admission in the year after having twins vs singletons. Study Design: This retrospective cohort study used International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedure codes within the Florida State Inpatient Database and State Emergency Department Database, which have an encrypted identifier allowing nearly all inpatient and emergency department encounters statewide to be linked to the medical record. The first delivery of Florida residents at the age of 13 to 55 years from 2005 to 2014 was included, regardless of parity; women with International Classification of Diseases, Ninth Revision, Clinical Modification coding for psychiatric illness or substance misuse during pregnancy or for stillbirth or higher-order gestations were excluded. The exposure was an International Classification of Diseases, Ninth Revision, Clinical Modification code during delivery hospitalization of live-born twins. The primary outcome was an International Classification of Diseases, Ninth Revision, Clinical Modification code during an emergency department encounter or inpatient admission within 1 year of delivery for a psychiatric morbidity composite (suicide attempt, depression, anxiety, posttraumatic stress disorder, psychosis, acute stress reaction, or adjustment disorder). The secondary outcome was drug or alcohol use or dependence within 1 year of delivery. We compared outcomes after delivery of live-born twins with singletons using multivariable logistic regression adjusting for sociodemographic and medical factors. We tested for interactions between independent variables in the primary model and conducted sensitivity analyses stratifying women by insurance type and presence of severe intrapartum morbidity or medical comorbidities. Results: A total of 17,365 women who had live-born twins and 1,058,880 who had singletons were included. Within 1 year of birth, 1.6% of women delivering twins (n=270) and 1.6% of women delivering singletons (n=17,236) had an emergency department encounter or inpatient admission coded for psychiatric morbidity (adjusted odds ratio, 1.00; 95% confidence interval, 0.88–1.14). Coding for drug or alcohol use or dependence in an emergency department encounter or inpatient admission in the year after twin vs singleton delivery was also similar (n=96 [0.6%] vs n=6222 [0.6%]; adjusted odds ratio, 1.11; 95% confidence interval, 0.91–1.36). However, women with public health insurance were more likely to be coded for drug or alcohol use or dependence after twin than singleton delivery (n=75 [1.2%] vs n=4858 [1.0%]; adjusted odds ratio, 1.27; 95% confidence interval, 1.01–1.60). Women with ≥1 medical comorbidity, severe maternal morbidity, or low income also had an increased risk of psychiatric morbidity after twin delivery (comorbidities, n=7438 [42.8%]; adjusted odds ratio, 1.30; 95% confidence interval, 1.25–1.34; severe maternal morbidity, n=940 [5.4%]; adjusted odds ratio, 1.65; 95% confidence interval, 1.49–1.81; lowest income quartile, n=4409 [26.8%]; adjusted odds ratio, 1.31; 95% confidence interval, 1.23–1.40; second-lowest income quartile, n=4770 [29.0%]; adjusted odds ratio, 1.34; 95% confidence interval, 1.26–1.43). Conclusion: Overall, diagnostic codes for psychiatric illness or substance misuse in emergency department visits or hospital admissions in the year after twin vs singleton delivery are similar. However, women with who are low income or have public health insurance, comorbidities, or severe maternal morbidity are at an increased risk of postpartum psychiatric morbidity after twin vs singleton delivery. © 2020 Elsevier Inc.

Author Keywords
postpartum anxiety; postpartum depression; postpartum psychiatric illness; postpartum substance misuse; twins

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

“In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves” (2020) Molecular Neurobiology

In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves
(2020) Molecular Neurobiology, .

Jeon, Y.^a , Shin, J.E.^b , Kwon, M.^a , Cho, E.^a , Cavalli, V.^c ^d ^e , Cho, Y.^a

^a Department of Life Sciences, Lab of Axon Regeneration & Degeneration, Korea University, Anam-ro 145, Seongbuk-gu, Seoul, 02841, South Korea
^b Department of Molecular Neuroscience, Dong-A University College of Medicine, Busan, 49201, South Korea
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Neurons are vulnerable to injury, and failure to activate self-protective systems after injury leads to neuronal death. However, sensory neurons in dorsal root ganglions (DRGs) mostly survive and regenerate their axons. To understand the mechanisms of the neuronal injury response, we analyzed the injury-responsive transcriptome and found that Stc2 is immediately upregulated after axotomy. Stc2 is required for axon regeneration in vivo and in vitro, indicating that Stc2 is a neuronal factor regulating axonal injury response. The application of the secreted stanniocalcin 2 to injured DRG neurons promotes regeneration. Stc2 thus represents a potential secretory protein with a feedback function regulating regeneration. Finally, the in vivo gene delivery of STC2 increases regenerative growth after injury in peripheral nerves in mice. These results suggest that Stc2 is an injury-responsive gene required for axon regeneration and a potential target for developing therapeutic applications. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Axotomy; Calcium ion; Degeneration; Regeneration; Stanniocalcin 2; Stc2

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