Arts & Sciences Brown School McKelvey School of Engineering School of Law School of Medicine Weekly Publications

WashU weekly Neuroscience publications

"Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial" (2020) The Lancet Neurology

Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial
(2020) The Lancet Neurology, 19 (12), pp. 998-1009. Cited 1 time.

Wolinsky, J.S.a , Arnold, D.L.b c , Brochet, B.d , Hartung, H.-P.e , Montalban, X.f , Naismith, R.T.g , Manfrini, M.h , Overell, J.h , Koendgen, H.h , Sauter, A.h , Bennett, I.h , Hubeaux, S.h , Kappos, L.i , Hauser, S.L.j

a Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
b Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
c NeuroRx Research, Montreal, QC, Canada
d Department of Neurology, University of Bordeaux, Bordeaux, France
e Department of Neurology, Universitätsklinikum Düsseldorf, Center of Neurology and Neuropsychiatry, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
f Neurology-Neuroimmunology Department and Neurorehabilitation Unit, Vall d’Hebron University Hospital, Barcelona, Spain
g Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
h F Hoffmann-La Roche, Basel, Switzerland
i Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Basel, Switzerland
j Department of Neurology, University of California, San Francisco, CA, United States

Abstract
Background: The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO. Methods: ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18–55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0–6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing. Findings: From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9–21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1–20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [–0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6–16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8–13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71–243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41–13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45–4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO. Interpretation: Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods. Funding: F Hoffmann-La Roche. © 2020 Elsevier Ltd

Funding details
Bayer FundBF
Novartis
Multiple Sclerosis FoundationMSF
Biogen
National Multiple Sclerosis Society
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries
Innosuisse – Schweizerische Agentur für InnovationsförderungInnosuisse
European CommissionEC
Universitätsspital BaselUHB
F. Hoffmann-La Roche

Document Type: Article
Publication Stage: Final
Source: Scopus

"The cost of a single concussion in American high school football: A retrospective cohort study" (2020) Concussion

The cost of a single concussion in American high school football: A retrospective cohort study
(2020) Concussion, 5 (4), art. no. 0012, . 

Yengo-Kahn, A.M.a b , Kelly, P.D.a , Liles, D.C.a , McKeithan, L.J.b c , Grisham, C.J.b c , Khan, M.S.d , Lee, T.b , Kuhn, A.W.b e , Bonfield, C.M.a b , Zuckerman, S.L.a b

a Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States
b Vanderbilt Sport Concussion Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States
c School of Medicine, Vanderbilt University, Nashville, TN 37232, United States
d School of Medicine, Meharry Medical College, Nashville, TN 37208, United States
e Department of Orthopedic Surgery, Washington University in St Louis, St Louis, MO 63110, United States

Abstract
Aim: The potential financial burden of American football-related concussions (FRC) is unknown. Our objective was to describe the healthcare costs associated with an FRC and determine factors associated with increased costs. Methodology/results: A retrospective cohort study of concussed high school football players presenting between November 2017 and March 2020 was undertaken; 144 male high school football players were included. Total costs were about $115,000, for an average direct healthcare cost of $800.10/concussion. Visiting the emergency department (β = 502.29, 95% CI: 105.79-898.61; p = 0.01), the initial post-concussion symptom scale score (β = 0.39, 95% CI: 0.11-0.66; p = 0.01) and a post-concussion syndrome diagnosis (β = 670.37, 95% CI: 98.96-1241.79; p = 0.02) were each independently associated with total costs. Conclusion: A granular understanding of cost-driving factors associated with FRC is the first step in understanding the cost-effectiveness of prevention and treatment methods. © 2020 Aaron Yengo-Kahn.

Author Keywords
American football;  healthcare costs;  post-concussion symptom scale;  post-concussion syndrome;  sport-related concussion

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

"Natural bladder filling alters resting brain function at multiple spatial scales: a proof-of-concept MAPP Network Neuroimaging Study" (2020) Scientific Reports

Natural bladder filling alters resting brain function at multiple spatial scales: a proof-of-concept MAPP Network Neuroimaging Study
(2020) Scientific Reports, 10 (1), art. no. 19901, . 

Mawla, I.a b , Schrepf, A.b , Ichesco, E.b , Harte, S.E.b , Klumpp, D.J.c , Griffith, J.W.d , Strachan, E.e , Yang, C.C.f , Lai, H.g h , Andriole, G.h , Magnotta, V.A.i , Kreder, K.j , Clauw, D.J.b , Harris, R.E.b , Clemens, J.Q.k , Landis, J.R.l , Mullins, C.m , Rodriguez, L.V.n , Mayer, E.A.o , Kutch, J.J.p

a Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
b Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, United States
c Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
d Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
e Department of Psychiatry, University of Washington, Seattle, WA, United States
f Department of Urology, University of Washington, Seattle, WA, United States
g Department of Anesthesiology, Washington University, St. Louis, MO, United States
h Division of Urologic Surgery, Department of Surgery, Washington University, St. Louis, MO, United States
i Department of Radiology, University of Iowa, Iowa City, IA, United States
j Department of Urology, University of Iowa, Iowa City, IA, United States
k Department of Urology, University of Michigan, Ann Arbor, MI, United States
l Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
m National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
n Department of Urology, University of Southern California, Los Angeles, CA, United States
o G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, CA, United States
p Division of Biokinesiology and Physical Therapy, University of Southern California, 1540 E. Alcazar Street, CHP 155, Los Angeles, CA 90033, United States

Abstract
Neural circuitry regulating urine storage in humans has been largely inferred from fMRI during urodynamic studies driven by catheter infusion of fluid into the bladder. However, urodynamic testing may be confounded by artificially filling the bladder repeatedly at a high rate and examining associated time-locked changes in fMRI signals. Here we describe and test a more ecologically-valid paradigm to study the brain response to bladder filling by (1) filling the bladder naturally with oral water ingestion, (2) examining resting state fMRI (rs-fMRI) which is more natural since it is not linked with a specific stimulus, and (3) relating rs-fMRI measures to self-report (urinary urge) and physiologic measures (voided volume). To establish appropriate controls and analyses for future clinical studies, here we analyze data collected from healthy individuals (N = 62) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants orally ingested approximately 350 mL of water, and had a 10 min “fuller bladder” rs-fMRI scan approximately 1 h later. A second 10 min “empty bladder” rs-fMRI scan was conducted immediately following micturition. We examined multiple spatial scales of brain function, including local activity, circuits, and networks. We found changes in brain function distributed across micturition loci (e.g., subregions of the salience, sensorimotor, and default networks) that were significantly related to the stimulus (volume) and response (urinary urge). Based on our results, this paradigm can be applied in the future to study the neurobiological underpinnings of urologic conditions. © 2020, The Author(s).

Funding details
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK082342, DK082315, DK082370, DK082344, DK121724, DK082345, DK110669, DK082316, DK082325

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

"Medications for Opioid Use Disorder Demonstrate Clear Benefit for Patients With Invasive Infections" (2020) Journal of Addiction Medicine

Medications for Opioid Use Disorder Demonstrate Clear Benefit for Patients With Invasive Infections
(2020) Journal of Addiction Medicine, 14 (6), p. 518. 

Marks, L.R., Liang, S.Y., Durkin, M.J., Martin, M., White, K.D., See, I.

Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO Division of Hospital Medicine, Zuckerberg San Francisco General Hospital and the Department of Medicine, University of California, San Francisco School of Medicine, San Francisco, CA Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GA

Document Type: Article
Publication Stage: Final
Source: Scopus

"Utility of shape evolution and displacement in the classification of chronic multiple sclerosis lesions" (2020) Scientific Reports

Utility of shape evolution and displacement in the classification of chronic multiple sclerosis lesions
(2020) Scientific Reports, 10 (1), art. no. 19560, . 

Okuda, D.T.a , Moog, T.M.a , McCreary, M.a , Bachand, J.N.b , Wilson, A.c , Wright, K.a , Winkler, M.D.a , Ramos, O.G.a , Blinn, A.P.d , Wang, Y.c , Stanley, T.c , Pinho, M.C.e , Newton, B.D.f , Guo, X.c

a Department of Neurology, Neuroinnovation Program, Multiple Sclerosis and Neuroimmunology Imaging Program, Clinical Center for Multiple Sclerosis, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8806, United States
b School of Medicine, UT Southwestern Medical Center, 6011 Harry Hines Blvd., Dallas, TX 75235, United States
c Department of Computer Science, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080, United States
d Washington University, 1 Brookings Dr., St. Louis, MO 63130, United States
e Department of Radiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75019, United States
f Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada

Abstract
The accurate recognition of multiple sclerosis (MS) lesions is challenged by the high sensitivity and imperfect specificity of MRI. To examine whether longitudinal changes in volume, surface area, 3-dimensional (3D) displacement (i.e. change in lesion position), and 3D deformation (i.e. change in lesion shape) could inform on the origin of supratentorial brain lesions, we prospectively enrolled 23 patients with MS and 11 patients with small vessel disease (SVD) and performed standardized 3-T 3D brain MRI studies. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion morphology and disease state. A total of 248 MS and 157 SVD lesions were studied. Individual MS lesions demonstrated significant decreases in volume &lt; 3.75mm3 (p = 0.04), greater shifts in 3D displacement by 23.4% with increasing duration between MRI time points (p = 0.007), and greater transitions to a more non-spherical shape (p &lt; 0.0001). If 62.2% of lesions within a given MRI study had a calculated theoretical radius &gt; 2.49 based on deviation from a perfect 3D sphere, a 92.7% in-sample and 91.2% out-of-sample accuracy was identified for the diagnosis of MS. Longitudinal 3D shape evolution and displacement characteristics may improve lesion classification, adding to MRI techniques aimed at improving lesion specificity. © 2020, The Author(s).

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

"Motor Control: Memory and Motor Control in the Dorsal Striatum" (2020) Current Biology

Motor Control: Memory and Motor Control in the Dorsal Striatum
(2020) Current Biology, 30 (22), pp. R1366-R1368. 

Kravitz, A.V., Matikainen-Ankney, B.A.

Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, CSRB 5536, Saint Louis, MO 63110, United States

Abstract
The dorsal striatum is important for motor control. Yet whether that control encompasses procedural memories, kinematic refinement, or both is still debated. A recent study has shed new light on the role of the dorsal striatum in learned movement sequences and the effort required to refine them. © 2020 Elsevier Inc.

The dorsal striatum is important for motor control. Yet whether that control encompasses procedural memories, kinematic refinement, or both is still debated. A recent study has shed new light on the role of the dorsal striatum in learned movement sequences and the effort required to refine them. © 2020 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Cold Nights, City Lights: Artificial Light at Night Reduces Photoperiodically Induced Diapause in Urban and Rural Populations of Aedes albopictus (Diptera: Culicidae)" (2020) Journal of Medical Entomology

Cold Nights, City Lights: Artificial Light at Night Reduces Photoperiodically Induced Diapause in Urban and Rural Populations of Aedes albopictus (Diptera: Culicidae)
(2020) Journal of Medical Entomology, 57 (6), pp. 1694-1699. 

Westby, K.M., Medley, K.A.

Tyson Research Center, Washington University in Saint Louis, Eureka, MO

Abstract
As the planet becomes increasingly urbanized, it is imperative that we understand the ecological and evolutionary consequences of urbanization on species. One common attribute of urbanization that differs from rural areas is the prevalence of artificial light at night (ALAN). For many species, light is one of the most important and reliable environmental cues, largely governing the timing of daily and seasonal activity patterns. Recently, it has been shown that ALAN can alter behavioral, phenological, and physiological traits in diverse taxa. For temperate insects, diapause is an essential trait for winter survival and commences in response to declining daylight hours in the fall. Diapause is under strong selection pressure in the mosquito, Aedes albopictus (Skuse); local adaptation and rapid evolution has been observed along a latitudinal cline. It is unknown how ALAN affects this photosensitive trait or if local adaptation has occurred along an urbanization gradient. Using a common garden experiment, we experimentally demonstrated that simulated ALAN reduces diapause incidence in this species by as much as 40%. There was no difference, however, between urban and rural demes. We also calculated diapause incidence from wild demes in urban areas to determine whether wild populations exhibited lower than predicted incidence compared to estimates from total nocturnal darkness. In early fall, lower than predicted diapause incidence was recorded, but all demes reached nearly 100% diapause before terminating egg laying. It is possible that nocturnal resting behavior in vegetation limits the amount of ALAN exposure this species experiences potentially limiting local adaptation. © The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Aedes albopictus;  artificial light at night;  common garden;  diapause;  urban ecology

Document Type: Article
Publication Stage: Final
Source: Scopus

"Effects of personality on the developmental trajectories of academic burnout among Korean medical students" (2020) PeerJ

Effects of personality on the developmental trajectories of academic burnout among Korean medical students
(2020) PeerJ, 8, art. no. e10362, . 

Chae, H.a , Cloninger, C.R.b , Lee, S.J.c

a School of Korean Medicine, Pusan National University, Busan, South Korea
b Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychology, Kyungsung University, Busan, South Korea

Abstract
Background: Medical students have a high risk of burnout from tremendous academic stress, and previous cross-sectional studies have explained this risk from the personality perspective. However, the relationship between complex personality profiles and developmental trajectory of burnout has not been delineated yet. Methods: The longitudinal changes in burnout were measured by the Maslach Burnout Inventory-Student Survey (MBI-SS) at baseline (1st week), mid-term (9th week), and end-term (17th week), and personality was examined at baseline using the Temperament and Character Inventory (TCI). Latent trajectory groups based on the MBI-SS total scores were extracted using the General Growth Mixture Model (GGMM), and significant differences in personality profiles among the latent groups were identified using profile analysis and Analysis of Variance. Results: Three burnout trajectory groups of high-increasing (HI), moderate-increasing (MI), and low-stable (LS) were identified, and these groups had significantly different TCI subscale profiles. The HI group had the highest score in Harm-Avoidance (HA) and lowest score in Self-Directedness (SD), and the MI group had a higher score in HA and lower scores in SD and Cooperativeness (CO) when compared to the LS group with the lowest score in HA and highest scores in SD and CO. Conclusion: The current study showed that the HA, SD, and CO subscales of the TCI might explain the longitudinal development of academic burnout in medical students. Prevention of burnout and promotion of well-being in medical education concerning personality are discussed. Copyright 2020 Chae et al.

Author Keywords
Academic burnout;  Character Inventory (TCI);  Developmental trajectory;  General Growth Mixture Model (GGMM);  Maslach Burnout Inventory-Student Survey (MBI-SS);  Medical student;  Temperament

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

"Plasma neurofilament light predicts mortality in patients with stroke" (2020) Science Translational Medicine

Plasma neurofilament light predicts mortality in patients with stroke
(2020) Science Translational Medicine, 12 (569), art. no. eaay1913, . 

Gendron, T.F.a b , Badi, M.K.c , Heckman, M.G.d , Jansen-West, K.R.a , Vilanilam, G.K.c , Johnson, P.W.d , Burch, A.R.a , Walton, R.L.a , Ross, O.A.a b e , Brott, T.G.c , Miller, T.M.f , Berry, J.D.g , Nicholson, K.A.g , Wszolek, Z.K.c , Oskarsson, B.E.c , Sheth, K.N.h , Sansing, L.H.i , Falcone, G.J.h , Cucchiara, B.L.j , Meschia, J.F.c , Petrucelli, L.a b

a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
b Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, United States
c Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, United States
d Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, United States
e Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, United States
f Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States
g Harvard Medical School, Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
h Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University, School of Medicine, New Haven, CT 06520, United States
i Division of Vascular Neurology, Department of Neurology, Yale University, School of Medicine, New Haven, CT 06520, United States
j Department of Neurology, University of Pennsylvania, University of Pennsylvania Medical Center, Philadelphia, PA 19104, United States

Abstract
Given the heterogeneity of stroke brain injury, there is a clear need for a biomarker that determines the degree of neuroaxonal injury across stroke types. We evaluated whether blood neurofilament light (NFL) would fulfill this purpose for patients with acute cerebral infarction (ACI; N = 227), aneurysmal subarachnoid hemorrhage (aSAH; N = 58), or nontraumatic intracerebral hemorrhage (ICH; N = 29). We additionally validated our findings in two independent cohorts of patients with ICH (N = 96 and N = 54) given the scarcity of blood biomarker studies for this deadliest stroke type. Compared to healthy individuals (N = 79 and N = 48 for the discovery and validation cohorts, respectively), NFL was higher for all stroke types. NFL associated with radiographic markers of brain tissue damage. It correlated with the extent of early ischemic injury in patients with ACI, hemorrhage severity in patients with aSAH, and intracranial hemorrhage volume in patients with ICH. In all patients, NFL independently correlated with scores from the NIH Stroke Scale, the modified Rankin Scale, and the Mini-Mental State Examination at blood draw, which respectively assess neurological, functional, and cognitive status. Furthermore, higher NFL concentrations independently associated with 3- or 6-month functional disability and higher all-cause mortality. These data support NFL as a uniform method to estimate neuroaxonal injury and forecast mortality regardless of stroke mechanism. As a prognostic biomarker, blood NFL has the potential to assist with planning supportive and rehabilitation services and improving clinical trial efficiency for stroke therapeutics and devices. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Funding details
Mayo Clinic
National Institutes of HealthNIHK76AG059992, U24NS107136, U24NS107215, U01NS106513, P01NS084974, R01NR01833, R01NS075209, R35NS097273, P30AG021342, R03NS112859, P01NS099114, R01NS110721, U01NS113445
Mayo Foundation for Medical Education and ResearchMFMER

Document Type: Article
Publication Stage: Final
Source: Scopus

"Multivariate lesion-behavior mapping of general cognitive ability and its psychometric constituents" (2020) Journal of Neuroscience

Multivariate lesion-behavior mapping of general cognitive ability and its psychometric constituents
(2020) Journal of Neuroscience, 40 (46), pp. 8924-8937. 

Bowren, M., Jr.a , Adolphs, R.b , Bruss, J.c , Manzel, K.c , Corbetta, M.d e , Tranel, D.a c , Boes, A.D.f

a Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA 52242, United States
b Division of Humanities and Social Sciences, California Technical Institute, Pasadena, CA 91125, United States
c Department of Neurology, Carver College of Medicine, Iowa City, IA 52242, United States
d Department of Neuroscience, Venetian Institute of Molecular Medicine, Padova Neuroscience Center, University of Padua, Padova PD, 32122, Italy
e Departments of Neurology, Radiology, and Neuroscience, Washington University, School of Medicine, St. Louis, MO 63110, United States
f Departments of Neurology Psychiatry, and Pediatrics, Carver College of Medicine, Iowa City, IA 52242, United States

Abstract
General cognitive ability, or general intelligence (g), is central to cognitive science, yet the processes that constitute it remain unknown, in good part because most prior work has relied on correlational methods. Large-scale behavioral and neuroanatomical data from neurologic patients with focal brain lesions can be leveraged to advance our understanding of the key mechanisms of g, as this approach allows inference on the independence of cognitive processes along with elucidation of their respective neuroanatomical substrates. We analyzed behavioral and neuroanatomical data from 402 humans (212 males; 190 females) with chronic, focal brain lesions. Structural equation models (SEMs) demonstrated a psychometric isomorphism between g and working memory in our sample (which we refer to as g/Gwm), but not between g and other cognitive abilities. Multivariate lesion-behavior mapping analyses indicated that g and working memory localize most critically to a site of converging white matter tracts deep to the left temporo-parietal junction. Tractography analyses demonstrated that the regions in the lesion-behavior map of g/Gwm were primarily associated with the arcuate fasciculus. The anatomic findings were validated in an independent cohort of acute stroke patients (n = 101) using model-based predictions of cognitive deficits generated from the Iowa cohort lesion-behavior maps. The neuroanatomical localization of g/ Gwm provided the strongest prediction of observed g in the new cohort (r = 0.42, p, 0.001), supporting the anatomic specificity of our findings. These results provide converging behavioral and anatomic evidence that working memory is a key mechanism contributing to domain-general cognition. © 2020 the authors

Author Keywords
Brain networks;  General cognitive ability;  General intelligence;  Lesion method;  Psychometrics;  Working memory

Funding details
1 P50 MH094258, 1 R21 MH120441-01
National Institutes of HealthNIH1S10OD025025-01
Ministero dell’Istruzione, dell’Università e della RicercaMIUR
National Institute of Neurological Disorders and StrokeNINDS1 R01 NS114405-01, NS095741
National Institute of General Medical SciencesNIGMST32GM108540

Document Type: Article
Publication Stage: Final
Source: Scopus

"Prepronociceptin-Expressing Neurons in the Extended Amygdala Encode and Promote Rapid Arousal Responses to Motivationally Salient Stimuli" (2020) Cell Reports

Prepronociceptin-Expressing Neurons in the Extended Amygdala Encode and Promote Rapid Arousal Responses to Motivationally Salient Stimuli
(2020) Cell Reports, 33 (6), art. no. 108362, . 

Rodriguez-Romaguera, J.a b , Ung, R.L.b c , Nomura, H.a b , Otis, J.M.a b , Basiri, M.L.b c , Namboodiri, V.M.K.a b , Zhu, X.a b , Robinson, J.E.b c , van den Munkhof, H.E.a b , McHenry, J.A.a b , Eckman, L.E.H.a b , Kosyk, O.a b , Jhou, T.C.d , Kash, T.L.c e , Bruchas, M.R.f , Stuber, G.D.a b c g

a Department of Psychiatry, University of North Carolina, Chapel Hill, NC 72599, United States
b Neuroscience Center, University of North Carolina, Chapel Hill, NC 72599, United States
c Neuroscience Curriculum, University of North Carolina, Chapel Hill, NC 72599, United States
d Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, United States
e Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 72599, United States
f Department of Anesthesiology, Washington University Pain Center, Department of Neuroscience, Division of Biology & Biomedical Sciences; and Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
g Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 72599, United States

Abstract
Rodriguez-Romaguera et al. find an ensemble of neurons within the extended amygdala (BNST) that expresses the prepronociceptin gene and functions to encode the rapid arousal responses that are triggered by motivational stimuli. © 2020 The Authors

Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (PnocBNST) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that PnocBNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in PnocBNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that PnocBNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli. © 2020 The Authors

Author Keywords
and pupillometry;  anxiety-like behavior;  aversion;  BNST;  hyperarousal;  reward

Funding details
National Institute on Drug AbuseNIDAR37-DA032750, R01-DA038168, F32-DA041184
Children’s Tumor FoundationCTF016-01-006
Brain and Behavior Research FoundationBBRF
National Heart, Lung, and Blood InstituteNHLBIR01-HL150836
University of North CarolinaUNCP30-NS045892
National Institute of Mental HealthNIMHR01-MH112355, F30-MH115693, T32-MH093315, F32-MH113327, K99-MH115165, K99-MH118422
National Institute of Neurological Disorders and StrokeNINDST32-NS007431

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

"Sourcing photoreceptor-like cells for treating vision loss" (2020) New England Journal of Medicine

Sourcing photoreceptor-like cells for treating vision loss
(2020) New England Journal of Medicine, 383 (19), pp. 1888-1890. 

Apte, R.S.

Departments of Ophthalmology, Developmental Biology, and Medicine, Washington University in St. Louis School of Medicine, St. Louis, United States

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

"Food addiction and psychosocial adversity: Biological embedding, contextual factors, and public health implications" (2020) Nutrients

Food addiction and psychosocial adversity: Biological embedding, contextual factors, and public health implications
(2020) Nutrients, 12 (11), art. no. 3521, pp. 1-26. 

Wiss, D.A.a , Avena, N.b c , Gold, M.d

a Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, United States
b Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
c Department of Psychology, Princeton University, Princeton, NJ 08540, United States
d School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
The role of stress, trauma, and adversity particularly early in life has been identified as a contributing factor in both drug and food addictions. While links between traumatic stress and substance use disorders are well documented, the pathways to food addiction and obesity are less established. This review focuses on psychosocial and neurobiological factors that may increase risk for addiction-like behaviors and ultimately increase BMI over the lifespan. Early childhood and adolescent adversity can induce long-lasting alterations in the glucocorticoid and dopamine systems that lead to increased addiction vulnerability later in life. Allostatic load, the hypothalamic-pituitary-adrenal axis, and emerging data on epigenetics in the context of biological embedding are highlighted. A conceptual model for food addiction is proposed, which integrates data on the biological embedding of adversity as well as upstream psychological, social, and environmental factors. Dietary restraint as a feature of disordered eating is discussed as an important contextual factor related to food addiction. Discussion of various public health and policy considerations are based on the concept that improved knowledge of biopsychosocial mechanisms contributing to food addiction may decrease stigma associated with obesity and disordered eating behavior. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Adverse childhood experience;  Biopsychosocial;  Dopamine;  Early life adversity;  Eating disorder;  Epigenetics;  Food addiction;  Obesity;  Stress;  Trauma

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

"The landscape of novel therapeutics and challenges in glioblastoma multiforme: Contemporary state and future directions" (2020) Pharmaceuticals

The landscape of novel therapeutics and challenges in glioblastoma multiforme: Contemporary state and future directions
(2020) Pharmaceuticals, 13 (11), art. no. 389, pp. 1-26.

Khaddour, K.a b , Johanns, T.M.b , Ansstas, G.b 

a Division of Hematology and Oncology, University of Illinois at Chicago, Chicago, IL 60612, United States
b Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
CART therapy;  Glioblastoma multiforme;  Immune checkpoint inhibitors;  Immunosuppressive;  Immunotherapy;  Oncolytic virus;  Vaccine

Funding details
National Institutes of HealthNIHK12 CA167540
National Cancer InstituteNCI
National Institutes of HealthNIH

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

"Variability of T2-relaxation times of healthy lumbar intervertebral discs is more homogeneous within an individual than across healthy individuals" (2020) American Journal of Neuroradiology

Variability of T2-relaxation times of healthy lumbar intervertebral discs is more homogeneous within an individual than across healthy individuals
(2020) American Journal of Neuroradiology 41 (11), pp. 2160-2165. 

Sharma, A.a , Walk, R.E.b , Tang, S.Y.b c , Eldaya, R.a , Owen, P.J.d , Belavy, D.L.d

a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, United States
d School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia

Abstract
Background and Purpose: When one uses T2 relaxometry to classify lumbar intervertebral discs as degenerated, it is unclear whether the normative data should be based on other intervertebral discs from the same individual or from a pool of extraneous controls. This study aimed to explore the extent of intra- versus intersubject variation in the T2 times of healthy intervertebral discs. Materials and Methods: Using prospectively acquired T2-relaxometry data from 606 intervertebral discs in 101 volunteers without back pain (47 men, 54 women) in a narrow age range (25-35 years), we calculated intra- and intersubject variation in T2 times of intervertebral discs graded by 2 neuroradiologists on the Pfirrmann scale. Intrasubject variation of intervertebral discs was assessed relative to other healthy intervertebral discs (Pfirrmann grade, ≤2) in the same individual. Multiple intersubject variability measures were calculated using healthy extraneous references ranging from a single randomly selected intervertebral disc to all healthy extraneous intervertebral discs, without and with segmental stratification. These variability measures were compared for healthy and degenerated (Pfirrmann grade ≤3) intervertebral discs. Results: The mean T2 values of healthy (493/606, 81.3%) and degenerated intervertebral discs were 121.1 ± 22.5 ms and 91.5 ± 18.6 ms, respectively (P<.001). The mean intrasubject variability for healthy intervertebral discs was 9.8 ± 10.7 ms, lower than all intersubject variability measures (P<.001), and provided the most pronounced separation for healthy and degenerated intervertebral discs. Among intersubject variability measures, using all segment-matched healthy discs as references provided the lowest variability (P<.001). Conclusions: Normative measures based on the T2 times of healthy intervertebral discs from the same individual are likely to provide the most discriminating means of identifying degenerated intervertebral discs on the basis of T2 relaxometry. © 2020 American Society of Neuroradiology. All rights reserved.

Funding details
National Institutes of HealthNIHK01AR069116, R01AR074441

Document Type: Article
Publication Stage: Final
Source: Scopus

"Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal Slices ex vivo and 24S-Hydroxycholesterol Levels in Mice in vivo" (2020) Frontiers in Molecular Neuroscience

Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal Slices ex vivo and 24S-Hydroxycholesterol Levels in Mice in vivo
(2020) Frontiers in Molecular Neuroscience, 13, art. no. 568641, . 

Popiolek, M.a , Izumi, Y.b , Hopper, A.T.a , Dai, J.a , Miller, S.a , Shu, H.-J.b , Zorumski, C.F.b , Mennerick, S.b

a Sage Therapeutics, Cambridge, MA, United States
b Department of Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, Washington University, University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous system is CYP46A1, a brain enriched enzyme responsible for metabolism of cholesterol into 24S-hydroxycholesterol. Inhibition of this enzyme may negatively modulate NMDARs as 24S-hydroxycholesterol was shown to enhance NMDAR function. In addition, alterations of local cholesterol or other changes mediated by CYP46A1 activity could have important influences on central nervous system function. Here we demonstrate that humans and mice display brain region specific and similar CYP46A1 and 24S-hydroxycholesterol distribution. Treatment with distinct classes of CYP46A1 inhibitors led to central 24S-hydroxycholesterol reduction in vivo and ablation of long term depression in hippocampal slices. Our results suggest that rodents show similarity to humans for studying the impact of CYP46A1 inhibitors and that rapid, local modulation of oxysterols can be achieved through CYP46A1 inhibition. © Copyright © 2020 Popiolek, Izumi, Hopper, Dai, Miller, Shu, Zorumski and Mennerick.

Author Keywords
24S-hydroxycholesterol;  cholesterol;  CYP46A1;  LTD;  NMDAR

Funding details
Sage Therapeutics

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

"Human iPSC-Derived Neuronal Cells From CTBP1-Mutated Patients Reveal Altered Expression of Neurodevelopmental Gene Networks" (2020) Frontiers in Neuroscience

Human iPSC-Derived Neuronal Cells From CTBP1-Mutated Patients Reveal Altered Expression of Neurodevelopmental Gene Networks
(2020) Frontiers in Neuroscience, 14, art. no. 562292, . 

Vijayalingam, S.a , Ezekiel, U.R.b , Xu, F.c , Subramanian, T.a , Geerling, E.a , Hoelscher, B.c , San, K.b , Ganapathy, A.b , Pemberton, K.c , Tycksen, E.d , Pinto, A.K.a , Brien, J.D.a , Beck, D.B.e , Chung, W.K.f , Gurnett, C.A.g , Chinnadurai, G.a

a Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Edward A. Doisy Research Center, St. LouisMO, United States
b Department of Clinical Health Sciences, Doisy College of Health Science, Saint Louis University School of Medicine, Saint Louis, MO, United States
c Department of Biology and Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, MO, United States
d McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
e National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
f Department of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
A recurrent de novo mutation in the transcriptional corepressor CTBP1 is associated with neurodevelopmental disabilities in children (Beck et al., 2016, 2019; Sommerville et al., 2017). All reported patients harbor a single recurrent de novo heterozygous missense mutation (p.R342W) within the cofactor recruitment domain of CtBP1. To investigate the transcriptional activity of the pathogenic CTBP1 mutant allele in physiologically relevant human cell models, we generated induced pluripotent stem cells (iPSC) from the dermal fibroblasts derived from patients and normal donors. The transcriptional profiles of the iPSC-derived “early” neurons were determined by RNA-sequencing. Comparison of the RNA-seq data of the neurons from patients and normal donors revealed down regulation of gene networks involved in neurodevelopment, synaptic adhesion and anti-viral (interferon) response. Consistent with the altered gene expression patterns, the patient-derived neurons exhibited morphological and electrophysiological abnormalities, and susceptibility to viral infection. Taken together, our studies using iPSC-derived neuron models provide novel insights into the pathological activities of the CTBP1 p.R342W allele. © Copyright © 2020 Vijayalingam, Ezekiel, Xu, Subramanian, Geerling, Hoelscher, San, Ganapathy, Pemberton, Tycksen, Pinto, Brien, Beck, Chung, Gurnett and Chinnadurai.

Author Keywords
CtBP;  de novo mutation;  intellectual and developmental disabilities;  interferon response;  transcriptional repression;  transcriptome analysis

Funding details
JPB Foundation
National Science FoundationNSF1916563
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Saint Louis UniversitySLU
National Institutes of HealthNIHU54 HD087011
National Center for Advancing Translational SciencesNCATS
UL1TR002345
Simons Foundation Autism Research InitiativeSFARI

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

"Evaluation of Naturalistic Driving Behavior Using In-Vehicle Monitoring Technology in Preclinical and Early Alzheimer’s Disease" (2020) Frontiers in Psychology

Evaluation of Naturalistic Driving Behavior Using In-Vehicle Monitoring Technology in Preclinical and Early Alzheimer’s Disease
(2020) Frontiers in Psychology, 11, art. no. 596257, . 

Davis, J.D.a b , Babulal, G.M.c , Papandonatos, G.D.d , Burke, E.M.b , Rosnick, C.B.c , Ott, B.R.e , Roe, C.M.c

a Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, United States
b Neuropsychology Program, Department of Psychiatry, Rhode Island Hospital, Providence, RI, United States
c Department of Neurology, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biostatistics, Brown University, Providence, RI, United States
e Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States

Abstract
Cognitive impairment is a significant risk factor for hazardous driving among older drivers with Alzheimer’s dementia, but little is known about how the driving behavior of mildly symptomatic compares with those in the preclinical, asymptomatic phase of Alzheimer’s disease (AD). This study utilized two in-car technologies to characterize driving behavior in symptomatic and preclinical AD. The goals of this pilot study were to (1) describe unsafe driving behaviors in individuals with symptomatic early AD using G-force triggered video capture and (2) compare the driving habits of these symptomatic AD drivers to two groups of cognitively normal drivers, those with and those without evidence of cerebral amyloidosis (CN/A+ and CN/A−) using a global positioning system (GPS) datalogger. Thirty-three drivers (aged 60+ years) were studied over 3 months. G-force triggered video events captured instances of near-misses/collisions, traffic violations, risky driver conduct, and driving fundamentals. GPS data were sampled every 30 s and all instances of speeding, hard braking, and sudden acceleration were recorded. For the early AD participants, video capture identified driving unbelted, late response, driving too fast for conditions, traffic violations, poor judgment, and not scanning intersections as the most frequently occurring safety errors. When evaluating driving using the GPS datalogger, hard breaking events occurred most frequently on a per trip basis across all three groups. The CN/A+ group had the lowest event rate across all three event types with lower instances of speeding. Slower psychomotor speed (Trail Making Part A) was associated with fewer speeding events, more hard acceleration events, and more overall events. GPS tracked instances of speeding were correlated with total number of video-captured near-collisions/collisions and driving fundamentals. Results demonstrate the utility of electronic monitoring to identify potentially unsafe driving events in symptomatic and preclinical AD. Results suggest that drivers with preclinical AD may compensate for early, subtle cognitive changes by driving more slowly and cautiously than healthy older drivers or those with cognitive impairment. Self-regulatory changes in driving behavior appear to occur in the preclinical phase of AD, but safety concerns may not arise until symptoms of cognitive impairment emerge and the ability to self-monitor declines. © Copyright © 2020 Davis, Babulal, Papandonatos, Burke, Rosnick, Ott and Roe.

Author Keywords
Alzheimer’s disease;  driving;  driving mobility;  naturalistic;  preclinical Alzheimer’s disease;  technology

Funding details
National Institute on AgingNIAR01AG056466, P01AG003991, R01AG067428, P50AG005681, P01AG026276

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

"The Language of Recollection in Support of Recognition Memory Decisions" (2020) Zeitschrift fur Psychologie / Journal of Psychology

The Language of Recollection in Support of Recognition Memory Decisions
(2020) Zeitschrift fur Psychologie / Journal of Psychology, 228 (4), pp. 291-295. Cited 1 time.

Dobbins, I.G.a , Kantner, J.b

a Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO 63130-4899, United States
b Department of Psychology, California State University, Northridge, CA, United States

Abstract
Researchers often augment recognition memory decisions with confidence ratings or reports of Remember and Know experiences. While important, these ratings are subject to variation in interpretation and misspecification. Here we review recent findings from a verbal reports as data procedure in which subjects justify, in their own words, the basis of recognition. The application of a language pattern classifier to these justifications demonstrates that it: (a) is sensitive to the presence of recollection, (b) tracks individual differences in recognition accuracy, and (c) generalizes in a theoretically meaningful way to justifications from a separate experiment. More broadly, this approach should be useful for any cognitive decision task in which competing theories suggest different explicit bases underlying the judgments, or for which the explicit versus implicit basis of the decisions is in question. © 2020 Hogrefe Publishin.

Author Keywords
language classifier;  recognition memory;  recollection;  statistical learning

Document Type: Article
Publication Stage: Final
Source: Scopus

"Reactivity of Judgments of Learning in a Levels-of-Processing Paradigm" (2020) Zeitschrift fur Psychologie / Journal of Psychology

Reactivity of Judgments of Learning in a Levels-of-Processing Paradigm
(2020) Zeitschrift fur Psychologie / Journal of Psychology, 228 (4), pp. 278-290. Cited 1 time.

Tekin, E., Roediger, H.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Drive, St Louis, MO 63130-4899, United States

Abstract
Recent studies have shown that judgments of learning (JOLs) are reactive measures in paired-associate learning paradigms. However, evidence is scarce concerning whether JOLs are reactive in other paradigms. In old/new recognition experiments, we investigated the reactivity effects of JOLs in a levels-of-processing (LOP) paradigm. In Experiments 1 and 2, for each word, subjects saw a yes/no orienting question followed by the target word and a response. Then, they either did or did not make a JOL. The yes/no questions were about target words appearances, rhyming properties, or category memberships. In Experiment 3, for each word, subjects gave a pleasantness rating or counted the letter ? e . Our results revealed that JOLs enhanced recognition across all orienting tasks in Experiments 1 and 2, and for the ecounting task in Experiment 3. This reactive effect was salient for shallow tasks, attenuating but not eliminating ? the LOP effect after making JOLs. We conclude that JOLs are reactive in LOP paradigms and subjects encode words more effectively when providing JOLs. © 2020 Hogrefe Publishin.

Author Keywords
judgments of learning;  levels of processing;  metacognition;  reactivity

Document Type: Article
Publication Stage: Final
Source: Scopus

"How Public Opinion Can Inform Cognitive Enhancement Regulation" (2020) AJOB Neuroscience

How Public Opinion Can Inform Cognitive Enhancement Regulation
(2020) AJOB Neuroscience, 11 (4), pp. 245-247. 

McCall, I.C.a , McIntosh, T.b , Dubljević, V.a

a North Carolina State University, United States
b Washington University in Saint Louis, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

"Morality, Valuation and Coalitional Psychology" (2020) AJOB Neuroscience

Morality, Valuation and Coalitional Psychology
(2020) AJOB Neuroscience, 11 (4), pp. 287-289. 

Boyer, P.

Washington University in St. Louis, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

"The Utility of Diffusion-weighted Imaging Sequences to Differentiate Aggressive From Benign Intracranial Neoplasms" (2020) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and) European Academy of Otology and Neurotologyrdion

The Utility of Diffusion-weighted Imaging Sequences to Differentiate Aggressive From Benign Intracranial Neoplasms
(2020) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and) European Academy of Otology and Neurotology, 41 (8), pp. e1069-e1071. 

Chen, S.Y., Shew, M., Durakovic, N., Buchman, C., Herzog, J.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

"Live Neuron High-Content Screening Reveals Synaptotoxic Activity in Alzheimer Mouse Model Homogenates" (2020) Scientific Reports

Live Neuron High-Content Screening Reveals Synaptotoxic Activity in Alzheimer Mouse Model Homogenates
(2020) Scientific Reports, 10 (1), p. 3412. 

Jiang, H.a , Esparza, T.J.a b c , Kummer, T.T.a , Zhong, H.d , Rettig, J.e , Brody, D.L.a c f

a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St Louis, Missouri, 63110, USA
b Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, United States
c National Institute of Neurological Disorders and Stroke, 10 Center Drive, Bethesda, MD 20892, United States
d Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, Oregon, 97239, USA
e Department of Physiology, Saarland University, Center for Integrative Physiology and Molecular Medicine (CIPMM), Building 48, Homburg, 66421, Germany
f Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States

Abstract
Accurate quantification of synaptic changes is essential for understanding the molecular mechanisms of synaptogenesis, synaptic plasticity, and synaptic toxicity. Here we demonstrate a robust high-content imaging method for the assessment of synaptic changes and apply the method to brain homogenates from an Alzheimer’s disease mouse model. Our method uses serial imaging of endogenous fluorescent labeled presynaptic VAMP2 and postsynaptic PSD95 in long-term cultured live primary neurons in 96 well microplates, and uses automatic image analysis to quantify the number of colocalized mature synaptic puncta for the assessment of synaptic changes in live neurons. As a control, we demonstrated that our synaptic puncta assay is at least 10-fold more sensitive to the toxic effects of glutamate than the MTT assay. Using our assay, we have compared synaptotoxic activities in size-exclusion chromatography fractioned protein samples from 3xTg-AD mouse model brain homogenates. Multiple synaptotoxic activities were found in high and low molecular weight fractions. Amyloid-beta immunodepletion alleviated some but not all of the synaptotoxic activities. Although the biochemical entities responsible for the synaptotoxic activities have yet to be determined, these proof-of-concept results demonstrate that this novel assay may have many potential mechanistic and therapeutic applications.

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

"Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus" (2020) JAMA Pediatrics

Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus
(2020) JAMA Pediatrics, . 

Sullivan, W.a , Reeves, B.C.a , Duy, P.Q.a , Nelson-Williams, C.b , Dong, W.b , Jin, S.C.c , Kahle, K.T.a

a Department of Neurosurgery, Yale School of Medicine, New Haven, CA, United States
b Department of Genetics, Yale University School of Medicine, New Haven, CA, United States
c Department of Genetics, Washington University School of Medicine, St Louis, MI, United States

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

"Neuroticism predicts informant reported cognitive problems through health behaviors" (2020) Aging and Mental Health

Neuroticism predicts informant reported cognitive problems through health behaviors
(2020) Aging and Mental Health, . 

Best, R.D., Cruitt, P.J., Oltmanns, T.F., Hill, P.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: Personality traits have been linked to cognitive impairment, though work is needed to understand the mechanisms involved. Research also needs to consider alternative markers of cognitive impairment, such as informant report measures. The aim of the current study was to examine the role of health behaviors and social engagement as mediators for the relationship between personality and informant reported cognitive problems. It was expected that neuroticism would predict cognitive problems through negative health behaviors, while conscientiousness might predict cognitive problems through positive health behaviors. Methods: Using data from the St. Louis Personality and Aging Network study at three time points, spanning approximately 2.27years (N= 829, M age = 65.95), correlations were computed between the Big Five personality traits and health behaviors at wave 1, social engagement at wave 2, and informant reported cognitive problems at wave 3. Mediation tests examined whether health behaviors and social engagement explained the relationships found between personality and informant reported cognitive problems. Results: Findings showed that neuroticism at wave 1 significantly predicted informant reported cognitive problems at wave 3 and that health behaviors, specifically wellness maintenance, partially explained this relationship. No significant associations were found between informant reported cognitive problems and conscientiousness, agreeableness, extraversion, openness, or social engagement. Conclusion: This study supports claims that neuroticism predicts later cognitive problems and expands on previous literature by demonstrating this relationship using an informant report measure. Furthermore, we found that health behaviors, and specifically wellness maintenance, account for some of the relationship between neuroticism and informant reported cognitive problems. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
age associated memory problems;  cognitive functioning;  Psychological and social aspects

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

"Assessing the Reliability of Reported Medical History in Older Adults" (2020) Journal of Alzheimer's Disease

Assessing the Reliability of Reported Medical History in Older Adults
(2020) Journal of Alzheimer’s Disease, 78 (2), pp. 643-652. 

Day, G.S.a , Long, A.b c , Morris, J.C.c d

a Mayo Clinic, Department of Neurology, Jacksonville, FL, United States
b Hendrix College, Conway, AR, United States
c Charles F. and Joanne Knight Alzheimer Disease Research Center, St. Louis, MO, United States
d Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background: Age-associated increases in medical complexity, frailty, and cognitive impairment may compromise reliable reporting of medical history. Objective: To evaluate the influence of increasing age and cognitive impairment on concordance between reported history of stroke and cerebral infarction, and reported history of diabetes and elevated hemoglobinA1c in community-dwelling older adults. Methods: The association between participant-specific factors and accurate reporting of stroke or diabetes was evaluated using multivariable logistic regression in 1,401 participants enrolled in longitudinal studies of memory and aging, including 425 participants with dementia (30.3%). Stroke and diabetes were selected as index variables as gold standard measures of both were obtained in all participants: magnetic resonance neuroimaging for cerebral infarcts and hemoglobinA1c (≥6.5%) for diabetes. Results: Concordance between reported history of stroke and imaging-confirmed cerebral infarction was low (sensitivity: 17.4%, 8/46; specificity: 97.9%, 799/816). Small infarcts were strongly associated with inaccurate reporting (OR = 265.8; 95% CI: 86.2, 819.4), suggesting that occult/silent infarcts contributed to discordant reporting. Reporting accuracy was higher concerning diabetes (sensitivity: 83.5%, 147/176; specificity: 96.2%, 1100/1143). A history of hypertension (OR = 2.3; 95% CI: 1.3, 4.2), higher hemoglobinA1c (OR = 1.9; 95% CI: 1.5, 2.4), and hemoglobinA1c compatible with impaired glucose tolerance (OR = 3.1; 95% CI 1.8, 5.3) associated with increased odds of discordant reporting. Cognitive impairment and increased age were not independently associated with reliable reporting. Conclusion: Factors beyond advancing age and cognitive impairment appear to drive discordance in reported medical history in older participants. Objective testing for cerebral infarcts or diabetes should be performed when relevant to diagnostic or therapeutic decisions in clinical and research settings. © 2020 – IOS Press and the authors. All rights reserved.

Author Keywords
Alzheimer’s disease;  cerebral infarct;  cognitive impairment;  dementia;  diabetes;  medical history;  reporting accuracy;  stroke

Funding details
National Institutes of HealthNIHP01AG02627, P01AG003991, K23AG064029, P50AG005681
Washington University School of Medicine in St. Louis

Document Type: Review
Publication Stage: Final
Source: Scopus

"Review and Consensus on Pharmacogenomic Testing in Psychiatry" (2020) Pharmacopsychiatry

Review and Consensus on Pharmacogenomic Testing in Psychiatry
(2020) Pharmacopsychiatry, . 

Bousman, C.A.a b c d , Bengesser, S.A.e , Aitchison, K.J.f , Amare, A.T.g h , Aschauer, H.i , Baune, B.T.d j k , Asl, B.B.f , Bishop, J.R.l , Burmeister, M.m , Chaumette, B.n o , Chen, L.-S.p , Cordner, Z.A.q , Deckert, J.r , Degenhardt, F.s t , Delisi, L.E.u , Folkersen, L.v , Kennedy, J.L.w x , Klein, T.E.y , McClay, J.L.z , McMahon, F.J.aa , Musil, R.ab , Saccone, N.L.p , Sangkuhl, K.y , Stowe, R.M.ac , Tan, E.-C.ad , Tiwari, A.K.w x , Zai, C.C.w x , Zai, G.w x , Zhang, J.ae , Gaedigk, A.af , Müller, D.J.w x

a Department of Medical Genetics, Psychiatry, Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW 228 HMRB, Calgary, AB T2N 4N1, Canada
b Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
c Alberta Children’s Hospital Research Institute, Calgary, AB, Canada
d Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia
e Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Austria
f Department of Psychiatry, Medical Genetics and the Neuroscience, Mental Health Institute, University of Alberta, Edmonton, AB, Canada
g Department of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia
h South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
i Biopsychosocial Corporation (BioPsyC), Non-profit Association, Vienna, Austria
j Department of Psychiatry and Psychotherapy, University of Münster, Germany
k Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
l Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, University of Minnesota Medical School, Minneapolis, MN, United States
m Michigan Neuroscience Institute, Department of Computational Medicine and Bioinformatics, Human Genetics and Psychiatry, University of Michigan, Ann Arbor, MI, United States
n Institute of Psychiatry and Neuroscience of Paris, GHU Paris Psychiatrie and Neurosciences, University of Paris, Paris, France
o Department of Psychiatry, McGill University, Montreal, Canada
p Department of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, United States
q Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
r Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, Würzburg, Germany
s Institute of Human Genetics, University of Bonn, School of Medicine, University Hospital Bonn, Bonn, Germany
t Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany
u Department of Psychiatry, Harvard Medical School, Cambridge Health Alliance, Cambridge, MA, United States
v Institute of Biological Psychiatry, Capital Region Hospitals, Copenhagen, Denmark
w Department of Psychiatry, University of Toronto, 250 College Street R132, Toronto, ON M5T 1R8, Canada
x Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
y Department of Biomedical Data Science, Stanford University, Stanford, CA, United States
z Department of Pharmacotherapy and Outcome Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA, United States
aa Human Genetics Branch, National Institute of Mental Health, Bethesda, MD, United States
ab Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany
ac Department of Psychiatry and Neurology (Medicine), University of British Columbia, United States
ad KK Research Centre, KK Women’s and Children’s Hospital, Singapore, Singapore
ae Department of Psychiatry, Weill Cornell Medical College, New York-Presbyterian Westchester Division, White Plains, NY, United States
af Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Kansas City, Kansas City, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States

Abstract
The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry. © 2020 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
pharmacogenetics;  precision medicine;  prescribing

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

"Correction: Identifying and validating subtypes within major psychiatric disorders based on frontal–posterior functional imbalance via deep learning (Molecular Psychiatry, (2020), 10.1038/s41380-020-00892-3)" (2020) Molecular Psychiatry

Correction: Identifying and validating subtypes within major psychiatric disorders based on frontal–posterior functional imbalance via deep learning (Molecular Psychiatry, (2020), 10.1038/s41380-020-00892-3)
(2020) Molecular Psychiatry, . 

Chang, M.a , Womer, F.Y.b , Gong, X.c , Chen, X.d , Tang, L.e , Feng, R.a , Dong, S.d , Duan, J.e , Chen, Y.e , Zhang, R.e , Wang, Y.e , Ren, S.a , Wang, Y.c , Kang, J.f , Yin, Z.e , Wei, Y.e , Wei, S.a , Jiang, X.a , Xu, K.a , Cao, B.g , Zhang, Y.h , Zhang, W.i j , Tang, Y.e , Zhang, X.d k l , Wang, F.a e

a Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c State Key Laboratory of Genetic Engineering and Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, China
d School of Computer Science and Engineering, Northeastern University, Shenyang, Liaoning, China
e Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
f Shanghai Center for Mathematical Science, Fudan University, Shanghai, China
g Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
h Department of Psychiatry, College of Medicine University of Saskatchewan Ellis Hall, Royal University Hospital, Saskatoon, SK, Canada
i Department of Computer Science and Engineering, Washington University, St. Louis, MO, United States
j Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
k School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China
l Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, The Author(s).

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

"Central Nervous System Infections in the Immunocompromised Adult Presenting to the Emergency Department" (2020) Emergency Medicine Clinics of North America

Central Nervous System Infections in the Immunocompromised Adult Presenting to the Emergency Department
(2020) Emergency Medicine Clinics of North America, . 

Stephens, R.J.a , Liang, S.Y.b c

a Department of Emergency Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
b Department of Emergency Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
c Department of Internal Medicine, Division of Infectious Disease, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
Over the past 2 decades, the population of immunocompromised patients has increased dramatically in the United States. These patients are at elevated risk for both community-acquired and opportunistic central nervous system infections. We review the most common and serious central nervous system pathogens affecting these patients and outline a diagnostic and therapeutic approach to their management in the emergency department. We recommend a broad diagnostic evaluation, including neuroimaging and cerebrospinal fluid studies where appropriate, empiric antimicrobial therapy, and early involvement of subspecialists to provide comprehensive care for these complex patients. © 2020 Elsevier Inc.

Author Keywords
CNS infection;  HIV;  Immunocompromise;  Meningitis;  Transplant

Funding details
Foundation for Barnes-Jewish Hospital
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATSUL1TR002345

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

"Neuroprotective versus Neuroinflammatory Roles of Complement: From Development to Disease" (2020) Trends in Neurosciences

Neuroprotective versus Neuroinflammatory Roles of Complement: From Development to Disease
(2020) Trends in Neurosciences, . 

Kanmogne, M.a , Klein, R.S.a b c

a Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Complement proteins are ancient components of innate immunity that have emerged as crucial regulators of neural networks. We discuss these roles in the context of the CNS development, acute CNS viral infections, and post-infectious and noninfectious CNS disorders, with an emphasis on microglia-mediated loss of synapses. Despite extensive examples that implicate classical complement proteins and their receptors in CNS dysfunction, recent data suggest that they exert neuroprotective roles in CNS homeostasis through continued refinement of synaptic connections. Thorough understanding of the mechanisms involved in these processes may lead to novel targets for the treatment of CNS diseases involving aberrant complement-mediated synapse loss. © 2020 Elsevier Ltd

Author Keywords
astrocytes;  microglia;  neurodegenerative disease;  synapse;  viral encephalitis

Funding details
National Multiple Sclerosis SocietyT32 88194A, RG 1801-29766
National Institutes of HealthNIHUH3NS100126, R01NS052632, R01NS104471, R01AI101400

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

"Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial" (2020) JAMA – Journal of the American Medical Association

Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial
(2020) JAMA – Journal of the American Medical Association, . Cited 1 time.

Lenze, E.J.a , Mattar, C.b , Zorumski, C.F.a , Stevens, A.a , Schweiger, J.a , Nicol, G.E.a , Miller, J.P.c , Yang, L.a , Yingling, M.a , Avidan, M.S.d , Reiersen, A.M.a

a Department of Psychiatry, School of Medicine, Washington University in St Louis, St Louis, MO, United States
b Division of Infectious Diseases, Department of Internal Medicine, School of Medicine Washington University in St Louis, St Louis, MO, United States
c Division of Biostatistics, Informatics Institute, School of Medicine, Washington University in St Louis, St Louis, MO, United States
d Department of Anesthesiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
Importance: Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production. Objective: To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease. Design, Setting, and Participants: Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-Two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020. Interventions: Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days. Main Outcomes and Measures: The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Results: Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P =.009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. Conclusions and Relevance: In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures. Trial Registration: ClinicalTrials.gov Identifier: NCT04342663. © 2020 American Medical Association. All rights reserved.

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

"A neuroactive steroid with a therapeutically interesting constellation of actions at GABAA and NMDA receptors" (2020) Neuropharmacology

A neuroactive steroid with a therapeutically interesting constellation of actions at GABAA and NMDA receptors
(2020) Neuropharmacology, art. no. 108358, . 

Ziolkowski, L.a , Mordukhovich, I.a , Chen, D.M.a , Chisari, M.a , Shu, H.-J.a , Lambert, P.M.a , Qian, M.b , Zorumski, C.F.a c , Covey, D.F.a b c , Mennerick, S.a c

a Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
b Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
Neuroactive steroids are an ascendant class of treatment for neuropsychiatric illness. Effects on ligand-gated neurotransmitter receptors appear to be a major mechanism of action. Here we describe a neuroactive steroid with a unique constellation of receptor actions. MQ-221 is a sulfated, 3β-hydroxy neurosteroid analogue that inhibits NMDAR function but also potentiates GABAAR function, thereby exhibiting unusual but potentially clinically desirable effects. Although the compound also exhibited features of other sulfated steroids, namely activation-dependent inhibition of GABAAR function, net potentiation dominated under physiological conditions. Potentiation of GABAAR function was distinct from the mechanism governing potentiation by anesthetic neurosteroids. Inhibition of NMDAR function showed weaker channel activation dependence than pregnanolone sulfate (3α5βPS). MQ-221 was unique among four stereoisomers explored in the pattern of effects at GABAA and NMDARs. Taken together, MQ-221 may represent a new class of compound with unique psychoactive effects and beneficial prospects for treating neuropsychiatric disorders. © 2020 Elsevier Ltd

Author Keywords
Antidepressant;  GABA;  Glutamate;  Neurosteroid;  NMDA

Funding details
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
National Institutes of HealthNIHMH101874, AA026753, MH114866, MH110550
Utah Science Technology and ResearchUSTAR
National Institute of Mental HealthNIMHHHSN-271-2018-00023-C
National Institute of Mental HealthNIMH

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

"Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back" (2020) Experimental Neurology

Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back
(2020) Experimental Neurology, art. no. 113519, . 

Geisler, S.

Department of Neurology, Washington University School of Medicine in St. LouisMO, United States

Abstract
Vincristine and bortezomib are effective chemotherapeutics widely used to treat hematological cancers. Vincristine blocks tubulin polymerization, whereas bortezomib is a proteasome inhibitor. Despite different mechanisms of action, the main non-hematological side effect of both is peripheral neuropathy that can last long after treatment has ended and cause permanent disability. Many different cellular and animal models of various aspects of vincristine and bortezomib-induced neuropathies have been generated to investigate underlying molecular mechanisms and serve as platforms to develop new therapeutics. These models revealed that bortezomib induces several transcriptional programs in dorsal root ganglia that result in the activation of different neuroinflammatory pathways and secondary central sensitization. In contrast, vincristine has direct toxic effects on the axon, which are accompanied by changes similar to those observed after nerve cut. Axon degeneration following both vincristine and bortezomib is mediated by a phylogenetically ancient, genetically encoded axon destruction program that leads to the activation of the Toll-like receptor adaptor SARM1 (sterile alpha and TIR motif containing protein 1) and local decrease of nicotinamide dinucleotide (NAD+). Here, I describe current in vitro and in vivo models of vincristine- and bortezomib induced neuropathies, present discoveries resulting from these models in the context of clinical findings and discuss how increased understanding of molecular mechanisms underlying different aspects of neuropathies can be translated to effective treatments to prevent, attenuate or reverse vincristine- and bortezomib-induced neuropathies. Such treatments could improve the quality of life of patients both during and after cancer therapy and, accordingly, have enormous societal impact. © 2020 Elsevier Inc.

Author Keywords
Axon degeneration;  Chemotherapy-induced neuropathy;  Neuroinflammation;  Pain;  SARM1;  Therapeutics

Funding details
5128
Foundation for Barnes-Jewish Hospital
National Institutes of HealthNIHK08NS091448
American Cancer SocietyACSIRG-18-158-61

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

"Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma" (2020) ACS Applied Nano Materials

Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma
(2020) ACS Applied Nano Materials, . 

Zhang, X.a , Ye, D.b , Yang, L.c , Yue, Y.d , Sultan, D.a , Pacia, C.P.d , Pang, H.d , Detering, L.a , Heo, G.S.a , Luehmann, H.a , Choksi, A.e , Sethi, A.a , Limbrick, D.D.f , Becher, O.J.g , Tai, Y.-C.a , Rubin, J.B.c h , Chen, H.d i , Liu, Y.a

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MI 63110, United States
b Department of Mechanical Engineering and Material Science, Washington University in St. Louis, St. Louis, MI 63130, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MI 63110, United States
d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MI 63130, United States
e School of Medicine, University of Maryland, Baltimore, MD 21201, United States
f Department of Neurosurgery, Washington University in St. Louis, St. Louis, MI 63110, United States
g Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
h Department of Neuroscience, Washington University School of Medicine, St. Louis, MI 63110, United States
i Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MI 63108, United States

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters (64Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for the effective delivery of 64Cu-CuNCs to pons in wild-type mice. Then, the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low-molecular-weight, short-lived 68Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of 64Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of 64Cu-CuNCs within the tumor. ©

Author Keywords
diffuse intrinsic pontine glioma;  focused ultrasound;  magnetic resonance imaging;  nanoclusters;  positron emission tomography

Funding details
MC-II-2017-661
Children’s Hospital of Michigan FoundationCHMF
National Institutes of HealthNIHR01MH116981, R01EB027223

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

"Continuing professional development module: An updated introduction to electroencephalogram-based brain monitoring during intended general anesthesia (Module de développement professionnel continu: Une introduction mise à jour du monitorage cérébral par encéphalogramme pour une anesthésie générale planifiée)" (2020) Canadian Journal of Anesthesia

Continuing professional development module: An updated introduction to electroencephalogram-based brain monitoring during intended general anesthesia [Module de développement professionnel continu: Une introduction mise à jour du monitorage cérébral par encéphalogramme pour une anesthésie générale planifiée]
(2020) Canadian Journal of Anesthesia, . 

Hight, D.F.a , Kaiser, H.K.a , Sleigh, J.W.b , Avidan, M.S.c

a Department of Anaesthesiology and Pain Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
b Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
c Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8054, St. Louis, MO, United States

Abstract
The electroencephalogram (EEG) provides a reliable reflection of the brain’s electrical state, so it can reassure us that the anesthetic agents are actually reaching the patient’s brain, and are having the desired effect. In most patients, the EEG changes somewhat predictably in response to propofol and volatile agents, so a frontal EEG channel can guide avoidance of insufficient and excessive administration of general anesthesia. Persistent alpha-spindles (around 10 Hz) phase-amplitude coupled with slow delta waves (around 1 Hz) are commonly seen during an “appropriate hypnotic state of general anesthesia”. Such patterns can be appreciated from the EEG waveform or from the spectrogram (a colour-coded display of how the power in the various EEG frequencies changes with time). Nevertheless, there are exceptions to this. For example, administration of ketamine and nitrous oxide is generally not associated with the aforementioned alpha-spindle coupled with delta wave pattern. Also, some patients, including older adults and those with neurodegenerative disorders, are less predisposed to generate a strong electroencephalographic “alpha-spindle” pattern during general anesthesia. There might also be some rare instances when the frontal EEG shows a pattern suggestive of general anesthesia, while the patient has some awareness and is able to follow simple commands, albeit this is typically without obvious distress or memory formation. Thus, the frontal EEG alone, as currently analyzed, is an imperfect but clinically useful mirror, and more scientific insights will be needed before we can claim to have a reliable readout of brain “function” during general anesthesia. © 2020, Canadian Anesthesiologists’ Society.

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

"Four Actionable Bottlenecks and Potential Solutions to Translating Psychiatric Genetics Research: An Expert Review" (2020) Public Health Genomics

Four Actionable Bottlenecks and Potential Solutions to Translating Psychiatric Genetics Research: An Expert Review
(2020) Public Health Genomics, . 

Bourdon, J.L.a , Davies, R.A.b , Long, E.C.c

a Department of Psychiatry, Brown School of Social Work, Washington University in St. Louis, 4560 Clayton Avenue, St. Louis, MO 63110, United States
b Yerkes National Primate Research Center, Division of Behavioral Neuroscience and Psychiatric Disorders, Emory University, Atlanta, GA, United States
c Edna Bennett Pierce Prevention Research Center, Pennsylvania State University, University Park, PA, United States

Abstract
Background: Psychiatric genetics has had limited success in translational efforts. A thorough understanding of the present state of translation in this field will be useful in the facilitation and assessment of future translational progress. Purpose: A narrative literature review was conducted. Combinations of 3 groups of terms were searched in EBSCOhost, Google Scholar, and PubMed. The review occurred in multiple steps, including abstract collection, inclusion/exclusion criteria review, coding, and analysis of included papers. Results: One hundred and fourteen articles were analyzed for the narrative review. Across those, 4 bottlenecks were noted that, if addressed, may provide insights and help improve and increase translation in the field of psychiatric genetics. These 4 bottlenecks are emphasizing linear translational frameworks, relying on molecular genomic findings, prioritizing certain psychiatric disorders, and publishing more reviews than experiments. Conclusions: These entwined bottlenecks are examined with one another. Awareness of these bottlenecks can inform stakeholders who work to translate and/or utilize psychiatric genetic information. Potential solutions include utilizing nonlinear translational frameworks as well as a wider array of psychiatric genetic information (e.g., family history and gene-environment interplay) in this area of research, expanding which psychiatric disorders are considered for translation, and when possible, conducting original research. Researchers are urged to consider how their research is translational in the context of the frameworks, genetic information, and psychiatric disorders discussed in this review. At a broader level, these efforts should be supported with translational efforts in funding and policy shifts. © 2020 S. Karger AG, Basel. All rights reserved.

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

"Clearance of amyloid-beta with bispecific antibody constructs bound to erythrocytes" (2020) Alzheimer's and Dementia: Translational Research and Clinical Interventions

Clearance of amyloid-beta with bispecific antibody constructs bound to erythrocytes
(2020) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 6 (1), art. no. e12067, . 

Taylor, R.P.a , Lindorfer, M.A.a , Atkinson, J.P.b

a Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States
b Department of Medicine and Division of Rheumatology, Washington University, St. Louis, MO, United States

Abstract
We propose use of bispecific monoclonal antibody (mAb) complexes bound to erythrocytes to redress the lack of efficacy of anti-amyloid beta mAbs in Alzheimer’s disease treatment. Our paradigm leverages erythrocyte complement receptor 1 to promote rapid and quantitative removal of amyloid beta from the circulation, and its subsequent removal from the brain as well. © 2020 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  amyloid beta;  bispecific monoclonal antibodies;  complement receptor 1;  erythrocyte;  human

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

"Trends in Nerve Transfer Procedures Among Board-Eligible Orthopedic Hand Surgeons" (2020) Journal of Hand Surgery Global Online

Trends in Nerve Transfer Procedures Among Board-Eligible Orthopedic Hand Surgeons
(2020) Journal of Hand Surgery Global Online, . 

Morris, M.a , Brogan, D.M.a , Boyer, M.I.a , Dy, C.J.a b

a Department of Orthopaedic Surgery, Division of Hand and Upper Extremity Surgery, Washington University School of Medicine, St Louis, MO, United States
b Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, United States

Abstract
Purpose: Enthusiasm for peripheral nerve transfers increased over the past several years, but further studies are still needed to establish the role of these procedures in peripheral nerve reconstruction. The primary goal of this study was to describe the frequency of nerve transfer surgery among newly trained orthopedic surgeons. Methods: We queried the American Board of Orthopaedic Surgery Part II case log database for all nerve reconstruction Current Procedural Terminology codes for examination years 2004 to 2018 for surgeries performed between 2003 and 2017. Information collected for each patient included examination year, year of surgery, surgeon fellowship training subspecialty, geographic region (as defined by the American Board of Orthopaedic Surgery Part II case log database), patient age, and patient sex. Results: A total of 3,359 nerve reconstruction cases were logged by 1,542 individual candidates from examination years 2004 to 2018. Of the nerve reconstruction codes, 2.1% were nerve transfer codes. There was a statistically significant increase in the proportion of nerve transfer codes over the study period, from 0% of nerve reconstruction codes in examination years 2004 to 2006 to 4.1% of nerve reconstruction codes in examination years 2016 to 2018 (Z = –6.82; P < .001). Conclusions: There has been an increase in the number of nerve transfer procedures relative to all nerve reconstruction codes for peripheral nerve conditions. Clinical relevance: There is a modest but significant increase in nerve transfer procedures over time among newly trained orthopedic surgeons, which suggests the need for long-term outcomes studies for nerve transfers procedures performed in the setting of peripheral nerve conditions. © 2020 American Society for Surgery of the Hand

Author Keywords
Hand surgery;  Nerve reconstruction;  Nerve surgery;  Nerve transfers;  Peripheral nerve

Funding details
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
American Foundation for Surgery of the HandAFSH

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

"Relationship of amyloid beta and neurofibrillary tau deposition in Neurodegeneration in Aging Down Syndrome (NiAD) study at baseline" (2020) Alzheimer's and Dementia: Translational Research and Clinical Interventions

Relationship of amyloid beta and neurofibrillary tau deposition in Neurodegeneration in Aging Down Syndrome (NiAD) study at baseline
(2020) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 6 (1), art. no. e12096, . 

Tudorascu, D.L.a , Laymon, C.M.b , Zammit, M.c , Minhas, D.S.b , Anderson, S.J.d , Ellison, P.A.c , Zaman, S.e , Ances, B.M.f , Sabbagh, M.g , Johnson, S.C.h , Mathis, C.A.b , Klunk, W.E.a , Handen, B.L.a , Christian, B.T.c , Cohen, A.D.a

a Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
d Department of Biostatistics, University of Pittsburgh, Pittsburgh, United States
e Department of Psychiatry, University of CambridgeCambridge, United Kingdom
f Department of Neurology, Washington University, St. Louis, MO, United States
g Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
h Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States

Abstract
Importance: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer’s disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30′s and have a 70% to 80% chance of clinical dementia by their 60′s. Our previous studies have assessed longitudinal changes in amyloid beta (Aβ) accumulation in DS. Objective: The goal of the present study was to assess the presence of brain tau using [18F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aβ using Pittsburgh Compound B (PiB)-PET. Design: Cohort study. Setting: Multi-center study. Participants: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning. Exposures: PET brain scans to assess Aβ ([11C]PiB) and tau ([18F]AV-1451) burden. Main outcomes and measures: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [18F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [11C]PiB SUVR (as both a continuous and dichotomous variable). Results: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aβ and tau pathology in DS. As a dichotomous variable, [18F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [18F]AV-1451 SUVR deposition with [11C]PiB SUVR increases. © 2020 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  Down syndrome;  PET amyloid;  TAU

Funding details
National Institutes of HealthNIHR01AG031110
National Institutes of HealthNIHU01AG051406

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

"The pathway to secondary prevention of Alzheimer's disease" (2020) Alzheimer's and Dementia: Translational Research and Clinical Interventions

The pathway to secondary prevention of Alzheimer’s disease
(2020) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 6 (1), art. no. e12069, . 

McDade, E.a , Bednar, M.M.b , Brashear, H.R.c , Miller, D.S.d , Maruff, P.e , Randolph, C.f g , Ismail, Z.h , Carrillo, M.C.i , Weber, C.J.i , Bain, L.J.j , Hake, A.M.k l

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
b Takeda Pharmaceuticals International Co., Americas, Inc., Cambridge, MA, United States
c Janssen Research and Development, South San Francisco, CA, United States
d Signant Health, Blue Bell, PA, United States
e Cogstate Ltd, Melbourne, VIC, Australia
f MedAvante-ProPhase, Hamilton, NJ, United States
g Department of Neurology, Loyola University Medical Center, Maywood, IL, United States
h Cumming School of Medicine, The University of Calgary, Calgary, Canada
i Alzheimer’s Association, Chicago, IL, United States
j Independent Science Writer, Elverson, PA, United States
k Eli Lilly and Company, Indianapolis, IN, United States
l Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Alzheimer’s disease (AD) is a continuum consisting of a preclinical stage that occurs decades before symptoms appear. As researchers make advances in investigating the continuum, the importance of developing drugs for secondary prevention is garnering increased discussion. For efficacious drug development for secondary prevention it is important to define what are the earliest biological stages of AD. The Alzheimer’s Association Research Roundtable convened November 27 to 28, 2018 to focus on pre-clinical AD. This review will address the biological approach to defining pre-clinical AD, detection, identification of at-risk individuals, and lessons learned from trials such as A4 and TOMMORROW. © 2020 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  biomarkers;  clinical trials;  research roundtable

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

"GRPR/Extracellular Signal–Regulated Kinase and NPRA/Extracellular Signal–Regulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch" (2020) Journal of Investigative Dermatology

GRPR/Extracellular Signal–Regulated Kinase and NPRA/Extracellular Signal–Regulated Kinase Signaling Pathways Play a Critical Role in Spinal Transmission of Chronic Itch
(2020) Journal of Investigative Dermatology, . 

Liu, X.a , Wang, Y.a , Tao, T.a , Zeng, L.a , Wang, D.a , Wen, Y.a , Li, Y.a , Zhao, Z.b c , Tao, A.a

a The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Center for Immunology, Inflammation, & Immune-Mediated Disease, Guangzhou Medical University, Guangzhou, China
b Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Respiratory Care Services, Barnes-Jewish Hospital, St. Louis, MO, United States

Abstract
Intractable or recurrent chronic itch greatly reduces the patients’ QOL and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal–regulated kinase (ERK) 1/2 cascade is the most significantly upregulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MAPK/ERK kinase inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK was observed in the interneurons expressing the receptors of different neuropeptides for itch, including gastrin-releasing peptide receptor, natriuretic peptide receptor A, neuromedin B receptor, and sst2A. Blocking gastrin-releasing peptide receptor and natriuretic peptide receptor A by genetic approaches or toxins in mice significantly attenuated or ablated spinal phosphorylated ERK. When human embryonic kidney 293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that phosphorylated ERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch. © 2020 The Authors

Funding details
Guangzhou Municipal Science and Technology Project201804020042
National Science and Technology Major Project2016ZX08011-005
National Natural Science Foundation of ChinaNSFC81301948

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

"Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma" (2020) Cancer Letters

Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma
(2020) Cancer Letters, . 

Massey, S.C.a , Whitmire, P.a , Doyle, T.E.b , Ippolito, J.E.c , Mrugala, M.M.d , Hu, L.S.e , Canoll, P.f , Anderson, A.R.A.g , Wilson, M.A.h , Fitzpatrick, S.M.i , McCarthy, M.M.j k , Rubin, J.B.l m , Swanson, K.R.a n o

a Mathematical NeuroOncology Laboratory, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, United States
b College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Mayo Clinic, Phoenix, AZ, United States
e Department of Radiology, Mayo Clinic, Phoenix, AZ, United States
f Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, United States
g Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, United States
h School of Life Sciences, Arizona State University, Tempe, AZ, United States
i James S. McDonnell Foundation, St. Louis, MO, United States
j Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, United States
k Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, United States
l Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
m Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
n Department of Neurological Surgery, Mayo Clinic, Phoenix, AZ, United States
o School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ, United States

Abstract
The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies. © 2020

Author Keywords
Glioma;  Patient-specific computational modeling;  Precision medicine;  Sex differences;  Sex factors

Funding details
James S. McDonnell FoundationJSMF

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

"Ether-a-go-go related gene-1a potassium channel abundance varies within specific skeletal muscle fiber type" (2019) European Journal of Translational Myology

Ether-a-go-go related gene-1a potassium channel abundance varies within specific skeletal muscle fiber type
(2019) European Journal of Translational Myology, 29 (3), pp. 235-245. 

Anderson, L.B.a , Latour, C.D.b , Khader, O.a , Massey, B.H.c , Cobb, B.a , Pond, A.L.a

a Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
c Brown University, Providence, RI, United States

Abstract
The ERG1A K+channel, which is partially responsible for repolarization of the cardiac action potential, has also been reported in skeletal muscle where it modulates ubiquitin proteolysis. Because ERG1A protein appears variably expressed in muscles composed of mixed fiber types, we hypothesized that its abundance in skeletal muscle might differ with fiber type. Indeed, skeletal muscle fibers vary in speed of contraction (fast or slow), which is mainly determined by myosin heavy chain (MyHC) isoform content, but a sarcolemmal K+channel might also modulate contraction speed. To test our hypothesis, we cryo-sectioned Soleus (SOL), Extensor Digitorum Longus (EDL), and Gastrocnemius muscles from five rats. These muscles were chosen because the SOL and EDL contain an abundance of slow- and fast-twitch fibers, respectively, while the Gastrocnemius has a more heterogeneous composition. The muscle sections were co-immunostained for the ERG1A protein and either the fast- or slow-twitch MyHC to identify fiber type. ERG1A fluorescence was then measured in the sarcolemma of each fiber type and compared. The data reveal that the ERG1A protein is more abundant in the fibers of the SOL than in the EDL muscles, suggesting ERG1A may be more abundant in the slow than the fast fibers, and this was confirmed with immunoblot. However, because of the homogeneity of fiber type within these muscles, it was not possible to get enough data from both fiber types within a single muscle to compare ERG1A composition within fiber type. However, immunohistochemistry of sections from the fiber type heterogeneous Gastrocnemius muscle reveals that slow fibers had, on average, a 17.2% greater ERG1A fluorescence intensity than fast fibers (p&lt;0.03). Further, immunoblot reveals that ERG1A protein is 41.6% more abundant (p=0.051) in old than in young rat Gastrocnemius muscle. We postulate that this membrane bound voltage-gated channel may affect membrane characteristics, the duration of the action potential generated, and/or the speed of contraction. Indeed, ERG1A protein is more abundant in aged and atrophic skeletal muscle, both of which exhibit slower rates of contraction. © 2019 PAGEPress Publications. All rights reserved.

Author Keywords
Atrophy;  Ether-a-go-go related gene;  Muscle fiber type;  Skeletal muscle

Funding details
Southern Illinois UniversitySIU
School of Medicine, Southern Illinois University

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