WashU weekly Neuroscience publications

Distinct modes of functional connectivity induced by movie-watching
(2019) NeuroImage, 184, pp. 335-348. 

Demirtaş, M.^{a b} , Ponce-Alvarez, A.^b , Gilson, M.^b , Hagmann, P.^d , Mantini, D.^{e f} , Betti, V.^{g h} , Romani, G.L.ⁱ , Friston, K.^j , Corbetta, M.^{k l} , Deco, G.^{b c m n}

^a N3 Division, Department of Psychiatry, Yale University, 40 Temple Street, New Haven, Connecticut 06511, United States
^b Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Roc Boronat 138, Barcelona, 08018, Spain
^c Institució Catalana de la Recerca i Estudis Avançats (ICREA), Universitat Pompeu Fabra, Passeig Lluís Companys 23, Barcelona, 08010, Spain
^d Department of Radiology, Lausanne University Hospital and University of Lausanne (CHUV-UNIL), Rue du Bugnon 46, Lausanne, 1011, Switzerland
^e Research Center for Motor Control and Neuroplasticity, KU Leuven, Tervuursevest 101, Leuven, 3001, Belgium
^f Functional Neuroimaging Laboratory, IRCCS San Camillo Hospital Foundation, via Alberoni 70, Venice Lido30126, Italy
^g Department of Psychology, Sapienza University of Rome, via dei Marsi 78, Rome, 00185, Italy
^h Fondazione Santa Lucia and Istituto Di Ricovero e Cura a Carattere Scientifico, Rome, 00142, Italy
ⁱ Institute for Advanced Biomedical Technologies, “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
^j Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, 12 Queen Square, London, WC1N 3BG, United Kingdom
^k Department of Neuroscience and Padova Neuroscience Center (PNC), University of Padova, Italy
^l Departments of Neurology, Radiology, Anatomy of Neurobiology, School of Medicine, Washington University, St. Louis, St Louis, United States
^m Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, 04103, Germany
ⁿ School of Psychological Sciences, Monash University, Clayton VIC, Melbourne, 3800, Australia

Abstract
A fundamental question in systems neuroscience is how endogenous neuronal activity self-organizes during particular brain states. Recent neuroimaging studies have demonstrated systematic relationships between resting-state and task-induced functional connectivity (FC). In particular, continuous task studies, such as movie watching, speak to alterations in coupling among cortical regions and enhanced fluctuations in FC compared to the resting-state. This suggests that FC may reflect systematic and large-scale reorganization of functionally integrated responses while subjects are watching movies. In this study, we characterized fluctuations in FC during resting-state and movie-watching conditions. We found that the FC patterns induced systematically by movie-watching can be explained with a single principal component. These condition-specific FC fluctuations overlapped with inter-subject synchronization patterns in occipital and temporal brain regions. However, unlike inter-subject synchronization, condition-specific FC patterns were characterized by increased correlations within frontal brain regions and reduced correlations between frontal-parietal brain regions. We investigated these condition-specific functional variations as a shorter time scale, using time-resolved FC. The time-resolved FC showed condition-specificity over time; notably when subjects watched both the same and different movies. To explain self-organisation of global FC through the alterations in local dynamics, we used a large-scale computational model. We found that condition-specific reorganization of FC could be explained by local changes that engendered changes in FC among higher-order association regions, mainly in frontal and parietal cortices. © 2018

Document Type: Article
Source: Scopus

Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function
(2018) Nature Communications, 9 (1), art. no. 3816, . 

Koizumi, K.^a , Hattori, Y.^a , Ahn, S.J.^a , Buendia, I.^a , Ciacciarelli, A.^a , Uekawa, K.^a , Wang, G.^a , Hiller, A.^a , Zhao, L.^a , Voss, H.U.^b , Paul, S.M.^c , Schaffer, C.^{a d} , Park, L.^a , Iadecola, C.^a

^a Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, United States
^b Department of Radiology, Weill Cornell Medicine, New York, NY 10065, United States
^c Department of Neurology and Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, United States

Abstract
The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele. © 2018, The Author(s).

Document Type: Article
Source: Scopus

Enhancing contrast to noise ratio of hippocampi affected with mesial temporal sclerosis: A case-control study in children undergoing epilepsy surgeries
(2018) Clinical Neurology and Neurosurgery, 174, pp. 144-148. 

Orlowski, H.L.P.^a , Smyth, M.D.^b , Parsons, M.S.^a , Dahiya, S.^c , Sharifai, N.^c , Hildebolt, C.^d , Sharma, A.^a

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Boulevard, St. Louis, MO 63110, United States
^b Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid, Box 8057, St. Louis, MO 63110, United States
^c Department of Pathology & Immunology, Washington University School of Medicine, 509 S. Euclid Ave, St. Louis, MO 63110, United States
^d Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Abstract
Objective: Detection of mesial temporal sclerosis (MTS) in children with epilepsy is important. We assessed whether an image-processing algorithm (Correlative Image Enhancement, CIE) could facilitate recognition of hippocampal signal abnormality in the presence of MTS by increasing contrast to noise ratio between affected hippocampus and normal gray matter. Patients and Methods: Baseline coronal FLAIR images from brain MRIs of 27 children with epilepsy who underwent hippocampal resection were processed using CIE. These included 19 hippocampi with biopsy proven MTS and 8 biopsy proven normal hippocampi resected in conjunction with hemispherotomy. We assessed the effect of processing on contrast to noise ratio (CNR) between hippocampus and normal insular gray matter, and on assessment of hippocampal signal abnormality by two masked neuroradiologists. Results: Processing resulted in a significant increase in mean CNR (from 3.9 ± 5.3 to 25.3 ± 25.8; P < 0.01) for hippocampi with MTS, with a substantial (>100%) increase from baseline seen in 15/19 (78.9%) cases. Baseline CNR of 1.7 ± 5.3 for normal hippocampi did not change significantly after processing (1.8 ± 5.3; P = 1.00). For one reader, baseline sensitivity (14/19; 73.6%) was unaffected but the specificity improved from 62.5% (5/8) to 100%. An increase in both sensitivity (from 73.6% to 78.9%) and specificity (from 62.5% to 75%) was seen for the second reader. Conclusion: By enhancing CNR for diseased hippocampi while leaving normal hippocampi relatively unaffected, CIE may improve the diagnostic accuracies of radiologists in detecting MTS-related signal alteration within the affected hippocampus. © 2018 Elsevier B.V.

Author Keywords
Contrast to noise ratio;  Epilepsy;  Hippocampus;  Image processing;  Magnetic resonance imaging;  Mesial temporal sclerosis

Document Type: Article
Source: Scopus

Intrinsic network reactivity differentiates levels of consciousness in comatose patients
(2018) Clinical Neurophysiology, 129 (11), pp. 2296-2305. 

Khanmohammadi, S.^{a b} , Laurido-Soto, O.^b , Eisenman, L.N.^b , Kummer, T.T.^b , Ching, S.^{a c d}

^a Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^d Division of Biology and Biomedical Science, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Objective: We devise a data-driven framework to assess the level of consciousness in etiologically heterogeneous comatose patients using intrinsic dynamical changes of resting-state Electroencephalogram (EEG) signals. Methods: EEG signals were collected from 54 comatose patients (GCS ⩽ 8) and 20 control patients (GCS > 8). We analyzed the EEG signals using a new technique, termed Intrinsic Network Reactivity Index (INRI), that aims to assess the overall lability of brain dynamics without the use of extrinsic stimulation. The proposed technique uses three sigma EEG events as a trigger for ensuing changes to the directional derivative of signals across the EEG montage. Results: The INRI had a positive relationship with GCS and was significantly different between various levels of consciousness. In comparison, classical band-limited power analysis did not show any specific patterns correlated to GCS. Conclusions: These findings suggest that reaching low variance EEG activation patterns becomes progressively harder as the level of consciousness of patients deteriorate, and provide a quantitative index based on passive measurements that characterize this change. Significance: Our results emphasize the role of intrinsic brain dynamics in assessing the level of consciousness in coma patients and the possibility of employing simple electrophysiological measures to recognize the severity of disorders of consciousness (DOC). © 2018 International Federation of Clinical Neurophysiology

Author Keywords
Coma;  Consciousness;  Electroencephalography;  Intrinsic dynamics;  Intrinsic Network Reactivity Index (INRI);  Traumatic brain injury

Document Type: Article
Source: Scopus

Dietary Nitrate Enhances the Contractile Properties of Human Skeletal Muscle
(2018) Exercise and Sport Sciences Reviews, 46 (4), pp. 254-261. 

Coggan, A.R.^{a b} , Peterson, L.R.^{c d}

^a Departments of Kinesiology, Indiana University Purdue, University Indianapolis, IF 101C, 250 University Blvd, Indianapolis, IN 46202, United States
^b Departments of Cellular and Integrative Physiology, Indiana University Purdue, University Indianapolis, Indianapolis, IN, United States
^c Departments of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^d Departments of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Dietary nitrate, a source of nitric oxide (NO), improves the contractile properties of human muscle. We present the hypothesis that this is due to nitrosylation of the ryanodine receptor and increased NO signaling via the soluble guanyl cyclase-cyclic guanosine monophosphate-protein kinase G pathway, which together increase the free intracellular Ca2+ concentration along with the Ca2+ sensitivity of the myofilaments themselves. © 2018 by the American College of Sports Medicine.

Author Keywords
calcium sensitivity;  cyclic guanosine monophosphate;  dietary nitrate;  free intracellular calcium;  muscle contractile function;  nitric oxide;  ryanodine receptor

Document Type: Article
Source: Scopus

Parathyroid hormone-related peptide activates and modulates TRPV1 channel in human DRG neurons
(2018) European Journal of Pain (United Kingdom), 22 (9), pp. 1685-1690. 

Shepherd, A.J.^a , Mickle, A.D.^a , McIlvried, L.A.^a , Gereau, R.W., IV^a , Mohapatra, D.P.^{a b}

^a Department of Anesthesiology, Washington University Pain Center, Washington University in St. Louis School of Medicine, United States
^b Center for the Investigation of Membrane Excitable Diseases, Washington University in St. Louis School of Medicine, United States

Abstract
Parathyroid hormone-related peptide (PTHrP) is associated with advanced tumor growth and metastasis, especially in breast, prostate and myeloma cancers that metastasize to bones, resulting in debilitating chronic pain conditions. Our recent studies revealed that the receptor for PTHrP, PTH1R, is expressed in mouse DRG sensory neurons, and its activation leads to flow-activation and modulation of TRPV1 channel function, resulting in peripheral heat and mechanical hypersensitivity. In order to verify the translatability of our findings in rodents to humans, we explored whether this signalling axis operates in primary human DRG sensory neurons. Analysis of gene expression data from recently reported RNA deep sequencing experiments performed on mouse and human DRGs reveals that PTH1R is expressed in DRG and tibial nerve. Furthermore, exposure of cultured human DRG neurons to PTHrP leads to slow-sustained activation of TRPV1 and modulation of capsaicin-induced channel activation. Both activation and modulation of TRPV1 by PTHrP were dependent on PKC activity. Our findings suggest that functional PTHrP/PTH1R-TRPV1 signalling exists in human DRG neurons, which could contribute to local nociceptor excitation in the vicinity of metastatic bone tumor microenvironment. © 2018 European Pain Federation – EFIC®

Document Type: Article
Source: Scopus

Sleep and Internalizing Symptoms in Emerging Adulthood: The Role of Ethnicity and Subjective Social Status
(2018) Emerging Adulthood, 6 (5), pp. 299-311. 

Kelly, R.J.^a , Bagley, E.J.^b , Gordon, J.D.^c

^a Department of Individual, Family, and Community Education, University of New Mexico, Albuquerque, NM, United States
^b Muhlenberg College, Allentown, PA, United States
^c Washington University in St. Louis, St. Louis, MO, United States

Abstract
We examined relations between objectively and subjectively assessed sleep and self-reported psychological distress from internalizing symptoms. Consistent with a health disparities perspective, ethnicity and subjective social status (SSS) were examined as moderators of these associations. Participants were 219 individuals (18–29 years old; 51% female) from diverse ethnic (55% non-Latino White, 27% Latino, and 18% other) and socioeconomic backgrounds. Individuals self-reported on their daytime sleepiness and actigraphs measured sleep duration, sleep efficiency, and variability in sleep onset time. Path models revealed that greater daytime sleepiness and variability in sleep onset time were more robustly related to distress from internalizing symptoms for Latinos and those with lower SSS. Other interactions emerged; longer sleep duration in conjunction with higher SSS related to less distress from internalizing symptoms. The results are novel and indicate that the consideration of ethnicity and socioeconomic position holds promise for better understanding sleep during emerging adulthood. © 2017 Society for the Study of Emerging Adulthood and SAGE Publishing.

Author Keywords
actigraphy;  emerging adulthood;  internalizing symptoms;  sleep;  subjective social status

Document Type: Article
Source: Scopus

Comparison of the personality traits of male and female BASE jumpers
(2018) Frontiers in Psychology, 9 (SEP), art. no. 1665, . 

Monasterio, E.^a , Mei-Dan, O.^b , Hackney, A.C.^c , Cloninger, R.^d

^a Canterbury District Health Board, Christchurch, New Zealand
^b Department of Orthopedics, University of Colorado Boulder, Boulder, CO, United States
^c Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BASE jumping is an extreme adventure sport which consists of jumping from a fixed object with specially adapted parachutes. A few studies of the personality of BASE jumpers have been conducted, but little is known about how the women in this sport compare to the men. The purpose of this study is to compare the personality traits among a sample of men and women who are experienced BASE jumpers, as this provides an interesting and important opportunity to better understand the motivation for extreme sports. Eighty-three participants completed the Temperament and Character Inventory the day before the jump at the New River Gorge Bridge Day BASE Jumping event, West Virginia, United States. The sample included 64 men and 19 women. Results show that men and women BASE jumpers shared similar personality traits both in terms of temperament and character, except for the character trait of cooperativeness on which women scored higher than men. This suggests that the basic drive for participation in extreme sports is self-regulation of personal emotional drives and needs for self-actualization, rather than to oppose social pressure or cultural bias against female participation. These findings are discussed in relation with other studies conducted among extreme athletes and in terms of congruence between personality and activity. © 2018 Monasterio, Mei-Dan, Carl Hackney and Cloninger.

Author Keywords
BASE jumping;  Character;  Extreme sport;  Sex differences;  Temperament

Document Type: Article
Source: Scopus

Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease
(2018) Orphanet Journal of Rare Diseases, 13 (1), art. no. 152, . 

Vu, M.^a , Li, R.^a , Baskfield, A.^a , Lu, B.^a , Farkhondeh, A.^a , Gorshkov, K.^a , Motabar, O.^a , Beers, J.^b , Chen, G.^{b c} , Zou, J.^b , Espejo-Mojica, A.J.^d , Rodríguez-López, A.^{d e} , Alméciga-Díaz, C.J.^d , Barrera, L.A.^d , Jiang, X.^f , Ory, D.S.^f , Marugan, J.J.^a , Zheng, W.^a

^a National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, United States
^b Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
^c Faculty of Health Sciences, University of Macau, Macau
^d Institute for the Study of Inborn Errors of Metabolism, Faculty of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia
^e Chemistry Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia
^f Diabetic Cardiovascular Disease Center, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background: Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. Results: We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-β-cyclodextrin (HPβCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPβCD and δ-tocopherol. Conclusion: Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model. © 2018 The Author(s).

Author Keywords
Cyclodextrin;  Drug discovery;  Enzyme replacement therapy;  GM2 gangliosidosis;  Hexosaminidase A;  High throughput screening;  HPβCD;  Induced pluripotent stem cells;  Neural stem cells;  Tay-Sachs disease;  δ-tocopherol

Document Type: Article
Source: Scopus

SCN VIP neurons are essential for normal light-mediated resetting of the circadian system
(2018) Journal of Neuroscience, 38 (37), pp. 7986-7995. 

Jones, J.R.^a , Simon, T.^a , Lones, L.^b , Herzog, E.D.^a

^a Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
The suprachiasmatic nucleus (SCN) synchronizes circadian rhythms in behavior and physiology to the external light cycle, but the mechanisms by which this occurs are unclear. As the neuropeptide vasoactive intestinal peptide (VIP) is important for circadian light responses, we tested the hypothesis that rhythmic VIP-producing SCN neurons mediate circadian light responses in male and female mice. Using in vivo fiber photometry over multiple days, we found daily rhythms in spontaneous calcium events of SCN VIP neurons that peaked during the subjective day and were disrupted by constant light. The light-evoked calcium responses peaked around subjective dusk and were greater during the subjective night. Using novel VIP sensor cells, we found that the activity patterns in SCN VIP neurons correlated tightly with spontaneous and NMDA-evoked VIP release. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons exhibit circadian rhythms in spontaneous and light-responsive activity and are essential for the normal resetting of daily rhythms by environmental light. © 2018 the authors.

Author Keywords
Calcium;  Circadian;  Light;  Neuropeptide;  Suprachiasmatic;  Vasoactive intestinal peptide

Document Type: Article
Source: Scopus

Differences in word and phoneme recognition in quiet, sentence recognition in noise, and subjective outcomes between manufacturer first-fit and hearing aids programmed to NAL-NL2 using real-ear measures
(2018) Journal of the American Academy of Audiology, 29 (8), pp. 706-721. 

Valente, M., Oeding, K., Brockmeyer, A., Smith, S., Kallogjeri, D.

Department of Otolaryngology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: The American Speech-Language-Hearing Association (ASHA) and American Academy of Audiology (AAA) have created Best Practice Guidelines for fitting hearing aids to adult patients. These guidelines recommend using real-ear measures (REM) to verify that measured output/gain of hearing aid(s) match a validated prescriptive target. Unfortunately, approximately 70-80% of audiologists do not routinely use REM when fitting hearing aids, instead relying on a manufacturer default ”first-fit” setting. This is problematic because numerous studies report significant differences in REM between manufacturer first-fit and the same hearing aids using a REM or programmed-fit. These studies reported decreased prescribed gain/output in the higher frequencies for the first-fit compared with the programmed fit, which are important for recognizing speech. Currently, there is little research in peer-reviewed journals reporting if differences between hearing aids fitted using a manufacturer first-fit versus a programmed-fit result in significant differences in speech recognition in quiet, noise, and subjective outcomes. Purpose: To examine if significant differences were present in monosyllabic word and phoneme recognition (consonant-nucleus-consonant; CNC) in quiet, sentence recognition in noise (Hearing in Noise Test; HINT), and subjective outcomes using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Speech, Spatial and Qualities of Hearing (SSQ) questionnaires between hearing aids fit using one manufacturer’s first-fit and the same hearing aids with a programmed-fit using REM to National Acoustic Laboratories Nonlinear Version 2 (NAL-NL2) prescriptive target. Research Design: A double-blind randomized crossover design was used. Throughout the study, one investigator performed all REM whereas a second investigator measured speech recognition in quiet, noise, and scored subjective outcome measures. Study Sample: Twenty-four adults with bilateral normal sloping to moderately severe sensorineural hearing loss with no prior experience with amplification. Data Collection and Analysis: The hearing aids were fit using the proprietary manufacturer default first-fit and a programmed-fit to NAL-NL2 using real-ear insertion gain measures. The order of the two fittings was randomly assigned and counterbalanced. Participants acclimatized to each setting for four weeks and returned for assessment of performance via the revised CNC word lists, HINT, APHAB, and SSQ for the respective fitting. Results: (1) A significant median advantage of 15% (p, 0.001; 95% CI: 9.7-24.3%) for words and 7.7% (p, 0.001; 95% CI: 5.9-10.9%) for phonemes for the programmed-fit compared with first-fit at 50 dB sound pressure level (SPL) and 4% (p < 0.01; 95% CI: 1.7 6.3%) for words at 65 dB SPL; (2) No significant differences for the HINT reception threshold for sentences (RTS); (3) Asignificant median advantageof4.2%[p < 0.04;95% confidenceinterval (CI):20.6 13.2%]fortheprogrammed-fitcomparedwith thefirst-fitfor the background noisesubscale problemscore for theAPHAB; (4)Nosignificantdifferences on the SSQ.Conclusions:Improvedwordandphonemerecognitionforsoftandwordsforaveragespeechinquietwere reported for the programmed-fit. Seventy-nine percent of the participants preferred the programmed-fitting versus first-fit. Hearing aids, therefore, should be verified and programmed using REM to a prescriptive target versus no verification using a first-fit.

Author Keywords
Hearing aid;  Manufacturer first-fit;  Programmed-fit;  Real-ear insertion gain (REIG);  Real-ear measures (REM);  Reception threshold for sentences (RTS)

Document Type: Conference Paper
Source: Scopus

Mental Health Disparities Among College Students of Color
(2018) Journal of Adolescent Health, 63 (3), pp. 348-356. 

Lipson, S.K.^a , Kern, A.^b , Eisenberg, D.^c , Breland-Noble, A.M.^d

^a Boston University School of Public Health, Department of Health Law Policy and Management, Boston, Massachusetts 02118, United States
^b Washington University in St. Louis, George Warren Brown School of Social Work, St. Louis, Missouri, United States
^c University of Michigan School of Public Health, Department of Health Management and Policy, University of Michigan Institute for Social Research, Ann Arbor, Michigan, United States
^d Georgetown University Medical Center, Department of Psychiatry, Washington, DC, United States

Abstract
Purpose: Understanding the mental health needs of students of color is a growing priority on college and university campuses nationwide. This study aims to capture the state of mental health among students of color, including the prevalence of mental health problems and treatment utilization. Methods: The sample is comprised of 43,375 undergraduate and graduate students at 60 institutions that participated in the survey-based Healthy Minds Study from 2012 to 2015. These data include over 13,000 students of color; we look separately at African-American, Latinx, Asian/Asian American, and Arab/Arab American students. Data are analyzed at the individual level using bivariate and multivariate modeling to elucidate variations across race/ethnicity. We examine symptom prevalence (measured by validated screens such as the Patient Health Questionnaire-9 for depression), help-seeking behaviors, and related factors (including knowledge and stigma). Results: Across race/ethnicity, we find modest variation in symptom prevalence and larger variation in service utilization. Overall, treatment use is lower among students of color relative to white students, even when controlling for other variables in regression models. Asian/Asian American students have the lowest prevalence of treatment, at only 20% among those with apparent mental health conditions. Attitudes related to mental health treatment also vary significantly and help to explain the primary findings. Conclusions: College students of color represent a disparities population based on greater levels of unmet mental health needs relative to white students. This paper takes an important step toward understanding these needs and points to implications for future research and practice. © 2018

Author Keywords
Adolescent and young adult mental health;  Campus mental health;  College students of color;  Disparities;  Help-seeking;  Prevalence

Document Type: Article
Source: Scopus

Curriculum for neurogastroenterology and motility training: A report from the joint ANMS-ESNM task force
(2018) Neurogastroenterology and Motility, 30 (9), art. no. e13341, .

Gyawali, C.P.^a , Savarino, E.^b , Lazarescu, A.^c , Bor, S.^d , Patel, A.^e , Dickman, R.^f , Pressman, A.^g , Drewes, A.M.^h , Rosen, J.ⁱ , Drug, V.^j , Saps, M.^k , Novais, L.^l , Vazquez-Roque, M.^m , Pohl, D.ⁿ , van Tilburg, M.A.L.^{o p q} , Smout, A.^r , Yoon, S.^s , Pandolfino, J.^t , Farrugia, G.^m , Barbara, G.^u , Roman, S.^{v w}  

^a Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States
^b Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
^c Division of Gastroenterology, University of Alberta, Edmonton, Canada
^d Department of Gastrenterology, Ege University, Izmir, Turkey
^e Duke University School of Medicine and the Durham VA Medical Center, Durham, NC, United States
^f Division of Gastroenterology, Rabin Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
^g Division of Gastroenterology, Brown University, Providence, RI, United States
^h Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
ⁱ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Hospital, Kansas City, United States
^j Institute of Gastroenterology and Hepatology, University Hospital “St Spiridon”, University of Medicine and Pharmacy “Gr T Popa”, Iasi, Romania
^k Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Miami, Miami, FL, United States
^l Neurogastroenterology and Gastrointestinal Motility Lab, New University of Lisbon, Lisbon, Portugal
^m Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, United States
ⁿ Klinik fur Gastroenterologie und Hepatologie, University of Zurich, Zurich, Switzerland
^o College of Pharmacy & Health Sciences, Campbell University, Buies Creek, NC, United States
^p Department of Medicine, University of North Carolina, Chapel Hill, NC, United States
^q School of Social Work, University of Washington, Seattle, WA, United States
^r Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands
^s Division of Gastroenterology and Hepatology, University of Rochester, Rochester, NY, United States
^t Division of Gastroenterology, Department of Medicine, Northwestern University, Chicago, IL, United States
^u Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
^v Digestive Physiology, Université de Lyon, Hospices Civils de Lyon, Lyon, France
^w Digestive Physiology, Université de Lyon, Lyon I University, Lyon, France

Abstract
Although neurogastroenterology and motility (NGM) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency-based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society (ANMS) and the European Society of Neurogastroenterology and Motility (ESNM) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM, consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro-esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy (surgery, endoscopic intervention, medications, other therapy), and transition of pediatric patients into adult practice. A 3-tiered training curriculum covering these domains is proposed here and endorsed by all NGM societies. Tier 1 NGM knowledge and training is expected of all gastroenterology trainees and practicing gastroenterologists. Tier 2 knowledge and training is appropriate for trainees who anticipate NGM disorder management and NGM function test interpretation being an important part of their careers, which may require competency assessment and credentialing of test interpretation skills. Tier 3 knowledge and training is undertaken by trainees interested in a dedicated NGM career and may be restricted to specific domains within the broad NGM field. The joint ANMS and ESNM task force anticipates that the NGM curriculum will streamline NGM training in North America and Europe and will lead to better identification of centers of excellence where Tier 2 and Tier 3 training can be accomplished. © 2018 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons, Ltd.

Author Keywords
curriculum;  motility testing;  neurogastroenterology

Document Type: Article
Source: Scopus
Access Type: Open Access

CBT for depression: What the evidence says
(2018) Current Psychiatry, 17 (9), pp. 14-22 and 55. 

Chand, S.P.^a , Ravi, C.^a , Chakkamparambil, B.^a , Prasad, A.^b , Vora, A.^c

^a Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO, United States
^b Zucker Hillside Hospital, Long Island Jewish Medical Center, Queens, NY, United States
^c Department of Child and Adolescent Psychiatry, Washington University, St. Louis, MO, United States

Document Type: Article
Source: Scopus

The endocannabinoid/cannabinoid receptor 2 system protects against cisplatin-induced hearing loss
(2018) Frontiers in Cellular Neuroscience, 12, art. no. 271, . 

Ghosh, S.^a , Sheth, S.^a , Sheehan, K.^b , Mukherjea, D.^b , Dhukhwa, A.^a , Borse, V.^c , Rybak, L.P.^{a b} , Ramkumar, V.^a

^a Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, United States
^b Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, United States
^c Department of Otolaryngology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans-tympanic administration of (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na+/K+-ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na+/K+-ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans-tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration. © 2018 Ghosh, Sheth, Sheehan, Mukherjea, Dhukhwa, Borse, Rybak and Ramkumar.

Author Keywords
CB2 receptor;  Cisplatin;  Endocannabinoids;  Hearing loss;  Ribbon synapse

Document Type: Article
Source: Scopus
Access Type: Open Access

Gating-induced large aqueous volumetric remodeling and aspartate tolerance in the voltage sensor domain of Shaker K+ channels
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (32), pp. 8203-8208. 

Díaz-Franulic, I.^{a b c} , González-Pérez, V.^d , Moldenhauer, H.^{a b} , Navarro-Quezada, N.^{a b} , Naranjo, D.^a

^a Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, 2360102, Chile
^b Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, 2360103, Chile
^c Center for Bioinformatics and Integrative Biology, Universidad Andrés Bello, Santiago, 8370186, Chile
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Neurons encode electrical signals with critically tuned voltage-gated ion channels and enzymes. Dedicated voltage sensor domains (VSDs) in these membrane proteins activate coordinately with an unresolved structural change. Such change conveys the transmembrane translocation of four positively charged arginine side chains, the voltage-sensing residues (VSRs; R1–R4). Countercharges and lipid phosphohead groups likely stabilize these VSRs within the low-dielectric core of the protein. However, the role of hydration, a sign-independent charge stabilizer, remains unclear. We replaced all VSRs and their neighboring residues with negatively charged aspartates in a voltage-gated potassium channel. The ensuing mild functional effects indicate that hydration is also important in VSR stabilization. The voltage dependency of the VSR aspartate variants approached the expected arithmetic summation of charges at VSR positions, as if negative and positive side chains faced similar pathways. In contrast, aspartates introduced between R2 and R3 did not affect voltage dependence as if the side chains moved outside the electric field or together with it, undergoing a large displacement and volumetric remodeling. Accordingly, VSR performed osmotic work at both internal and external aqueous interfaces. Individual VSR contributions to volumetric works approached arithmetical additivity but were largely dissimilar. While R1 and R4 displaced small volumes, R2 and R3 volumetric works were massive and vectorially opposed, favoring large aqueous remodeling during VSD activation. These diverse volumetric works are, at least for R2 and R3, not compatible with VSR translocation across a unique stationary charge transfer center. Instead, VSRs may follow separated pathways across a fluctuating low-dielectric septum. © National Academy of Sciences. All rights reserved.

Author Keywords
Charge hydration;  Conformational change;  Osmotic work;  Shaker;  Voltage sensor

Document Type: Article
Source: Scopus

Effect of Concussions on Lower Extremity Injury Rates at a Division I Collegiate Football Program
(2018) Orthopaedic Journal of Sports Medicine, 6 (8), . 

Krill, M.L.^a , Nagelli, C.^{b c d} , Borchers, J.^{e f} , Krill, M.K.^{a g} , Hewett, T.E.^{b c h i}

^a Motion Analysis and Performance Laboratory, Jameson Crane Sports Medicine Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
^b Orthopedic Biomechanics Laboratory and Sports Medicine Center, Mayo Clinic, Rochester, MN, United States
^c Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, United States
^d Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States
^e Jameson Crane Sports Medicine Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
^f Department of Family Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
^g Physical Medicine & Rehabilitation, Division of Neurorehabilitation, Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^h Department of Biomedical Engineering and Physiology, Mayo Clinic, Rochester, MN, United States
ⁱ Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, United States

Abstract
Background: Football has one of the highest injury rates (IRs) in sports, ranging from 4.1 to 8.6 per 1000 athlete-exposures (AEs). Previous research has reported that athletes may be at an increased risk of suffering lower extremity (LE) injuries after a concussion. Purpose/Hypothesis: The purpose of this study was to evaluate the rate of LE injuries in collegiate football athletes after a concussion. We predicted that the overall LE IR would increase after a concussion and that each position group would also demonstrate a similar increase in LE injuries after a concussion. Study Design: Cohort study; Level of evidence, 2. Methods: Daily attendance and injury records were prospectively collected by licensed team medical providers for the 2012 through 2016 college football regular seasons. Each injury report included the date of injury, position group, body part injured, and type of injury. IRs per 1000 AEs with 95% CIs were calculated to evaluate LE injuries at different time points after a concussion (remainder of season, next season, any additional seasons) and by months (<6 months, 6-12 months, >12 months). Mid-P exact tests were utilized to establish injury rate ratios (IRRs) to compare the IR between variables. Results: There was no significant difference in LE IRRs between the athletes post- versus preconcussion (P =.20) or between the postconcussion and no concussion (control) athletes (P =.08). There was an increased LE IR beyond 12 months in the postconcussion group (IR, 9.08 [95% CI, 3.68-18.89]) compared with the no concussion group (IR, 2.88 [95% CI, 2.04-3.96]) (IRR, 3.16 [95% CI, 1.21-7.15]; P =.02). Line position players had an increase in LE injuries after a concussion (IRR, 6.22 [95% CI, 1.31-23.68]; P =.03) compared with linemen with no concussion. Conclusion: There was no initial increase in LE IRs immediately after a concussion; however, there was an increased LE IR more than 12 months after a concussion. There was no increase in LE IRs demonstrated by skill and other position groups. Line position players experienced an increased LE IR the next season after a concussion or greater than 12 months after the injury. © The Author(s) 2018.

Author Keywords
concussion;  epidemiology;  football (American);  injury;  lower extremity;  position group

Document Type: Article
Source: Scopus

Age-specific genome-wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’-like features associated with younger age
(2018) International Journal of Cancer, . Article in Press. 

Ostrom, Q.T.^{a b c} , Kinnersley, B.^d , Armstrong, G.^a , Rice, T.^e , Chen, Y.^b , Wiencke, J.K.^e , McCoy, L.S.^e , Hansen, H.M.^e , Amos, C.I.^g , Bernstein, J.L.^f , Claus, E.B.^{h i} , Eckel-Passow, J.E.^j , Il’yasova, D.^{k l m} , Johansen, C.ⁿ , Lachance, D.H.^o , Lai, R.K.^p , Merrell, R.T.^q , Olson, S.H.^f , Sadetzki, S.^{r s} , Schildkraut, J.M.^t , Shete, S.^u , Rubin, J.B.^v , Andersson, U.^w , Rajaraman, P.^x , Chanock, S.J.^{x y} , Linet, M.S.^x , Wang, Z.^{x y z} , Yeager, M.^{x y} , Houlston, R.S.^d , Jenkins, R.B.^aa , Wrensch, M.R.^e , Melin, B.^w , Bondy, M.L.^a , Barnholtz-Sloan, J.S.^b , on behalf of the GliomaScan consortium^ab

^a Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
^b Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^c Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^d Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
^e Department of Neurological Surgery and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
^f Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
^g Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, TX, United States
^h School of Public Health, Yale University, New Haven, CT, United States
ⁱ Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, United States
^j Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, United States
^k Department of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, GA, United States
^l Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, United States
^m Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States
ⁿ Oncology clinic, Finsen Center, Rigshospitalet and Survivorship Research Unit, The Danish Cancer Society Research Center, Copenhagen, Denmark
^o Department of Neurology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, United States
^p Departments of Neurology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^q Department of Neurology, NorthShore University HealthSystem, Evanston, IL, United States
^r Cancer and Radiation Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel
^s Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
^t Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, United States
^u Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
^v Departments of Pediatrics and Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^w Department of Radiation Sciences, Faculty of Medicine, Umeå University, Umeå, Sweden
^x Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States
^y Core Genotyping Facility, National Cancer Institute, SAIC-Frederick, Inc, Gaithersburg, MD, United States
^z Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^aa Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, United States

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50×10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14×10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13×10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18×10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons &gt;54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’-like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’. © 2018 UICC

Author Keywords
age;  brain tumors;  glioma

Document Type: Article in Press
Source: Scopus

Postoperative opioids, endocrine changes,and immunosuppression [Postoperative Opioide, endokrine Veränderungen und Immunsuppression]
(2018) Schmerz, . Article in Press. 

Haroutounian, S.

Department of Anesthesiology und Washington University Pain Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States

Document Type: Article in Press
Source: Scopus

Cerebrospinal Fluid Ceruloplasmin, Haptoglobin, and Vascular Endothelial Growth Factor Are Associated with Neurocognitive Impairment in Adults with HIV Infection
(2018) Molecular Neurobiology, . Article in Press. 

Kallianpur, A.R.^{a b} , Gittleman, H.^c , Letendre, S.^d , Ellis, R.^e , Barnholtz-Sloan, J.S.^c , Bush, W.S.^c , Heaton, R.^f , Samuels, D.C.^g , Franklin, D.R., Jr.^f , Rosario-Cookson, D.^f , Clifford, D.B.^h , Collier, A.C.ⁱ , Gelman, B.^j , Marra, C.M.^k , McArthur, J.C.^l , McCutchan, J.A.^d , Morgello, S.^{m n o} , Grant, I.^f , Simpson, D.^m , Connor, J.R.^p , Hulgan, T.^q , the CHARTER Study Group^r

^a Department of Genomic Medicine and Department of Medicine, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue/NE50, Cleveland, OH, United States
^b Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
^c Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^d Department of Medicine, University of California–San Diego, San Diego, CA, United States
^e Department of Neurology, University of California–San Diego, San Diego, CA, United States
^f Department of Psychiatry, University of California–San Diego, San Diego, CA, United States
^g Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States
^j Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
^k Department of Neurology, University of Washington School of Medicine, Seattle, WA, United States
^l Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^m Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁿ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^o Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^p Department of Neurosurgery, Pennsylvania State Hershey Medical Center, Hershey, PA, United States
^q Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States

Abstract
Dysregulated iron transport and a compromised blood–brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis—ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)—as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p = 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p = 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p = 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p = 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p < 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values, p < 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both p < 0.01) and HAND (both p < 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Biomarker;  Cerebrospinal fluid (CSF);  Ceruloplasmin;  Haptoglobin;  HIV-associated neurocognitive disorder;  Vascular endothelial growth factor

Document Type: Article in Press
Source: Scopus

Single-Cell RNA-Seq Uncovers a Robust Transcriptional Response to Morphine by Glia
(2018) Cell Reports, 24 (13), pp. 3619-3629.e4. 

Avey, D.^{a b} , Sankararaman, S.^b , Yim, A.K.Y.^a , Barve, R.^c , Milbrandt, J.^a , Mitra, R.D.^{a b}

^a Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Center for Genome Sciences and Systems Biology, Washington University, School of Medicine, St. Louis, MO 63110, United States
^c Genome Technology Access Center, Department of Genetics. Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Molecular and behavioral responses to opioids are thought to be primarily mediated by neurons, although there is accumulating evidence that other cell types play a prominent role in drug addiction. To investigate cell-type-specific opioid responses, we performed single-cell RNA sequencing (scRNA-seq) of the nucleus accumbens of mice following acute morphine treatment. Differential expression analysis uncovered unique morphine-dependent transcriptional responses by oligodendrocytes and astrocytes. We examined the expression of selected genes, including Cdkn1a and Sgk1, by FISH, confirming their induction by morphine in oligodendrocytes. Further analysis using RNA-seq of FACS-purified oligodendrocytes revealed a large cohort of morphine-regulated genes. The affected genes are enriched for roles in cellular pathways intimately linked to oligodendrocyte maturation and myelination, including the unfolded protein response. Altogether, our data illuminate the morphine-dependent transcriptional response by oligodendrocytes and offer mechanistic insights into myelination defects associated with opioid abuse. Avey et al. use single-cell RNA-seq to uncover cell-type-specific responses to morphine in the brains of mice, revealing a unique and robust response by oligodendrocytes, which they further validate by multiple approaches. These analyses offer insights into the molecular mechanisms underlying oligodendrocyte dysfunction in the context of opioid abuse. © 2018 The Authors

Author Keywords
addiction;  glucocorticoid;  morphine;  myelin;  nucleus accumbens;  oligodendrocyte;  opioid;  RNA-seq;  single-cell;  UPR

Document Type: Article
Source: Scopus

Confidence carryover during interleaved memory and perception judgments
(2018) Memory and Cognition, . Article in Press. 

Kantner, J.^a , Solinger, L.A.^b , Grybinas, D.^b , Dobbins, I.G.^b

^a California State University, Northridge, United States
^b Washington University in Saint Louis, Saint Louis, United States

Abstract
Recognition memory tests typically consist of randomly intermixed studied and nonstudied items that subjects classify as old or new, often while indicating their confidence in these classifications. Under most decision theories, confidence ratings index an item’s memory strength—the extent to which it elicits evidence of prior occurrence. Because the test probes are randomly ordered, these theories predict that confidence judgments should be sequentially independent: confidence on trial n should not predict confidence on n + 1. However, analysis of two extant data sets demonstrated reliable serial correlations in recognition memory confidence (confidence carryover). In a new experiment, we examined the domain specificity of confidence carryover by serially interleaving recognition and perceptual classification judgments. Analysis revealed domain-general and domain-specific confidence carryover effects: The confidence of a current recognition judgment was shown to reflect both the confidence of an immediately preceding perceptual gender judgment (domain-general carryover at Lag 1) and also the confidence of the recognition judgment prior to that (domain-specific carryover at Lag 2). Moreover, the domain-specific effect was sensitive to response consistency: Confidence carryover was highest when old–new classifications repeated across trials. Whereas the domain-general effect may reflect metacognitive monitoring of internal factors such as alertness, the domain-specific effect was easily simulated by assuming that evidence within domains is “sticky,” such that current memory or perceptual evidence is pulled toward prior evidence representations. © 2018, Psychonomic Society, Inc.

Author Keywords
Confidence;  Recognition memory;  Sequential dependencies

Document Type: Article in Press
Source: Scopus

Intranasal Corticosteroids Do Not Lead to Ocular Changes: A Systematic Review and Meta-analysis
(2018) Laryngoscope, . Article in Press. 

Valenzuela, C.V.^a , Liu, J.C.^b , Vila, P.M.^a , Simon, L.^c , Doering, M.^c , Lieu, J.E.C.^a

^a Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Bernard Becker Medical Library, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Objectives: The safety and efficacy of intranasal corticosteroids (INCS) are well established, but there remains apprehension that INCS could lead to systemic side effects, as with oral steroids. The objective of this systematic review was to assess whether the use of INCS lead to increased intraocular pressure (IOP) above 20 mm Hg, glaucoma, or formation of posterior subcapsular cataracts in adult patients with rhinitis. Methods: Two medical librarians searched the published literature for records discussing the use of “nasal steroids” in “rhinitis” and their effect on “intraocular pressure,” “cataracts,” or “glaucoma.”. Results: A total of 484 studies were identified, and 10 randomized controlled trials met our inclusion criteria. Meta-analysis of 2,226 patients revealed that the relative risk of elevated IOP in those who received INCS was 2.24 (95% confidence interval [CI]: 0.68 to 7.34) compared to placebo. The absolute increased incidence of elevated IOP in patients using INCS compared to placebo was 0.8% (95% CI: 0% to 1.6%). There were zero cases of glaucoma in both placebo and INCS groups at 12 months. The absolute increased incidence of developing a posterior subcapsular cataract was 0.02% (95% CI: −0.3% to 0.4%). Conclusions: Use of INCS is not associated with a significant risk of elevating IOP or developing a posterior subcapsular cataract in patients with allergic rhinitis. Presence of glaucoma, however, is the real clinical adverse event of concern. There were zero reported cases of glaucoma at 12 months. Future studies should formally evaluate for glaucoma rather than use IOP measures as a surrogate. Laryngoscope, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
cataract formation;  glaucoma;  Intranasal steroids;  intraocular pressure

Document Type: Article in Press
Source: Scopus

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience
(2018) Journal of Neuro-Oncology, . Article in Press. 

Kline, C.^{a d} , Liu, S.J.^b , Duriseti, S.^c , Banerjee, A.^{a e} , Nicolaides, T.^{e f} , Raber, S.^a , Gupta, N.^{a e} , Haas-Kogan, D.^g , Braunstein, S.^h , Mueller, S.^{a d e}

^a Department of Pediatrics, University of California, San Francisco, CA, United States
^b School of Medicine, University of California, San Francisco, CA, United States
^c Department of Radiation Oncology, Washington University in Saint Louis, St Louis, MO, United States
^d Department of Neurology, University of California, San Francisco, CA, United States
^e Department of Neurological Surgery, University of California, San Francisco, CA, United States
^f Department of Pediatrics, New York University, New York, NY, United States
^g Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA, United States
^h Department of Radiation Oncology, University of California, San Francisco, CA, United States

Abstract
Background: Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG. Methods: We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT. Results: Thirty-one patients were included (8—reRT with nivolumab; 4—reRT alone; 19—no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months—reRT with nivolumab; 20.4 months—reRT alone; 8.3 months—no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity. Conclusions: Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
DIPG;  PD-1 inhibition;  Reirradiation;  Survival

Document Type: Article in Press
Source: Scopus

Prevalence and nature of hearing loss in a cohort of children with sickle cell disease
(2018) Pediatric Blood and Cancer, . Article in Press. 

Towerman, A.S.^a , Hayashi, S.S.^b , Hayashi, R.J.^a , Hulbert, M.L.^a

^a Division of Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Audiology, St. Louis Children’s Hospital, St. Louis, MO, United States

Abstract
Background: Sickle cell disease (SCD) may cause injury to any organ, including the auditory system. Although the association of SCD and hearing loss has been described, the nature of this complication is unknown. We sought to establish the prevalence and nature of hearing loss in a referred cohort of children with SCD and to identify correlating disease- or treatment-associated factors. Procedure: We conducted a retrospective review of patients with SCD < 22 years of age who had hearing evaluations between August 1990 and December 2014. Demographics, audiograms, and disease and treatment variables were analyzed. Results: Two hundred and ten audiograms among 81 patients were reviewed, and 189 were evaluable. Seventy-two children constituted the referred cohort. Fourteen (19.4%) had hearing loss documented on at least one audiogram. Seven (9.7%) patients had only conductive hearing loss, and the loss persisted for up to 10.3 years. The median age of first identification was eight years. Six (8.3%) patients had hearing loss that was at least partially sensorineural. One patient’s hearing loss was ambiguous. All sensorineural hearing losses were unilateral and 4/6 patients had prior documented normal hearing, indicating acquired loss. No correlations were identified. Conclusions: Both conductive and sensorineural hearing losses are more prevalent in our study population than those observed in the general pediatric population. In children with SCD, sensorineural hearing loss appears to be acquired and unilateral. Conductive hearing loss was identified in older children and can persist. Serial screening is needed for early detection and more prompt intervention in this population. © 2018 Wiley Periodicals, Inc.

Author Keywords
conductive hearing loss;  sensorineural hearing loss;  sickle cell disease

Document Type: Article in Press
Source: Scopus

Chronodisruption: An untimely cause of preterm birth?
(2018) Best Practice and Research: Clinical Obstetrics and Gynaecology, . Article in Press. 

Reschke, L.^a , McCarthy, R.^a , Herzog, E.D.^b , Fay, J.C.^{c d} , Jungheim, E.S.^a , England, S.K.^a

^a Department of Obstetrics and Gynecology, Washington University in St. LouisMO, United States
^b Department of Biology, Washington University in St. LouisMO, United States
^c Department of Biology, University of RochesterNY, United States
^d Washington University School of Medicine, St. Louis, MO, United States

Abstract
Circadian rhythms, endogenous and entrainable adaptations to 24-hour cycles of light and dark, influence almost all physiologic functions. Emerging evidence suggests that the disruption of normal circadian rhythms, termed chronodisruption, could affect a wide range of disease-related processes. In this review, we describe the molecular generation of circadian rhythms, the effects of chronodisruption on human health, the circadian timing of birth in multiple species, the possible effects of chronodisruption on preterm birth, and some of the open questions in this field. © 2018

Author Keywords
Chronodisruption;  Circadian rhythms;  Pregnancy;  Preterm birth

Document Type: Article in Press
Source: Scopus

Onyx embolization of a ruptured anterior inferior cerebellar artery in a neonate
(2018) Child’s Nervous System, . Article in Press. 

CreveCoeur, T.S.^a , Salehi, A.^a , Miller, B.A.^b , Austin, M.J.^c , Cross, D.T., III^d , Smyth, M.D.^a

^a Department of Neurosurgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, University of Kentucky, Lexington, KY, United States
^c Department of Interventional Neuroradiology, Lahey Hospital & Medical Center, Tufts University School of Medicine, Burlington, MA, United States
^d Department of Endovascular Surgical Neuroradiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is rare in neonates. The authors present a unique report of a neonate with SAH from anterior inferior cerebellar artery (AICA) aneurysm rupture that was successfully treated with Onyx embolization. This case report demonstrates the utility of Onyx embolization for posterior circulation aneurysms in neonates and the successful management of SAH in this population. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Aneurysm;  Anterior inferior cerebellar artery;  Liquid embolic agent;  Onyx embolization;  Posterior circulation;  Subarachnoid hemorrhage

Document Type: Article in Press
Source: Scopus

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory
(2018) Annals of Clinical and Translational Neurology, . Article in Press. 

Ljubenkov, P.A.^a , Staffaroni, A.M.^a , Rojas, J.C.^a , Allen, I.E.^b , Wang, P.^a , Heuer, H.^a , Karydas, A.^a , Kornak, J.^b , Cobigo, Y.^a , Seeley, W.W.^a , Grinberg, L.T.^a , Spina, S.^a , Fagan, A.M.^c , Jerome, G.^c , Knopman, D.^d , Boeve, B.F.^d , Dickerson, B.C.^e , Kramer, J.^a , Miller, B.^a , Boxer, A.L.^a , Rosen, H.J.^a

^a Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
^b Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Department of Neurology, Mayo Clinic, Rochester, MN, United States
^e Frontotemporal Dementia Unit, Department of Neurology, Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, Boston, MA, United States

Abstract
Objective: The prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1-42 was examined in frontotemporal dementia subtypes. Methods: We compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits. Results: Neurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1-42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP-43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia. Interpretation: High cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1-42 also predict some measures of disease aggressiveness in frontotemporal dementia. © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Document Type: Article in Press
Source: Scopus

Heterogeneity in association of remote herpesvirus infections and pediatric MS
(2018) Annals of Clinical and Translational Neurology, . Article in Press. 

Nourbakhsh, B.^a , Rutatangwa, A.^b , Waltz, M.^c , Rensel, M.^d , Moodley, M.^d , Graves, J.^e , Casper, T.C.^c , Waldman, A.^f , Belman, A.^g , Greenberg, B.^h , Goyal, M.ⁱ , Harris, Y.^j , Kahn, I.^k , Lotze, T.^l , Mar, S.ⁱ , Schreiner, T.^m , Aaen, G.ⁿ , Hart, J.^e , Ness, J.^j , Rubin, J.^o , Tillema, J.-M.^p , Krupp, L.^q , Gorman, M.^r , Benson, L.^r , Rodriguez, M.^p , Chitnis, T.^s , Rose, J.^t , Candee, M.^u , Weinstock-Guttman, B.^v , Shao, X.^w , Barcellos, L.^w , James, J.^x , Waubant, E.^e , On behalf of the US Network of Pediatric MS Centers^y

^a Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^b Department of Neurology, Stony Brook University Hospital, Stony Brook, NY, United States
^c Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
^d Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
^e UCSF Regional Pediatric MS Center, San Francisco, CA, United States
^f Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g Lourie Center for Pediatric MS at Stony Brook University Hospital, Stony Brook, NY, United States
^h University of Texas Southwestern Medical Center, Dallas, TX, United States
ⁱ Washington University Pediatric MS and other Demyelinating Disease Center, Washington University in St. Louis, St. Louis, MO, United States
^j Center for Pediatric-Onset Demyelinating Disease at the Children’s of Alabama, University of Alabama, Birmingham, AL, United States
^k Children’s National Medical Center, Washington, DC, United States
^l The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^m Rocky Mountain MS Center, Children’s Hospital Colorado, University of Colorado at Denver, Aurora, CO, United States
ⁿ Pediatric Multiple Sclerosis Center at Loma Linda University Children’s Hospital, Loma Linda University, Loma Linda, CA, United States
^o Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^p Mayo Clinic Pediatric MS Center, Mayo Clinic, Rochester, MN, United States
^q Pediatric MS Center, New York University, New York, NY, United States
^r Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^s Partners Pediatric MS Center, Massachusetts General Hospital, Boston, MA, United States
^t Department of Neurology, University of Utah, Salt Lake City, UT, United States
^u Primary Children’s Hospital, University of Utah, Salt Lake City, UT, United States
^v The Pediatric MS Center at the Jacobs Neurological Institute, State University of New York at Buffalo, Buffalo, NY, United States
^w School of Public Health, University of California, Berkeley, Berkeley, CA, United States
^x University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Abstract
Objective: While prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. Methods: Cases with pediatric-onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses-1 (HSV-1) and -2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA-DRB1:1501 status. Results: A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV-viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV-1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA-DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA-DRB1*15:01 status. Interpretation: EBV seropositivity is strongly associated with pediatric MS, as is HSV-1 seropositivity in subjects negative for HLA-DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development. © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Document Type: Article in Press
Source: Scopus