WashU weekly Neuroscience publications | Office of Neuroscience Research

“The transcriptional landscape of Shh medulloblastoma” (2021) Nature Communications

The transcriptional landscape of Shh medulloblastoma
(2021) Nature Communications, 12 (1), art. no. 1749, .

Skowron, P.^a ^b ^c , Farooq, H.^a ^b ^c , Cavalli, F.M.G.^a ^c , Morrissy, A.S.^d ^e ^f , Ly, M.^a ^b ^c , Hendrikse, L.D.^a ^c ^g , Wang, E.Y.^a ^c ^g , Djambazian, H.^h ⁱ , Zhu, H.^g ^j , Mungall, K.L.^k , Trinh, Q.M.^j , Zheng, T.^l , Dai, S.^m , Stucklin, A.S.G.^a ^c , Vladoiu, M.C.^a ^b ^c , Fong, V.^a ^c , Holgado, B.L.^a ^c , Nor, C.^a ^c , Wu, X.^a ^c , Abd-Rabbo, D.^j , Bérubé, P.^h , Wang, Y.C.^h , Luu, B.^a ^c , Suarez, R.A.^a ^c , Rastan, A.^a ^c ⁿ , Gillmor, A.H.^d ^e ^f , Lee, J.J.Y.^a ^b ^c , Zhang, X.Y.^a , Daniels, C.^a ^c , Dirks, P.^a ^c ^o ^p , Malkin, D.^g ^q , Bouffet, E.^c ^q , Tabori, U.^c ⁿ ^q , Loukides, J.^c , Doz, F.P.^r , Bourdeaut, F.^r , Delattre, O.O.^s , Masliah-Planchon, J.^t , Ayrault, O.^u , Kim, S.-K.^v , Meyronet, D.^w , Grajkowska, W.A.^x , Carlotti, C.G.^y , de Torres, C.^z , Mora, J.^z , Eberhart, C.G.^aa , Van Meir, E.G.^ab , Kumabe, T.^ac , French, P.J.^ad , Kros, J.M.^ae , Jabado, N.^af , Lach, B.^ag ^ah , Pollack, I.F.^ai , Hamilton, R.L.^aj , Rao, A.A.N.^ak , Giannini, C.^al , Olson, J.M.^am , Bognár, L.^an , Klekner, A.^an , Zitterbart, K.^ao , Phillips, J.J.^ap ^aq , Thompson, R.C.^ar , Cooper, M.K.^as , Rubin, J.B.^at , Liau, L.M.^au , Garami, M.^av , Hauser, P.^av , Li, K.K.W.^aw , Ng, H.-K.^aw , Poon, W.S.^ax , Yancey Gillespie, G.^ay , Chan, J.A.^f , Jung, S.^az , McLendon, R.E.^ba ^bb , Thompson, E.M.^bb , Zagzag, D.^bc , Vibhakar, R.^bd , Ra, Y.S.^be , Garre, M.L.^bf , Schüller, U.^bg ^bh ^bi , Shofuda, T.^bj , Faria, C.C.^bk ^bl , López-Aguilar, E.^bm , Zadeh, G.^bn ^bo , Hui, C.-C.^a ^p , Ramaswamy, V.^a ^c ^g ^q , Bailey, S.D.^bp ^bq , Jones, S.J.^k ^br ^bs , Mungall, A.J.^k , Moore, R.A.^k , Calarco, J.A.^bt , Stein, L.D.^p ^bu , Bader, G.D.^p ^bv , Reimand, J.^g ^j ^p , Ragoussis, J.^h ⁱ , Weiss, W.A.^l ^ap ^bw , Marra, M.A.^k ^br , Suzuki, H.^a ^c , Taylor, M.D.^a ^b ^c ^g ^o ^bx

^a Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
^b Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
^c The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
^d Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^e Alberta Children’s Hospital Research Institute, Calgary, AB, Canada
^f Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
^g Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
^h McGill University Genome Centre, McGill University, Montreal, QC, Canada
ⁱ Department of Human Genetics, McGill University, Montreal, QC, Canada
^j Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
^k Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
^l Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^m Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, United States
ⁿ Institute of Medical Science, University of Toronto, Toronto, ON, Canada
^o Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
^p Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
^q Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
^r SIREDO Center (pediatric, adolescent and young adults oncology), Institut Curie, University of Paris, Paris, France
^s INSERM U 830, Institut Curie, Paris, France
^t Unit of Somatic Genetics, Institut Curie, Paris, France
^u PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie, Paris, France
^v Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
^w Hospices Civils de Lyon, Institute of Pathology, University Lyon 1, Department of Cancer Cell Plasticity–INSERM U1052 Cancer Research Center of Lyon, Lyon, France
^x Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
^y Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
^z Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
^aa Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, MD, United States
^ab Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, United States
^ac Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
^ad Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands
^ae Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
^af Division of Experimental Medicine, McGill University, Montreal, QC, Canada
^ag Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada
^ah Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON, Canada
^ai Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^aj Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^ak Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, United States
^al Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^am Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
^an Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary
^ao Department of Pediatric Oncology, Masaryk University School of Medicine, Brno, Czech Republic
^ap Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
^aq Department of Pathology, University of California San Francisco, San Francisco, CA, United States
^ar Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States
^as Department of Neurology, Vanderbilt Medical Center, Nashville, TN, United States
^at Departments of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^au Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
^av 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
^aw Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
^ax Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
^ay Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States
^az Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Jeollanam-do, South Korea
^ba Department of Pathology, Duke University, Durham, NC, United States
^bb Department of Neurosurgery, Duke University, Durham, NC, United States
^bc Department of Pathology and Neurosurgery, NYU Grossman School of Medicine and NYU Langone Health, New York, NY, United States
^bd Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States
^be Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea
^bf U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy
^bg Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany
^bh Research Institute Children’s Cancer Center, Hamburg, Germany
^bi Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany
^bj Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan
^bk Division of Neurosurgery, Centro Hospitalar Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal
^bl Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
^bm Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional century XXI, Mexico City, Mexico
^bn Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
^bo MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
^bp Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
^bq Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
^br Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
^bs Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, BC, Canada
^bt Department of Cell & Systems Biology, University of Toronto, Toronto, ON, Canada
^bu Adaptive Oncology, Ontario Institute for Cancer Research, Toronto, ON, Canada
^bv The Donnelly Centre, University of Toronto, Toronto, ON, Canada
^bw Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
^bx Department of Surgery, University of Toronto, Toronto, ON, Canada

Abstract
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention. © 2021, The Author(s).

Funding details
Stand Up To CancerSU2CSU2C-AACR-DT1113
University of TorontoU of T
Brain Tumour Foundation of Canada
Cancer Research SocietyCRS
Cancer Research UKCRUK
Government of Canada
SU2C-AACR-DT-19-15
Government of Ontario
Genome British Columbia
National Institutes of HealthNIH
Swifty Foundation
Worldwide Cancer ResearchWCR
Brain Tumour Charity
Pediatric Brain Tumor FoundationPBTF
10XS170
Canadian Cancer Society
Genome Canada
National Institutes of HealthNIH
National Institutes of HealthNIHR01CA159859, R01CA148699
X10S172, HHSN268201000029C
Ontario Institute for Cancer ResearchOICR
National Center for Research ResourcesNCRRP41 GM103504
Hospital for Sick ChildrenSickKids
Canada Foundation for InnovationCFI
Canadian Institutes of Health ResearchCIHR
Roswell Park Cancer InstituteRPCI10XS171
Ontario Research FoundationORF
National Cancer InstituteNCI
Terry Fox Research InstituteTFRI

Document Type: Article
Publication Stage: Final
Source: Scopus

“The predictive value of absolute lymphocyte counts on tumor progression and pseudoprogression in patients with glioblastoma” (2021) BMC Cancer

The predictive value of absolute lymphocyte counts on tumor progression and pseudoprogression in patients with glioblastoma
(2021) BMC Cancer, 21 (1), art. no. 285, .

Xi, J.^a ^b , Hassan, B.^c , Katumba, R.G.N.^a , Khaddour, K.^d , Govindan, A.^e ^f , Luo, J.^g , Huang, J.^h , Campian, J.L.^a

^a Department of Medicine Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, St Louis, MO 63110, United States
^b Department of Internal Medicine, Washington University School of Medicine, 666 S. Euclid Ave, Campus Box#8056, St. Louis, MO 63110, United States
^c Trinity Health, 20555 Victor Parkway, Livonia, MI 48152, United States
^d Department of Internal Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, 820 S Wood Street (MC 675) Suite 100, Chicago, IL 60612, United States
^e University College, Washington University in St. Louis, St. Louis, MO 63110, United States
^f Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
^g Department of Surgery and Siteman Cancer Center Biostatistics Core, Division of Public Health Sciences, Washington University School of Medicine, 666 S. Euclid Ave, Campus Box #8100, St. Louis, United States
^h Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview Place, Campus Box #8224, St Louis, MO 63110, United States

Abstract
Background: Differentiating true glioblastoma multiforme (GBM) from pseudoprogression (PsP) remains a challenge with current standard magnetic resonance imaging (MRI). The objective of this study was to explore whether patients’ absolute lymphocyte count (ALC) levels can be utilized to predict true tumor progression and PsP. Methods: Patients were considered eligible for the study if they had 1) GBM diagnosis, 2) a series of blood cell counts and clinical follow-ups, and 3) tumor progression documented by both MRI and pathology. Data analysis results include descriptive statistics, median (IQR) for continuous variables and count (%) for categorical variables, p values from Wilcoxon rank sum test or Fisher’s exact test for comparison, respectively, and Kaplan-Meier analysis for overall survival (OS). OS was defined as the time from patients’ second surgery to their time of death or last follow up if patients were still alive. Results: 78 patients were included in this study. The median age was 56 years. Median ALC dropped 34.5% from baseline 1400 cells/mm3 to 917 cells/mm3 after completion of radiation therapy (RT) and temozolomide (TMZ). All study patients had undergone surgical biopsy upon MRI-documented progression. 37 had true tumor progression (47.44%) and 41 had pseudoprogression (52.56%). ALC before RT/TMZ, post RT/TMZ and at the time of MRI-documented progression did not show significant difference between patients with true progression and PsP. Although not statistically significant, this study found that patients with true progression had worse OS compared to those with PsP (Hazard Ratio [HR] 1.44, 95% CI 0.86–2.43, P = 0.178). This study also found that patients with high ALC (dichotomized by median) post-radiation had longer OS. Conclusion: Our results indicate that ALC level in GBM patients before or after treatment does not have predictive value for true disease progression or pseudoprogression. Patients with true progression had worse OS compared to those who had pseudoprogression. A larger sample size that includes CD4 cell counts may be needed to evaluate the PsP predictive value of peripheral blood biomarkers. © 2021, The Author(s).

Author Keywords
Absolute lymphocyte count; Glioblastoma; Prognosis; Pseudoprogression

Document Type: Article
Publication Stage: Final
Source: Scopus

“Severity of parkinsonism associated with environmental manganese exposure” (2021) Environmental Health: A Global Access Science Source

Severity of parkinsonism associated with environmental manganese exposure
(2021) Environmental Health: A Global Access Science Source, 20 (1), art. no. 27, .

Racette, B.A.^a ^b , Nelson, G.^b ^c , Dlamini, W.W.^a , Prathibha, P.^d , Turner, J.R.^d , Ushe, M.^a , Checkoway, H.^e , Sheppard, L.^f , Nielsen, S.S.^a

^a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, United States
^b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa
^c Research Department of Infection & Population Health, UCL Institute for Global Health, University College London, London, United Kingdom
^d Department of Energy, Environmental, and Chemical Engineering, Washington University, Campus Box 1180, One Brookings Drive, St. Louis, MO 63130, United States
^e Department of Family Medicine & Public Health, University of California, 9500 Gilman Drive, # 0725, La Jolla, San Diego, CA 92093-0725, United States
^f Departments of Biostatistics and Environmental and Occupational Health Sciences, University of Washington, Box 357232, Seattle, WA 98195, United States

Abstract
Background: Exposure to occupational manganese (Mn) is associated with neurotoxic brain injury, manifesting primarily as parkinsonism. The association between environmental Mn exposure and parkinsonism is unclear. To characterize the association between environmental Mn exposure and parkinsonism, we performed population-based sampling of residents older than 40 in Meyerton, South Africa (N = 621) in residential settlements adjacent to a large Mn smelter and in a comparable non-exposed settlement in Ethembalethu, South Africa (N = 95) in 2016–2020. Methods: A movement disorders specialist examined all participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3). Participants also completed an accelerometry-based kinematic test and a grooved pegboard test. We compared performance on the UPDRS3, grooved pegboard, and the accelerometry-based kinematic test between the settlements using linear regression, adjusting for covariates. We also measured airborne PM2.5-Mn in the study settlements. Results: Mean PM2.5-Mn concentration at a long-term fixed site in Meyerton was 203 ng/m3 in 2016–2017 – approximately double that measured at two other neighborhoods in Meyerton. The mean Mn concentration in Ethembalethu was ~ 20 times lower than that of the long-term Meyerton site. UPDRS3 scores were 6.6 (CI 5.2, 7.9) points higher in Meyerton than Ethembalethu residents. Mean angular velocity for finger-tapping on the accelerometry-based kinematic test was slower in Meyerton than Ethembalethu residents [dominant hand 74.9 (CI 48.7, 101.2) and non-dominant hand 82.6 (CI 55.2, 110.1) degrees/second slower]. Similarly, Meyerton residents took longer to complete the grooved pegboard, especially for the non-dominant hand (6.9, CI -2.6, 16.3 s longer). Conclusions: Environmental airborne Mn exposures at levels substantially lower than current occupational exposure thresholds in the United States may be associated with clinical parkinsonism. © 2021, The Author(s).

Author Keywords
Case control studies; Manganese; Parkinson disease; Parkinsonism

Funding details
National Institute of Environmental Health SciencesNIEHSK01ES028295, K24ES017765, R01ES025991-02S1

Document Type: Article
Publication Stage: Final
Source: Scopus

“Comparing two approaches to remote biochemical verification of self-reported cessation in very low-income smokers” (2021) Addictive Behaviors Reports

Comparing two approaches to remote biochemical verification of self-reported cessation in very low-income smokers
(2021) Addictive Behaviors Reports, 13, art. no. 100343, .

Garg, R.^a , McQueen, A.^a ^b , Wolff, J.^a , Butler, T.^a , Thompson, T.^a , Caburnay, C.^a , Kreuter, M.W.^a

^a Health Communication Research Laboratory, Brown School, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
^b Division of General Medical Sciences, School of Medicine, Washington University in St. Louis, 4523 Clayton Avenue, Campus, Box 8005, St. Louis, MO 63110, United States

Abstract
Little is known about the acceptability and use of remote biochemical verification of self-reported cessation among low-income and racially diverse smokers. We compared responses to an in-person carbon monoxide breath test and in-home urine cotinine test among 270 adults who reported 7-day continuous abstinence at 6-month follow-up in a community-based randomized cessation trial. Half of participants (50%) reported annual household income below $10,000, one in four (28%) had not completed high school, and 69% were Black or African American. Regardless of whether the two tests were offered separately, sequentially, or as a head-to-head choice, participants were more likely to accept an offer to take the urine test than the breath test (89% vs. 32%), and complete it (46% vs. 13%). The proportion of participants completing the urine test and returning a digital photo of the test result is comparable to several studies completed with less disadvantaged samples. Self-report was confirmed by urine test for 74% of participants with a conclusive test result, although a high percentage (39%) of test results were inconclusive. In-home urine testing appears both acceptable and feasible for many low-income smokers, but challenges with testing technology and response rates currently limit its value to increase confidence in self-reports. © 2021 The Authors

Author Keywords
Biochemical verification; Cotinine; Low-income; Minority health; Smoking cessation

Funding details
National Institutes of HealthNIHR01CA201429
National Cancer InstituteNCI

Document Type: Article
Publication Stage: Final
Source: Scopus

“Simulation of harmonic shear waves in the human brain and comparison with measurements from magnetic resonance elastography” (2021) Journal of the Mechanical Behavior of Biomedical Materials

Simulation of harmonic shear waves in the human brain and comparison with measurements from magnetic resonance elastography
(2021) Journal of the Mechanical Behavior of Biomedical Materials, 118, art. no. 104449, .

Li, Y.^a ^c , Okamoto, R.^b , Badachhape, A.^b , Wu, C.^a , Bayly, P.^b , Daphalapurkar, N.^c ^d

^a Department of Engineering Mechanics, Dalian University of Technology, Dalian, China
^b Department of Mechanical Engineering and Materials Science, Washington University in Saint Louis MO, United States
^c Hopkins Extreme Materials Institute, Johns Hopkins University, Baltimore, MD, United States
^d Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States

Abstract
Magnetic Resonance Elastography (MRE) provides a non-invasive method to characterize the mechanical response of the living brain subjected to harmonic loading conditions. The peak magnitude of the harmonic strain is small and the excitation results in harmless deformation waves propagating through the brain. In this paper, we describe a three-dimensional computational model of the brain for comparison of simulated harmonic deformations of the brain with MRE measurements. Relevant substructures of the head were constructed from MRI scans. Harmonic wave motions in a live human brain obtained in an MRE experiment were used to calibrate the viscoelastic properties at 50 Hz and assess accuracy of the computational model by comparing the measured and the simulated harmonic response of the brain. Quantitative comparison of strain field from simulations with measured data from MRE shows that the harmonic deformation of the brain tissue is responsive to changes in the viscoelastic properties, loss and storage moduli, of the brain. The simulation results demonstrate, in agreement with MRE measurements, that the presence of the falx and tentorium membranes alter the spatial distribution of harmonic deformation field and peak strain amplitudes in the computational model of the brain. © 2021

Author Keywords
Brain biomechanics; Finite element method; Shear waves; Viscoelasticity

Funding details
National Institutes of HealthNIHR01NS055951
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

“Predicting alcohol use disorder remission: a longitudinal multimodal multi-featured machine learning approach” (2021) Translational Psychiatry

Predicting alcohol use disorder remission: a longitudinal multimodal multi-featured machine learning approach
(2021) Translational Psychiatry, 11 (1), art. no. 166, .

Kinreich, S.^a , McCutcheon, V.V.^b , Aliev, F.^c ^d , Meyers, J.L.^a , Kamarajan, C.^a , Pandey, A.K.^a , Chorlian, D.B.^a , Zhang, J.^a , Kuang, W.^a , Pandey, G.^a , Viteri, S.S.-S.^a , Francis, M.W.^e , Chan, G.^f , Bourdon, J.L.^b , Dick, D.M.^c , Anokhin, A.P.^b , Bauer, L.^f , Hesselbrock, V.^f , Schuckit, M.A.^g , Nurnberger, J.I., Jr.^h , Foroud, T.M.ⁱ , Salvatore, J.E.^j ^k , Bucholz, K.K.^b , Porjesz, B.^a

^a Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
^b Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^d Faculty of Business, Karabuk University, Karabük, Turkey
^e Brown School of Social Work / Department of Psychiatry, Washington University in Saint Louis, St. Louis, MO, United States
^f Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^g Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, CA, United States
^h Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis, IN, United States
^j Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^k Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) who were initially assessed as having AUD (DSM-5) and reassessed years later as either having AUD or in remission. To predict this difference in AUD recovery status, we analyzed the initial data using multimodal, multi-features machine learning applications including EEG source-level functional brain connectivity, Polygenic Risk Scores (PRS), medications, and demographic information. Sex and ancestry age-matched stratified analyses were performed with supervised linear Support Vector Machine application and were calculated twice, once when the ancestry was defined by self-report and once defined by genetic data. Multifeatured prediction models achieved higher accuracy scores than models based on a single domain and higher scores in male models when the ancestry was based on genetic data. The AA male group model with PRS, EEG functional connectivity, marital and employment status features achieved the highest accuracy of 86.04%. Several discriminative features were identified, including collections of PRS related to neuroticism, depression, aggression, years of education, and alcohol consumption phenotypes. Other discriminated features included being married, employed, medication, lower default mode network and fusiform connectivity, and higher insula connectivity. Results highlight the importance of increasing genetic homogeneity of analyzed groups, identifying sex, and ancestry-specific features to increase prediction scores revealing biomarkers related to AUD remission. © 2021, The Author(s).

Funding details
National Institute on Alcohol Abuse and AlcoholismNIAAAU10AA008401

Document Type: Article
Publication Stage: Final
Source: Scopus

“Evaluation of interim MRI changes during limited-field radiation therapy for glioblastoma and implications for treatment planning” (2021) Radiotherapy and Oncology

Evaluation of interim MRI changes during limited-field radiation therapy for glioblastoma and implications for treatment planning
(2021) Radiotherapy and Oncology, 158, pp. 237-243.

Hassanzadeh, C.^a , Rudra, S.^a , Ma, S.^a , Brenneman, R.^a , Huang, Y.^a , Henke, L.^a , Abraham, C.^a , Campian, J.^b , Tsien, C.^a , Huang, J.^a

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, United States
^b Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, United States

Abstract
Background and purpose: Consensus for defining gross tumor volume (GTV) and clinical target volume (CTV) for limited-field radiation therapy (LFRT) of GBM are not well established. We leveraged a department MRI simulator to image patients before and during LFRT to address these questions. Materials and methods: Supratentorial GBM patients receiving LFRT (46 Gy + boost to 60 Gy) underwent baseline MRI (MRI1) and interim MRI during RT (MRI2). GTV1 was defined as T1 enhancement + surgical cavity on MRI1 without routine inclusion of T2 abnormality (unless tumor did not enhance). The initial CTV margin was 15 mm from GTV1, and the boost CTV margin was 5–7 mm. The GTV1 characteristics were categorized into three groups: identical T1 and T2 abnormality (Group A), T1 only with larger T2 abnormality not included (Group B), and T2 abnormality when tumor lacked enhancement (Group C). GTV2 was contoured on MRI2 and compared with GTV1 plus 5–15 mm expansions. Results: Among 120 patients treated from 2014-2019, 29 patients (24%) underwent replanning based on MRI2. On MRI2, 84% of GTV2 were covered by GTV1 + 5 mm, 93% by GTV1 + 7 mm, and 98% by GTV1 + 15 mm. On MRI1, 43% of GTV1 could be categorized into Group A, 39% Group B, and 18% Group C. Group B’s patterns of failure, local control, or progression-free survival were similar to Group A/C. Conclusions: Initial CTV margin of 15 mm followed by a boost CTV margin of 7 mm is a reasonable approach for LFRT of GBM. Omitting routine inclusion of T2 abnormality from GTV delineation may not jeopardize disease control. © 2021 Elsevier B.V.

Author Keywords
Chemoradiation; Glioblastoma; Interim MRI; Limited field RT; Pattern of failure

Funding details
Alvin J. Siteman Cancer Center
National Cancer InstituteNCIP30 CA091842
AbbVie
Pfizer

Document Type: Article
Publication Stage: Final
Source: Scopus

“Impact of New Motor Deficit on HRQOL After Adult Spinal Deformity Surgery: Subanalysis From Scoli Risk 1 Prospective Study” (2021) Spine

Impact of New Motor Deficit on HRQOL After Adult Spinal Deformity Surgery: Subanalysis From Scoli Risk 1 Prospective Study
(2021) Spine, 46 (7), pp. E450-E457.

Saigal, R.^a , Lau, D.^a , Berven, S.H.^a , Carreon, L.^b , Dekutoski, M.B.^c , Kebaish, K.M.^d , Qiu, Y.^e , Matsuyama, Y.^f , Kelly, M.^g , Dahl, B.T.^h , Mehdian, H.ⁱ ^j , Pellisé, F.^k , Lewis, S.J.^l , Cheung, K.M.C.^m , Shaffrey, C.I.ⁿ , Fehlings, M.G.^l , Lenke, L.G.^o , Ames, C.P.^a , AOSpine Knowledge Forum Deformity^p

^a Department of Neurosurgery and Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA
^b Norton Leatherman Spine Center, KY, Louisville, United States
^c Marshfield Medical Center – Eau Claire Center, WI, Eau Claire, United States
^d Department of Orthopaedic Surgery, Johns Hopkins Hospital, MD, Baltimore, United States
^e Spine Surgery, Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
^f Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
^g Department of Orthopedic Surgery, Washington University, St. Louis, MO
^h Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
ⁱ Texas Children’s Hospital and Baylor College of Medicine, TX, Houston
^j Centre for Spinal Studies and Surgery, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, United Kingdom
^k Hospital Universitari de la Vall d’Hebron, Barcelona, Spain
^l University of Toronto Spine Program, Toronto Western Hospital, Toronto, ON, Canada
^m Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
ⁿ Department of Orthopaedic Surgery, Duke University, Durham
^o Daniel and Jane Och Spine Hospital, Columbia University Department of Orthopaedic Surgery, NY, NY

Abstract
STUDY DESIGN: International, multicenter, prospective, longitudinal observational cohort. OBJECTIVE: To assess how new motor deficits affect patient reported quality of life scores after adult deformity surgery. SUMMARY OF BACKGROUND DATA: Adult spinal deformity surgery is associated with high morbidity, including risk of new postoperative motor deficit. It is unclear what effect new motor deficit has on Health-related Quality of Life scores (HRQOL) scores. METHODS: Adult spinal deformity patients were enrolled prospectively at 15 sites worldwide. Other inclusion criteria included major Cobb more than 80°, C7-L2 curve apex, and any patient undergoing three column osteotomy. American Spinal Injury Association (ASIA) scores and standard HRQOL scores were recorded pre-op, 6 weeks, 6 months, and 2 years. RESULTS: Two hundred seventy two complex adult spinal deformity (ASD) patients enrolled. HRQOL scores were worse for patients with lower extremity motor score (LEMS). Mean HRQOL changes at 6 weeks and 2 years compared with pre-op for patients with motor worsening were: ODI (+12.4 at 6 weeks and -4.7 at 2 years), SF-36v2 physical (-4.5 at 6 weeks and +2.3 at 2 years), SRS-22r (0.0 at 6 weeks and +0.4 at 2 years). Mean HRQOL changes for motor-neutral patients were: ODI (+0.6 at 6 weeks and -12.1 at 2 years), SF-36v2 physical (-1.6 at 6 weeks and +5.9 at 2 years), and SRS-22r (+0.4 at 6 weeks and +0.7 at 2 years). For patients with LEMS improvement, mean HRQOL changes were: ODI (-0.6 at 6 weeks and -16.3 at 2 years), SF-36v2 physical (+1.0 at 6 weeks and +7.0 at 2 years), and SRS-22r (+0.5 at 6 weeks and +0.9 at 2 years). CONCLUSION: In the subgroup of deformity patients who developed a new motor deficit, total HRQOLs and HRQOL changes were negatively impacted. Patients with more than 2 points of LEMS worsening had the worst changes, but still showed overall HRQOL improvement at 6 months and 2 years compared with pre-op baseline.Level of Evidence: 3. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Does Pollen Trigger Urological Chronic Pelvic Pain Syndrome Flares? A Case-Crossover Analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network” (2021) The Journal of Urology

Does Pollen Trigger Urological Chronic Pelvic Pain Syndrome Flares? A Case-Crossover Analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network
(2021) The Journal of Urology, 205 (4), pp. 1133-1138.

Javed, I.^a ^b , Yu, T.^a ^b ^c , Li, J.^a ^b ^d , Pakpahan, R.^a , Milbrandt, M.^a ^e , Andriole, G.L.^f , Lowder, J.L.^g , Lai, H.H.^e ^f , Colditz, G.A.^a , Sutcliffe, S.^a ^g

^a Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Brown School at Washington University in St. Louis, St. Louis, MO, United States
^c Health Advocate, Westlake Village, CA, United States
^d STATinMED Research, Plano, TX, United States
^e Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^f Division of Urological Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^g Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
PURPOSE: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares. MATERIALS AND METHODS: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants’ zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders. RESULTS: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples. CONCLUSIONS: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Author Keywords
cystitis, interstitial; pelvic pain; pollen; prostatitis; symptom flare up

Document Type: Article
Publication Stage: Final
Source: Scopus

“Physical activity, sedentary behaviour and cannabis use in 15,822 US adults: cross-sectional analyses from NHANES” (2021) Public Health

Physical activity, sedentary behaviour and cannabis use in 15,822 US adults: cross-sectional analyses from NHANES
(2021) Public Health, 193, pp. 76-82.

Smith, L.^a , Sherratt, F.^b , Barnett, Y.^c , Cao, C.^d , Tully, M.A.^e , Koyanagi, A.^f ^g , Jacob, L.^f ^h , Soysal, P.ⁱ , López Sánchez, G.F.^j , Shin, J.I.^k , Yang, L.^l

^a The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom
^b Engineering and the Built Environment, Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, United Kingdom
^c Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, United Kingdom
^d Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
^e Centre for Health and Rehabilitation Technologies, Institute of Nursing and Health Research, School of Health Sciences, Ulster University, Newtownabbey, United Kingdom
^f Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, Dr. Antoni Pujadas, 42, Sant Boi de Llobregat, Barcelona, 08830, Spain
^g ICREA, Pg. Lluis Companys 23, Barcelona, Spain
^h Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France
ⁱ Department of Geriatric Medicine, Bezmialem Vakif University, Istanbul, 34093, Turkey
^j Faculty of Sport Sciences, University of Murcia, Murcia, 30720, Spain
^k Department of Paediatrics, Yonsei University College of Medicine
^l Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Canada

Abstract
Objectives: The aim was to analyse the overall and sex-specific associations between cannabis use and physical activity and sedentary behaviour. Study design: Cross-sectional analyses from the National Health and Nutrition Examination Survey (NHANES). Methods: Data on cannabis use and leisure time physical activity and sedentary behaviour from NHANES cycles 2007–2008 to 2015–2016 were analysed. Multivariable regression models were carried out. Results: About 15,822 participants were analysed (mean age ± standard error = 37.5 ± 0.19 years, range 20–59 years). Significantly higher odds were found for being active and ever used cannabis in the overall sample (odds ratio [OR] = 1.2, 95% confidence interval [CI]: 1.1–1.4) and in males (OR = 1.3, 95% CI: 1.1 to 1.5) and females (OR = 1.2, 95% CI: 1.0–1.4), respectively. In respective of sedentary behaviour, ever used cannabis was associated with higher odds of TV viewing ≥2 h/day in the overall sample (OR = 1.2, 95% CI: 1.0–1.4). However, this association was observed in males only (OR = 1.3, 95% CI: 1.1–1.6). Ever used cannabis was associated with total sitting time (beta-coefficient = 0.3, 95%CI: 0.1–0.4), which was more evident in females (beta-coefficient = 0.4, 95% CI: 0.1–0.6). Conclusions: Cannabis consumption was associated with higher levels of physical activity and sitting time. When intervening to reduce cannabis consumption in the US populations, it may be appropriate to promote physical activity and ensure physical activity is maintained once cannabis consumption is stopped. © 2021 The Royal Society for Public Health

Author Keywords
Cannabis; NHANES; Physical activity; Sedentary; USA

Document Type: Article
Publication Stage: Final
Source: Scopus

“Brain network reorganisation in an adolescent after bilateral perinatal strokes” (2021) The Lancet Neurology

Brain network reorganisation in an adolescent after bilateral perinatal strokes
(2021) The Lancet Neurology, 20 (4), pp. 255-256.

Laumann, T.O.^a ^c , Ortega, M.^a , Hoyt, C.R.^a ^f , Seider, N.A.^a , Snyder, A.Z.^a ^b , Dosenbach, N.U.^a ^b ^d ^e ^f , Siegel, J.S.^g , Nguyen, A.L.^g , Dierker, D.L.^g , Coalson, R.S.^g , Adeyemo, B.^g , Marek, S.^g , Gilmore, A.W.^g , Nelson, S.M.^g , Shimony, J.S.^g , Greene, D.J.^g , Raichle, M.E.^g , Gordon, E.M.^g , Petersen, S.E.^g , Schlaggar, B.L.^g , Brain Network Plasticity Group^h

^a Department of Neurology, Washington University, St Louis, MO 63110, United States
^b Department of Radiology, Washington University, St Louis, MO 63110, United States
^c Department of Psychiatry, Washington University, St Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University, St Louis, MO 63110, United States
^e Department of Pediatrics, Washington University, St Louis, MO 63110, United States
^f Program in Occupational Therapy, Washington University, St Louis, MO 63110, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

“Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial” (2021) The Lancet Neurology

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial
(2021) The Lancet Neurology, 20 (4), pp. 284-293. Cited 1 time.

Day, J.W.^a , Finkel, R.S.^b ^c , Chiriboga, C.A.^d , Connolly, A.M.^e ^f ^g ^h , Crawford, T.O.ⁱ ^j , Darras, B.T.^k , Iannaccone, S.T.^l , Kuntz, N.L.^m , Peña, L.D.M.ⁿ ^o , Shieh, P.B.^p , Smith, E.C.^q , Kwon, J.M.^r , Zaidman, C.M.^s , Schultz, M.^u , Feltner, D.E.^u , Tauscher-Wisniewski, S.^u , Ouyang, H.^u , Chand, D.H.^t ^u ^u , Sproule, D.M.^u , Macek, T.A.^u , Mendell, J.R.^f ^g ^h

^a Department of Neurology, Stanford University Medical Center, Palo Alto, CA, United States
^b Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL, United States
^c Center for Experimental Neurotherapeutics, St Jude Children’s Research Hospital, Memphis, TN, United States
^d Division of Pediatric Neurology, Columbia University Medical Center, New York, NY, United States
^e Department of Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
^f Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States
^g Department of Pediatrics, Ohio State University, Columbus, OH, United States
^h Department of Neurology, Ohio State University, Columbus, OH, United States
ⁱ Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
^j Department of Pediatrics, Johns Hopkins Medicine, Baltimore, MD, United States
^k Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^l Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
^m Division of Neurology, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, United States
ⁿ Division of Human Genetics, Cincinnati Children’s Hospital, Cincinnati, OH, United States
^o Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^p Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
^q Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
^r Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^s Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^t Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^u Novartis Gene Therapies, Bannockburn, IL, United States

Abstract
Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy. Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30–60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed). Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36–100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79–100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8–44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus). Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. Funding: Novartis Gene Therapies. © 2021 Elsevier Ltd

Funding details
Spinal Muscular Atrophy FoundationSMAF
Advanced Manufacturing OfficeAMO
CytokineticsCYTK
Ionis Pharmaceuticals
Pfizer
National Institutes of HealthNIH
PTC TherapeuticsPTC
Roche
Spinal Muscular Atrophy FoundationSMAF
CSL Behring
Biogen
Sarepta TherapeuticsSRPT
Muscular Dystrophy AssociationMDA
FibroGen
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

“Biological Mechanisms of Cognitive and Physical Impairments after Critical Care Rethinking the Inflammatory Model?” (2021) American Journal of Respiratory and Critical Care Medicine

Biological Mechanisms of Cognitive and Physical Impairments after Critical Care Rethinking the Inflammatory Model?
(2021) American Journal of Respiratory and Critical Care Medicine, 203 (6), pp. 665-667.

Parker, A.M.^a ^b , Sinha, P.^c , Needham, D.M.^a ^b ^d

^a Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Outcomes After Surgery and Critical Illness Research Group, Johns Hopkins University, Baltimore, MD, United States
^c Department of Anesthesia, Washington University, St. Louis, MO, United States
^d Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Funding details
National Heart, Lung, and Blood InstituteNHLBIK23HL138206

Document Type: Editorial
Publication Stage: Final
Source: Scopus

“A conserved role for sleep in supporting Spatial Learning in Drosophila” (2021) Sleep

A conserved role for sleep in supporting Spatial Learning in Drosophila
(2021) Sleep, 44 (3), .

Melnattur, K.^a , Kirszenblat, L.^b ^c , Morgan, E.^a , Militchin, V.^d , Sakran, B.^a , English, D.^a , Patel, R.^a , Chan, D.^a , van Swinderen, B.^b , Shaw, P.J.^a

^a Department of Neuroscience, Washington University School of Medicine, St Louis, MO
^b Queensland Brain Institute, University of Queensland, St Lucia, Australia
^c RIKEN Center for Brain Science, Wako, Saitama, Japan
^d Department of Otolaryngology, Washington University School of Medicine, St Louis, MO

Abstract
Sleep loss and aging impair hippocampus-dependent Spatial Learning in mammalian systems. Here we use the fly Drosophila melanogaster to investigate the relationship between sleep and Spatial Learning in healthy and impaired flies. The Spatial Learning assay is modeled after the Morris Water Maze. The assay uses a “thermal maze” consisting of a 5 × 5 grid of Peltier plates maintained at 36-37°C and a visual panorama. The first trial begins when a single tile that is associated with a specific visual cue is cooled to 25°C. For subsequent trials, the cold tile is heated, the visual panorama is rotated and the flies must find the new cold tile by remembering its association with the visual cue. Significant learning was observed with two different wild-type strains-Cs and 2U, validating our design. Sleep deprivation prior to training impaired Spatial Learning. Learning was also impaired in the classic learning mutant rutabaga (rut); enhancing sleep restored learning to rut mutants. Further, we found that flies exhibited a dramatic age-dependent cognitive decline in Spatial Learning starting at 20-24 days of age. These impairments could be reversed by enhancing sleep. Finally, we find that Spatial Learning requires dopaminergic signaling and that enhancing dopaminergic signaling in aged flies restored learning. Our results are consistent with the impairments seen in rodents and humans. These results thus demonstrate a critical conserved role for sleep in supporting Spatial Learning, and suggest potential avenues for therapeutic intervention during aging. Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2020.

Author Keywords
Drosophila; aging; plasticity; sleep; Spatial Learning

Document Type: Article
Publication Stage: Final
Source: Scopus

“Prior sleep problems and adverse post-traumatic neuropsychiatric sequelae of motor vehicle collision in the AURORA study” (2021) Sleep

Prior sleep problems and adverse post-traumatic neuropsychiatric sequelae of motor vehicle collision in the AURORA study
(2021) Sleep, 44 (3), .

Neylan, T.C.^a ^b ^c , Kessler, R.C.^d , Ressler, K.J.^e ^f , Clifford, G.^g ^h , Beaudoin, F.L.ⁱ ^j ^k ^l , An, X.^m , Stevens, J.S.ⁿ , Zeng, D.^o , Linnstaedt, S.D.^m , Germine, L.T.^e ^p ^q , Sheikh, S.^r , Storrow, A.B.^s , Punches, B.E.^t ^u , Mohiuddin, K.^v ^w , Gentile, N.T.^x , McGrath, M.E.^y , van Rooij, S.J.H.ⁿ , Haran, J.P.^z , Peak, D.A.^aa , Domeier, R.M.^ab , Pearson, C.^ac , Sanchez, L.D.^ad ^ae , Rathlev, N.K.^af , Peacock, W.F.^ag , Bruce, S.E.^ah , Joormann, J.^ai , Barch, D.M.^aj ^ak , Pizzagalli, D.A.^e , Sheridan, J.F.^al ^am ^an , Harte, S.E.^ao , Elliott, J.M.^ap ^aq ^ar , Hwang, I.^d , Petukhova, M.V.^d , Sampson, N.A.^d , Koenen, K.C.^as , McLean, S.A.^m ^at

^a San Francisco VA Healthcare System, San Francisco, CA
^b Department of Psychiatry, University of California, San Francisco, CA
^c Department of Neurology, University of California, San Francisco, CA
^d Department of Health Care Policy, Harvard Medical School, MA, Boston
^e Department of Psychiatry, Harvard Medical School, MA, Boston
^f Division of Depression and Anxiety Disorders, McLean Hospital, MA, Belmont
^g Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, United States
^h Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States
ⁱ Department of Emergency Medicine, The Alpert Medical School of Brown University, Providence, RI
^j Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, RI
^k Department of Emergency Medicine, Rhode Island Hospital, Providence, RI
^l Department of Emergency Medicine, The Miriam Hospital, Providence, RI
^m Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill
ⁿ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, United States
^o Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill
^p Institute for Technology in Psychiatry, McLean Hospital, MA, Belmont
^q Many Brains Project, MA, Acton
^r Department of Emergency Medicine, University of Florida College of Medicine-Jacksonville, FL, Jacksonville, United States
^s Department of Emergency Medicine, Vanderbilt University Medical Center, TN, Nashville, United States
^t Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
^u Department of Emergency Medicine, University of Cincinnati College of Nursing, Cincinnati, OH
^v Department of Internal Medicine, Einstein Medical Center, Philadelphia, United States
^w Department of Emergency Medicine, Einstein Medical Center, Philadelphia, United States
^x Department of Emergency Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, United States
^y Department of Emergency Medicine, Boston Medical Center, MA, Boston
^z Department of Emergency Medicine, University of Massachusetts Medical School, MA, Worcester
^aa Department of Emergency Medicine, Massachusetts General Hospital, MA, Boston
^ab Department of Emergency Medicine, Saint Joseph Mercy Hospital, MI, Ann Arbor, United States
^ac Wayne State University Department of Emergency Medicine, Ascension St. John Hospital, MI, Detroit, United States
^ad Department of Emergency Medicine, Beth Israel Deaconess Medical Center, MA, Boston
^ae Department of Emergency Medicine, Harvard Medical School, MA, Boston
^af Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, MA, Springfield
^ag Henry JN Taub Department of Emergency Medicine, Baylor College of Medicine, TX, Houston
^ah Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO
^ai Department of Psychology, Yale University, CT, New Haven, United States
^aj Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO
^ak Department of Psychiatry, and Radiology, Washington University in St. Louis, St. Louis, MO
^al Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH
^am College of Dentistry Division of Bioscience, Ohio State University, Columbus, OH
^an Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH
^ao Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan Medical School, MI, Ann Arbor, United States
^ap Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, St Leonards, NSW, Australia
^aq Faculty of Medicine and Health, University of Sydney, CamperdownNSW, Australia
^ar Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Mexico
^as Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston
^at Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill

Abstract
STUDY OBJECTIVES: Many patients in Emergency Departments (EDs) after motor vehicle collisions (MVCs) develop post-traumatic stress disorder (PTSD) or major depressive episode (MDE). This report from the AURORA study focuses on associations of pre-MVC sleep problems with these outcomes 8 weeks after MVC mediated through peritraumatic distress and dissociation and 2-week outcomes. METHODS: A total of 666 AURORA patients completed self-report assessments in the ED and at 2 and 8 weeks after MVC. Peritraumatic distress, peritraumatic dissociation, and pre-MVC sleep characteristics (insomnia, nightmares, daytime sleepiness, and sleep duration in the 30 days before the MVC, trait sleep stress reactivity) were assessed retrospectively in the ED. The survey assessed acute stress disorder (ASD) and MDE at 2 weeks and at 8 weeks assessed PTSD and MDE (past 30 days). Control variables included demographics, MVC characteristics, and retrospective reports about PTSD and MDE in the 30 days before the MVC. RESULTS: Prevalence estimates were 41.0% for 2-week ASD, 42.0% for 8-week PTSD, 30.5% for 2-week MDE, and 27.2% for 8-week MDE. Pre-MVC nightmares and sleep stress reactivity predicted 8-week PTSD (mediated through 2-week ASD) and MDE (mediated through the transition between 2-week and 8-week MDE). Pre-MVC insomnia predicted 8-week PTSD (mediated through 2-week ASD). Estimates of population attributable risk suggest that blocking effects of sleep disturbance might reduce prevalence of 8-week PTSD and MDE by as much as one-third. CONCLUSIONS: Targeting disturbed sleep in the immediate aftermath of MVC might be one effective way of reducing MVC-related PTSD and MDE. © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Author Keywords
insomnia; major depressive episode; motor vehicle collision; nightmares; post-traumatic stress disorder; prospective design; sleep stress reactivity

Document Type: Article
Publication Stage: Final
Source: Scopus

“Guidelines for Conducting Virtual Cognitive Interviews During a Pandemic” (2021) Journal of Medical Internet Research

Guidelines for Conducting Virtual Cognitive Interviews During a Pandemic
(2021) Journal of Medical Internet Research, 23 (3), p. e25173.

Shepperd, J.A.^a , Pogge, G.^a , Hunleth, J.M.^b , Ruiz, S.^b , Waters, E.A.^b

^a Department of Psychology, University of Florida, FL, Gainesville, United States
^b Department of Surgery, Division of Public Health Sciences, Washington University, St. Louis, MO, United States

Abstract
The COVID-19 pandemic has challenged researchers working in physical contact with research participants. Cognitive interviews examine whether study components (most often questionnaire items) are worded or structured in a manner that allows study participants to interpret the items in a way intended by the researcher. We developed guidelines to conduct cognitive interviews virtually to accommodate interviewees who have limited access to the internet. The guidelines describe the essential communication and safety equipment requirements and outline a procedure for collecting responses while maintaining the safety of the participants and researchers. Furthermore, the guidelines provide suggestions regarding training of participants to use the technology, encouraging them to respond aloud (a potential challenge given that the researcher is not physically present with the participant), and testing and deploying the equipment prior to the interview. Finally, the guidelines emphasize the need to adapt the interview to the circumstances and anticipate potential problems that might arise. ©James A Shepperd, Gabrielle Pogge, Jean M Hunleth, Sienna Ruiz, Erika A Waters. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.03.2021.

Author Keywords
cognitive interview; COVID-19; guidelines; pandemic; tablet computer; telehealth; teleresearch; training

Document Type: Article
Publication Stage: Final
Source: Scopus

“A Better Blood Test to Differentiate Epileptic From Psychogenic Nonepileptic Seizures?” (2021) Neurology

A Better Blood Test to Differentiate Epileptic From Psychogenic Nonepileptic Seizures?
(2021) Neurology, 96 (10), pp. 467-468.

Young, G.B., Thio, L.L.

From the Department of Clinical Neurological Sciences (G.B.Y.), University of Western Ontario, London, Canada; and Paediatric Neurology (L.L.T.), Washington University, St. Louis, MO

Document Type: Editorial
Publication Stage: Final
Source: Scopus

“Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses” (2021) eLife

Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses
(2021) eLife, 10, .

Norris, A.J.^a , Shaker, J.R.^b , Cone, A.L.^a , Ndiokho, I.B.^a , Bruchas, M.R.^c

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^b Medical Scientist Training Program, University of Washington, Seattle, United States
^c Center for the Neurobiology of Addiction, Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, United States

Abstract
Maintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic area of the hypothalamus (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate that the opioid system within the POA is vital in regulating body temperature. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides dynorphin and enkephalin. Using mouse models, we determine that warm-activated PBN neuronal populations overlap with both prodynorphin (Pdyn) and proenkephalin (Penk) expressing PBN populations. Here we report that in the PBN Prodynorphin (Pdyn) and Proenkephalin (Penk) mRNA expressing neurons are partially overlapping subsets of a glutamatergic population expressing Solute carrier family 17 (Slc17a6) (VGLUT2). Using optogenetic approaches we selectively activate projections in the POA from PBN Pdyn, Penk, and VGLUT2 expressing neurons. Our findings demonstrate that Pdyn, Penk, and VGLUT2 expressing PBN neurons are critical for physiological and behavioral heat defense. © 2021, Norris et al.

Author Keywords
mouse; neuroscience; optogenetics; parabrachial nucelus; preoptic area; temperature regualtion; thermal defense

Document Type: Article
Publication Stage: Final
Source: Scopus

“The American Opioid Epidemic: From Patient Care to Public Health” (2021) Journal of Psychiatric Practice

The American Opioid Epidemic: From Patient Care to Public Health
(2021) Journal of Psychiatric Practice, 27 (2), pp. 147-148.

Gold, M.S.

GOLD: Washington University in St Louis School of Medicine, St Louis, MO

Document Type: Article
Publication Stage: Final
Source: Scopus

“Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes” (2021) Frontiers in Cell and Developmental Biology

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes
(2021) Frontiers in Cell and Developmental Biology, 9, art. no. 561086, .

Findeiss, E.^a ^b , Schwarz, S.C.^a , Evsyukov, V.^a ^b ^c , Rösler, T.W.^a ^b , Höllerhage, M.^a ^b ^c , Chakroun, T.^a ^b , Nykänen, N.-P.^a ^d , Shen, Y.^e , Wurst, W.^f ^g ^h , Kohl, M.ⁱ , Tost, J.^e , Höglinger, G.U.^a ^b ^c

^a Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases, Munich, Germany
^b Department of Neurology, School of Medicine, Technical University of Munich, Munich, Germany
^c Department of Neurology, Hannover Medical School, Hanover, Germany
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Laboratory for Epigenetics and Environment, Center National de Recherche en Génomique Humaine, CEA–Institut de Biologie François Jacob, Evry, France
^f Institute of Developmental Genetics, Helmholtz Center Munich, Munich, Germany
^g Genome Engineering, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^h Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
ⁱ Medizinisches Proteom-Center, Ruhr-University Bochum, Bochum, Germany

Abstract
Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson’s disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01; non-adjusted). The in silico analysis of known target genes of these miRNAs was complemented by the inclusion of a transcriptome dataset (BeadChip) of the same cellular system, revealing the G0/G1 cell cycle transition to be markedly enriched. Out of 124 KEGG-annotated cell cycle genes, 15 were present in the miRNA target gene dataset and six G0/G1 cell cycle genes were found to be significantly altered upon α-synuclein overexpression, with five genes up- (CCND1, CCND2, and CDK4 at P < 0.01; E2F3, MYC at P < 0.05) and one gene downregulated (CDKN1C at P < 0.001). Additionally, several of these altered genes are targeted by miRNAs hsa-miR-34a-5p and hsa-miR-34c-5p, which also modulate α-synuclein expression levels. Functional intervention by siRNA-mediated knockdown of the cell cycle gene cyclin D1 (CCND1) confirmed that silencing of cell cycle initiation is able to substantially reduce α-synuclein-mediated cytotoxicity. The present findings suggest that α-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of miRNAs might offer interesting novel therapeutic targets for PD. © Copyright © 2021 Findeiss, Schwarz, Evsyukov, Rösler, Höllerhage, Chakroun, Nykänen, Shen, Wurst, Kohl, Tost and Höglinger.

Author Keywords
alpha-synuclein; cell cycle; cyclin D; microRNA; next-generation sequencing; Parkinson’s disease

Document Type: Article
Publication Stage: Final
Source: Scopus

“CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease” (2021) Brain: A Journal of Neurology

CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease
(2021) Brain: A Journal of Neurology, 144 (2), pp. 515-527. Cited 1 time.

Horie, K.^a , Barthélemy, N.R.^a , Sato, C.^a , Bateman, R.J.^a ^b ^c

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
^c Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Tau is a microtubule associated protein in the brain that aggregates in Alzheimer’s disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer’s disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer’s disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer’s disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer’s disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer’s disease and could serve as biomarkers to stage Alzheimer’s disease and track the development of tau-directed therapeutics. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
Alzheimer’s disease; biomarkers; CSF; microtubule binding region; tau

Document Type: Article
Publication Stage: Final
Source: Scopus

“Targeting pre-synaptic tau accumulation: a new strategy to counteract tau-mediated synaptic loss and memory deficits” (2021) Neuron

Targeting pre-synaptic tau accumulation: a new strategy to counteract tau-mediated synaptic loss and memory deficits
(2021) Neuron, 109 (5), pp. 741-743.

Gratuze, M., Holtzman, D.M.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Synaptic tau accumulation is believed to promote synaptic loss, which contributes to cognitive deficits in Alzheimer’s disease and tauopathies. In this issue of Neuron, Largo-Barrientos et al. report that synaptic loss can be mitigated by lowering Synaptogyrin-3, a known mediator of tau binding to synaptic vesicles. © 2021 Elsevier Inc.

Synaptic tau accumulation is believed to promote synaptic loss, which contributes to cognitive deficits in Alzheimer’s disease and tauopathies. In this issue of Neuron, Largo-Barrientos et al. report that synaptic loss can be mitigated by lowering Synaptogyrin-3, a known mediator of tau binding to synaptic vesicles. © 2021 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Defining and Intervening on Cumulative Environmental Neurodevelopmental Risks: Introducing a Complex Systems Approach” (2021) Environmental Health Perspectives

Defining and Intervening on Cumulative Environmental Neurodevelopmental Risks: Introducing a Complex Systems Approach
(2021) Environmental Health Perspectives, 129 (3), p. 35001.

Payne-Sturges, D.C.^a , Cory-Slechta, D.A.^b , Puett, R.C.^a , Thomas, S.B.^c , Hammond, R.^d ^e , Hovmand, P.S.^f

^a Maryland Institute for Applied Environmental Health, University of Maryland School of UMD Public Health, College ParkMD, United States
^b University of Rochester School of Medicine, Rochester, NY, United States
^c Department of Health Policy and Management and Maryland Center for Health Equity, University of Maryland School of Public Health, College ParkMD, United States
^d Brown School of Social Work, Washington University, St. Louis, MO, United States
^e Center on Social Dynamics and Policy, Brookings Institution, DCWA, United States
^f Center for Community Health Integration, Case Western Reserve University, Cleveland, OH, United States

Abstract
BACKGROUND: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems contributing to health inequities. However cumulative environmental health risks and impacts have received little attention from U.S. policy makers at state and federal levels to develop comprehensive strategies to reduce these exposures, mitigate cumulative risks, and prevent harm. An area for which the inherent limitations of current approaches to cumulative environmental health risks are well illustrated is children’s neurodevelopment, which exhibits dynamic complexity of multiple interdependent and causally linked factors and intergenerational effects. OBJECTIVES: We delineate how a complex systems approach, specifically system dynamics, can address shortcomings in environmental health risk assessment regarding exposures to multiple chemical and nonchemical stressors and reshape associated public policies. DISCUSSION: Systems modeling assists in the goal of solving problems by improving the “mental models” we use to make decisions, including regulatory and policy decisions. In the context of disparities in children’s cumulative exposure to neurodevelopmental stressors, we describe potential policy insights about the structure and behavior of the system and the types of system dynamics modeling that would be appropriate, from visual depiction (i.e., informal maps) to formal quantitative simulation models. A systems dynamics framework provides not only a language but also a set of methodological tools that can more easily operationalize existing multidisciplinary scientific evidence and conceptual frameworks on cumulative risks. Thus, we can arrive at more accurate diagnostic tools for children’s’ environmental health inequities that take into consideration the broader social and economic environment in which children live, grow, play, and learn. https://doi.org/10.1289/EHP7333.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Bidirectional regulation of glial potassium buffering – glioprotection versus neuroprotection” (2021) eLife

Bidirectional regulation of glial potassium buffering – glioprotection versus neuroprotection
(2021) eLife, 10, .

Li, H.^a , Lones, L.^a , DiAntonio, A.^a ^b

^a Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, United States
^b Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, United States

Abstract
Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A salt inducible kinase 3 (SIK3)-regulated gene expression program controls the glial capacity to buffer K+ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here, we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic G-protein-coupled receptor (GPCR) OctβR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway is inactivated. Reactivation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened life span in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability. © 2021, Li et al.

Author Keywords
astrocytes; axon; cell biology; cell volume regulation; D. melanogaster; epilepsy; HDAC4; neuroscience; transporter

Document Type: Article
Publication Stage: Final
Source: Scopus

“Effects of Single-Dose Preoperative Pregabalin on Postoperative Pain and Opioid Consumption in Cleft Orthognathic Surgery” (2021) The Journal of Craniofacial Surgery

Effects of Single-Dose Preoperative Pregabalin on Postoperative Pain and Opioid Consumption in Cleft Orthognathic Surgery
(2021) The Journal of Craniofacial Surgery, 32 (2), pp. 517-520.

Said, A.M.^a , Zubovic, E.^a , Ha, A.Y.^a , Skolnick, G.B.^a , Naidoo, S.D.^a , AuBuchon, J.^b , Patel, K.B.^a

^a Division of Plastic & Reconstructive Surgery, Department of Surgery
^b Division of Pain Management, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO

Abstract
BACKGROUND: Several studies have illustrated the efficacy of pregabalin in decreasing postoperative opioid use in adults undergoing orthognathic surgery. We aimed to study the effects of a single dose of preoperative pregabalin on total opioid consumption after orthognathic surgery in individuals with cleft lip and palate. METHODS: This is a retrospective cohort study of consecutive patients who underwent Le Fort I midface advancement between June 2012 and July 2019. All patients had a diagnosis of cleft lip and palate. The treatment group received a 1-time preoperative dose of pregabalin; the control group did not. Total morphine milligram equivalent (MME) consumption was calculated by adding intraoperative and postoperative opioid use during admission. RESULTS: Twenty-three patients were included in this study; 12 patients received pregabalin. The pregabalin group had significantly lower total opioid consumption (total MME 70.95 MME; interquartile range [IQR]: 24.65-150.17) compared to the control group (138.00 MME; IQR: 105.00-232.48) (MU = 31.00, P = 0.031). The difference in mean pain scores in the treatment group (3.21 ± 2.03) and the control group (3.71 ± 2.95) was not statistically significant (P = 0.651, 95% confidence interval -1.75 to 2.75). CONCLUSIONS: A 1-time preoperative dose of pregabalin before orthognathic surgery in patients with cleft lip and palate reduced total opioid consumption during admission without increasing patient pain. A single preemptive dose of pregabalin should be considered an effective adjunct to pain management protocols in patients undergoing orthognathic surgery. Copyright © 2020 by Mutaz B. Habal, MD.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity” (2021) PLoS ONE

Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity
(2021) PLoS ONE, 16 (3 March), art. no. e0247749, .

Limbrick, D.D.^a , Morales, D.M.^a , Shannon, C.N.^b , Wellons, J.C.^b , Kulkarni, A.V.^c , Alvey, J.S.^d , Reeder, R.W.^d , Freimann, V.^d , Holubkov, R.^d , Riva-Cambrin, J.K.^e , Whitehead, W.E.^f , Rozzelle, C.J.^g , Tamber, M.^h , Jerry Oakes, W.^g , Drake, J.M.^c , Pollack, I.F.ⁱ , Naftel, R.P.^b , Inder, T.E.^j , Kestle, J.R.^k

^a Department of Neurosurgery, Washington University St. Louis, St. Louis, MO, United States
^b Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States
^c Department of Neurosurgery, University of Toronto, Toronto, ON, Canada
^d Data Coordinating Center, University of Utah, Salt Lake City, UT, United States
^e Division of Neurosurgery, University of Calgary, Calgary, AB, Canada
^f Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
^g Department of Neurosurgery, University of Alabama-Birmingham, Birmingham, AL, United States
^h Department of Surgery, University of British Columbia, Vancouver, BC, Canada
ⁱ Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^j Department of Pediatric Newborn Medicine, Harvard Medical School, Boston, MA, United States
^k Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States

Abstract
Objective Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-Term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH. Study design Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson?s partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores. Results CSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R =-0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R =-0.335, p = 0.030, FDR Q = 0.182) and language (R =-0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R =-0.2912) and cognitive scores (p = 0.0506 and R =-0.2966). Conclusion CSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-Associated neurological disability. © 2021 Public Library of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“How Adults With Stroke Conceptualize Physical Activity: An Exploratory Qualitative Study” (2021) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association

How Adults With Stroke Conceptualize Physical Activity: An Exploratory Qualitative Study
(2021) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 75 (2), pp. 7502345010p1-7502345010p6.

Bailey, R.R.^a , Stevenson, J.L.^b

^a Ryan R. Bailey, PhD, OTR/L, is Assistant Professor, Department of Occupational and Recreational Therapies, College of Health, University of Utah, Salt Lake City; . At the time of the study, Bailey was Postdoctoral Fellow, Brown School at Washington University in St. Louis, St. Louis, MO
^b Jennifer L. Stevenson, OTD, OTR/L, is Occupational Therapy Hand Fellow, Mayo Clinic College of Medicine and Science, Rochester, MN. At the time of the study, Stevenson was Occupational Therapy Student, School of Medicine, Washington University in St. Louis, St. Louis, MO

Abstract
IMPORTANCE: Physical activity (PA) is recommended for improving physical and cardiovascular function but can be challenging because of stroke-related impairments. A better understanding of how adults with stroke conceptualize PA could assist in developing effective interventions for increasing poststroke PA. OBJECTIVE: To explore how adults with stroke conceptualize PA. DESIGN: Phenomenological qualitative design. SETTING: Participants’ homes. PARTICIPANTS: Community-dwelling adults with chronic (>6 mo) stroke (N = 15). OUTCOMES AND MEASURES: Semistructured interviews were conducted with participants. Data were analyzed by means of inductive content analysis to identify key themes. RESULTS: Three key themes emerged: (1) moderate to vigorous PA, which includes exercise-related activities (going to the gym, walking, playing sports); (2) PA necessary for performing daily activities and occupations, which includes basic and instrumental activities of daily living; and (3) avoiding sedentary behavior, which includes not wanting to sit for long periods of time, avoiding boredom, and valuing PA over being sedentary. CONCLUSIONS AND RELEVANCE: Participants broadly categorized PA, encompassing multiple activity types, which is encouraging because reducing sedentary behavior and increasing PA of any intensity can improve cardiometabolic health. Interventions that complement and enhance these conceptualizations, alone or in combination with other mechanisms of action, should be explored for their efficacy in increasing PA in adults with stroke. WHAT THIS ARTICLE ADDS: After stroke, perceptions of PA encompass exercise, daily activities and occupations, and avoiding sedentary behavior; these perceptions could be harnessed to promote PA among adults after stroke. Copyright © 2021 by the American Occupational Therapy Association, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Primary Microglia Isolation from Postnatal Mouse Brains” (2021) Journal of Visualized Experiments: JoVE

Primary Microglia Isolation from Postnatal Mouse Brains
(2021) Journal of Visualized Experiments: JoVE, (168), .

Du, S.^a , Xiong, S.^b , Du, X.^c , Yuan, T.-F.^d , Peng, B.^e , Rao, Y.^f

^a Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; Division of Biology and Biomedical Science, Washington University in St. Louis
^b Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
^c Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
^d Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
^e Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University; Co-innovation Center of Neuroregeneration, Nantong University;
^f Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine;

Abstract
Microglia are the mononuclear phagocytes in the central nervous system (CNS), which play key roles in maintaining homeostasis and regulating the inflammatory process in the CNS. To study the microglial biology in vitro, primary microglia show great advantages compared to immortalized microglial cell lines. However, microglia isolation from the postnatal mouse brain is relatively less efficient and time-consuming. In this protocol, we provide a quick and easy-to-follow method to isolate primary microglia from the neonatal mouse brain. The overall steps of this protocol include brain dissection, primary brain cell culture, and microglia isolation. Using this approach, researchers can obtain primary microglia with high purity. In addition, the harvested primary microglia were able to respond to the lipopolysaccharides challenge, indicating they retained their immune function. Collectively, we developed a simplified approach to efficiently isolate primary microglia with high purity, which facilitates a wide range of microglial biology investigations in vitro.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011-2020)” (2021) Molecules (Basel, Switzerland)

Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011-2020)
(2021) Molecules (Basel, Switzerland), 26 (5), .

Li, X., Yu, Y., Tu, Z.

Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Boulevard St. Louis, MO, 63110, United States

Abstract
The remarkable prevalence of pyrazole scaffolds in a versatile array of bioactive molecules ranging from apixaban, an anticoagulant used to treat and prevent blood clots and stroke, to bixafen, a pyrazole-carboxamide fungicide used to control diseases of rapeseed and cereal plants, has encouraged both medicinal and organic chemists to explore new methods in developing pyrazole-containing compounds for different applications. Although numerous synthetic strategies have been developed in the last 10 years, there has not been a comprehensive overview of synthesis and the implication of recent advances for treating neurodegenerative disease. This review first presents the advances in pyrazole scaffold synthesis and their functionalization that have been published during the last decade (2011-2020). We then narrow the focus to the application of these strategies in the development of therapeutics for neurodegenerative diseases, particularly for Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Author Keywords
Alzheimer’s disease; antagonist; biological activity; functionalization; heterocyclic; inhibitor; neurodegeneration; Parkinson’s disease; pyrazole; synthesis

Document Type: Review
Publication Stage: Final
Source: Scopus

“Rates of Incidental Findings in Brain Magnetic Resonance Imaging in Children” (2021) JAMA Neurology

Rates of Incidental Findings in Brain Magnetic Resonance Imaging in Children
(2021) JAMA Neurology, .

Li, Y.^a , Thompson, W.K.^b , Reuter, C.^b , Nillo, R.^a , Jernigan, T.^c , Dale, A.^c , Sugrue, L.P.^a , Brown, J.^a , Dougherty, R.F.^d , Rauschecker, A.^a , Rudie, J.^a , Barch, D.M.^e , Calhoun, V.^f , Hagler, D.^g , Hatton, S.^h , Tanabe, J.ⁱ , Marshall, A.^j , Sher, K.J.^k , Heeringa, S.^l , Hermosillo, R.^m , Banich, M.T.ⁿ , Squeglia, L.^o , Bjork, J.^p , Zucker, R.^q , Neale, M.^p , Herting, M.^r , Sheth, C.^s , Huber, R.^s , Reeves, G.^t , Hettema, J.M.^u , Howlett, K.D.^v , Cloak, C.^w , Baskin-Sommers, A.^x , Rapuano, K.^x , Gonzalez, R.^y , Karcher, N.^z , Laird, A.^aa , Baker, F.^ab , James, R.^ac , Sowell, E.^j , Dick, A.^y , Hawes, S.^y , Sutherland, M.^y , Bagot, K.^ad , Bodurka, J.^ae , Breslin, F.^ae , Morris, A.^ae , Paulus, M.^ae , Gray, K.^o , Hoffman, E.^v , Weiss, S.^v , Rajapakse, N.^af , Glantz, M.^ag , Nagel, B.^ah , Ewing, S.F.^ah , Goldstone, A.^ab , Pfefferbaum, A.^ab , Prouty, D.^ab , Rosenberg, M.^ai , Bookheimer, S.^aj , Tapert, S.^ak , Infante, M.^ak , Jacobus, J.^ak , Giedd, J.^ak , Shilling, P.^ak , Wade, N.^ak , Uban, K.^al , Haist, F.^am , Heyser, C.^c , Palmer, C.^c , Kuperman, J.^g , Hewitt, J.^an , Cottler, L.^ao , Isaiah, A.^ap , Chang, L.^aq , Edwards, S.^t , Ernst, T.^ar , Heitzeg, M.^as , Puttler, L.^as , Sripada, C.^as , Iacono, W.^at , Luciana, M.^at , Clark, D.^au , Luna, B.^av , Schirda, C.^aw , Foxe, J.^ax , Freedman, E.^ax , Mason, M.^ay , McGlade, E.^s , Renshaw, P.^s , Yurgelun-Todd, D.^s , Albaugh, M.^az , Allgaier, N.^az , Chaarani, B.^az , Potter, A.^az , Ivanova, M.^az , Lisdahl, K.^az , Do, E.^ba , Maes, H.^bb , Bogdan, R.^bc , Anokhin, A.^z , Dosenbach, N.^bd , Glaser, P.^z , Heath, A.^z , Casey, B.J.^x , Gee, D.^x , Garavan, H.P.^az , Dowling, G.^v , Brown, S.^be

^a Department of Radiology and Biomedical Imaging, University of California, San Francisco, 513 Parnassus Ave, S-255, San Francisco, CA 94143-0628, United States
^b Department of Family Medicine and Public Health, University of California, San Diego, San Diego, United States
^c Center for Human Development, University of California, San Diego, San Diego, United States
^d Center for Cognitive and Neurobiological Imaging, Stanford University, Stanford, CA, United States
^e Department of Psychological and Brain Sciences, Psychiatry, Radiology, Washington University in St Louis, St Louis, MO, United States
^f Tri-institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Tech, Emory University, Atlanta, United States
^g Department of Radiology, University of California, San Diego, San Diego, United States
^h Department of Neurosciences, University of California, San Diego, San Diego, United States
ⁱ Department of Radiology, University of Colorado, Anschutz Medical Center, Aurora, United States
^j Department of Pediatrics, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, United States
^k Department of Psychological Sciences, University of Missouri, Columbia, United States
^l Institute for Social Research, University of Michigan, Ann Arbor, United States
^m Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, United States
ⁿ Institute of Cognitive Science, Department of Psychology and Neuroscience, University of Colorado, Boulder, United States
^o Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States
^p Department of Psychiatry, Virginia Commonwealth University, Richmond, United States
^q Department of Psychiatry and Psychology, University of Michigan, Ann Arbor, United States
^r Department of Preventive Medicine, University of Southern California, Los Angeles, United States
^s Department of Psychiatry, University of Utah, School of Medicine, Salt Lake City, United States
^t Department of Psychiatry, University of Maryland, Baltimore, United States
^u Department of Psychiatry, Texas AandM Health Science Center, Bryan, United States
^v Division of Extramural Research, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, United States
^w Department of Radiology and Nuclear Medicine, University of Maryland, Baltimore, United States
^x Department of Psychology, Yale University, New Haven, CT, United States
^y Department of Psychology, Florida International University, Miami, United States
^z Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^aa Department of Physics, Florida International University, Miami, United States
^ab SRI International, Menlo Park, CA, United States
^ac Department of Clinical Research, 2M Research Services, Arlington, VA, United States
^ad Department of Psychiatry, Icahn School of Medicine at Mt Sinai, New York, NY, United States
^ae Laureate Institute for Brain Research, Tulsa, OK, United States
^af Department of Scientific Programs, National Institute on Minority Health and Health Disparities, Bethesda, MD, United States
^ag Department of Psychology, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, United States
^ah Department of Psychiatry, Oregon Health and Science University, Portland, United States
^ai Department of Psychology, University of Chicago, Chicago, IL, United States
^aj Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, United States
^ak Department of Psychiatry, University of California, San Diego, San Diego, United States
^al Department of Public Health, University of California, Irvine, United States
^am Department of Psychiatry, Center for Human Development, University of California, San Diego, San Diego, United States
^an Institute for Behavioral Genetics, University of Colorado, Boulder, United States
^ao Department of Epidemiology, University of Florida, Gainesville, United States
^ap Department of Otorhinolaryngology/Head and Neck Surgery and Pediatrics, University of Maryland, School of Medicine, Baltimore, United States
^aq Departments of Radiology and Neurology, University of Maryland, Baltimore, United States
^ar Department of Radiology, University of Maryland, Baltimore, United States
^as Department of Psychiatry, University of Michigan, Ann Arbor, United States
^at Department of Psychology, University of Minnesota, Minneapolis, United States
^au Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^av Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^aw Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
^ax Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, United States
^ay Center for Behavioral Health Research, University of Tennessee, Knoxville, United States
^az Department of Psychiatry, University of Vermont, Burlington, United States
^ba Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, United States
^bb Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, United States
^bc Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
^bd Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^be Department of Psychiatry and Psychology, University of California, San Diego, San Diego, United States

Abstract
Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, Setting, and Participants: This cohort study was based on the April 2019 release of baseline data from 11810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main Outcomes and Measures: Percentage of children with IFs in each category and prevalence of specific IFs. Results: A total of 11679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2= 0.260; 95% CI, 0.135-0.387). Conclusions and Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.. © 2021 American Medical Association. All rights reserved.

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

“Outcomes and Risk Factors Associated with SARS-CoV-2 Infection in a North American Registry of Patients with Multiple Sclerosis” (2021) JAMA Neurology

Outcomes and Risk Factors Associated with SARS-CoV-2 Infection in a North American Registry of Patients with Multiple Sclerosis
(2021) JAMA Neurology, .

Salter, A.^a , Fox, R.J.^b , Newsome, S.D.^c , Halper, J.^d , Li, D.K.B.^e , Kanellis, P.^f , Costello, K.^g , Bebo, B.^g , Rammohan, K.^h , Cutter, G.R.ⁱ , Cross, A.H.^a

^a Washington University, School of Medicine in St Louis, St Louis, MO, United States
^b Cleveland Clinic, Cleveland, OH, United States
^c Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^d Consortium of MS Centers, Hackensack, NJ, United States
^e University of British Columbia, Vancouver, BC, Canada
^f MS Society of Canada, Toronto, ON, Canada
^g National Multiple Sclerosis Society, Chicago, IL, United States
^h University of Miami, School of Medicine, Miami, FL, United States
ⁱ University of Alabama at Birmingham, Birmingham, United States

Abstract
Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.. © 2021 American Medical Association. All rights reserved.

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

“Incidentalomas and the Ethical Dilemma behind Imaging in Clinical Research” (2021) JAMA Otolaryngology – Head and Neck Surgery

Incidentalomas and the Ethical Dilemma behind Imaging in Clinical Research
(2021) JAMA Otolaryngology – Head and Neck Surgery, .

Peterson, A.M.^a , Jiramongkolchai, P.^b , Piccirillo, J.F.^b ^c

^a University of Missouri-Kansas City, School of Medicine, Kansas City, United States
^b Clinical Outcomes Research Office, Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine in St Louis, Campus Box 8115, 660 S Euclid Ave, St Louis, MO 63110, United States
^c JAMA Otolaryngology-Head and Neck Surgery, United States

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

“Perceiving properties versus perceiving objects” (2021) Analytic Philosophy

Perceiving properties versus perceiving objects
(2021) Analytic Philosophy, .

Millar, B.

Department of Philosophy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The fact that you see some particular object seems to be due to the causal relation between your visual experience and that object, rather than to your experiences’ phenomenal character. On the one hand, whenever some phenomenal element of your experience stands in the right sort of causal relation to some object, your experience presents that object (your experience’s phenomenology does not need to match that object). On the other hand, you cannot have a perceptual experience that presents some object unless you stand in the right sort of causal relation to that object (no matter how closely your experience’s phenomenology matches some object). According to the continuity thesis, property perception is similar to object perception in these two respects. A standard reason to reject the continuity thesis is the assumption that the environmental properties that a perceptual experience presents are determined by its phenomenal properties (which are not determined by the environmental properties that cause the experience). I maintain that the continuity thesis is false but for a different reason: perceptual experiences present both objects and properties via manners of presentation; but, whereas perceptual manners of presentation for objects are purely relational, perceptual manners of presentation for properties are satisfactional. © 2021 John Wiley & Sons Ltd

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

“Association of Olfactory Training with Neural Connectivity in Adults with Postviral Olfactory Dysfunction” (2021) JAMA Otolaryngology – Head and Neck Surgery

Association of Olfactory Training with Neural Connectivity in Adults with Postviral Olfactory Dysfunction
(2021) JAMA Otolaryngology – Head and Neck Surgery, . Cited 1 time.

Jiramongkolchai, P.^a , Jones, M.S.^a , Peterson, A.^a , Lee, J.J.^a , Liebendorfer, A.^a , Klatt-Cromwell, C.N.^a , Schneider, J.S.^a , Drescher, A.J.^a , Ogden, M.A.^a , Brunworth, J.D.^a ^c , Kallogjeri, D.^a ^b , Kukuljan, S.^a , Peelle, J.E.^a , Piccirillo, J.F.^a ^b

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

Abstract
Importance: Viral upper respiratory tract infections are a major cause of olfactory loss. Olfactory training (OT) is a promising intervention for smell restoration; however, a mechanistic understanding of the changes in neural plasticity induced by OT is absent. Objective: To evaluate functional brain connectivity in adults with postviral olfactory dysfunction (PVOD) before and after OT using resting-state functional magnetic resonance imaging. Design, Setting, and Participants: This prospective cohort study, conducted from September 1, 2017, to November 30, 2019, recruited adults with clinically diagnosed or self-reported PVOD of 3 months or longer. Baseline olfaction was measured using the University of Pennsylvania Smell Identification Test (UPSIT) and the Sniffin’ Sticks test. Analysis was performed between December 1, 2020, and July 1, 2020. Interventions: Participants completed 12 weeks of OT using 4 essential oils: rose, eucalyptus, lemon, and clove. The resting-state functional magnetic resonance imaging measurements were obtained before and after intervention. Main Outcome and Measures: The primary outcome measure was the change in functional brain connectivity before and after OT. Secondary outcome measures included changes in UPSIT and Sniffin’ Sticks test scores, as well as patient-reported changes in treatment response as measured by subjective changes in smell and quality-of-life measures. Results: A total of 16 participants with PVOD (11 female [69%] and 14 White [88%]; mean [SD] age, 60.0 [10.5] years; median duration of smell loss, 12 months [range, 3-240 months]) and 20 control participants (15 [75%] female; 17 [85%] White; mean [SD] age, 55.0 [9.2] years; median UPSIT score, 37 [range, 34-39]) completed the study. At baseline, participants had increased connectivity within the visual cortex when compared with normosmic control participants, a connection that subsequently decreased after OT. Furthermore, 4 other network connectivity values were observed to change after OT, including an increase in connectivity between the left parietal occipital junction, a region of interest associated with olfactory processing, and the cerebellum. Conclusions and Relevance: The use of OT is associated with connectivity changes within the visual cortex. This case-control cohort study suggests that there is a visual connection to smell that has not been previously explored with OT and that further studies examining the efficacy of a bimodal visual and OT program are needed. © 2021 American Medical Association. All rights reserved.

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

“Cost Comparison of Botulinum Toxin Injections Versus Surgical Treatment in Pediatric Patients With Cerebral Palsy: A Markov Model” (2021) Journal of Hand Surgery

Cost Comparison of Botulinum Toxin Injections Versus Surgical Treatment in Pediatric Patients With Cerebral Palsy: A Markov Model
(2021) Journal of Hand Surgery, .

Kazarian, G.S.^a , Van Heest, A.E.^b , Goldfarb, C.A.^a , Wall, L.B.^a

^a Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^b Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN, United States

Abstract
Purpose: The purpose of this study was to compare the cost-effectiveness of surgical release to botulinum toxin injections in the treatment of upper-extremity (UE) cerebral palsy (CP). Methods: A Markov transition-state model was developed to assess the direct and indirect costs as well as accumulated quality-adjusted life-years associated with surgery (surgery group) and continuous botulinum toxin injections (botulinum group) for the treatment of UE CP in children aged 7 to 12 years. Direct medical costs were obtained from institutional billing departments. The number of parental missed workdays associated with each treatment was estimated and previously published regressions were used to calculate indirect costs associated with missed work. Total costs, cost-effectiveness, and incremental cost-effectiveness ratios were calculated. Incremental cost-effectiveness ratios and willingness to pay thresholds were used to make decisions regarding society’s willingness to pay for the incremental cost of each treatment given the incremental benefit. Results: The surgery group demonstrated lower direct, indirect, and total costs compared with the botulinum group. Direct costs were $29,250.50 for the surgery group and $50,596.00 for the botulinum group. Indirect costs were $9,467.46 for the surgery group and $44,428.60 for the botulinum group. Total costs were $38,717.96 for the surgery group and $95,024.60 for the botulinum group, a difference of $56,306.64. The incremental cost-effectiveness ratio was –$42,019.88, indicating that surgery is a less costly and more effective treatment and that botulinum injections fall outside the societal willingness to pay threshold. Excluding indirect costs associated with parental missed work during home occupational therapy did not have a significant impact on the model. Conclusions: Surgery is associated with lower direct, indirect, and total costs, as well as a greater number of accumulated quality-adjusted life-years. Surgery provides a greater benefit at a lower cost, which suggests that botulinum injections should be used sparingly in this population. Treatment with surgery could represent savings of $5.6 to $11.3 billion annually in the United States. Type of study/level of evidence: Economic/Decision Analysis II. © 2020 The Author(s)

Author Keywords
Botulinum; cerebral palsy; cost analysis; Markov model

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

“Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study” (2021) Therapeutic Advances in Neurological Disorders

Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study
(2021) Therapeutic Advances in Neurological Disorders, 14, .

Wundes, A.^a , Wray, S.^b , Gold, R.^c , Singer, B.A.^d , Jasinska, E.^e , Ziemssen, T.^f , de Seze, J.^g , Repovic, P.^h , Chen, H.ⁱ , Hanna, J.^j , Messer, J.^k , Miller, C.ⁱ , Naismith, R.T.^l

^a Department of Neurology, University of Washington Medical Center, Seattle, WA, United States
^b Hope Neurology MS Center, Knoxville, TN, United States
^c Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
^d The MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, United States
^e Collegium Medicum UJK and Clinical Center, RESMEDICA, Kielce, Poland
^f Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Dresden, Germany
^g Strasbourg University Hospital, Clinical Investigation Center, INSER 1434, Strasbourg, France
^h Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, WA, United States
ⁱ Biogen, Cambridge, MA, United States
^j Biogen, Maidenhead, United Kingdom
^k Biogen, 225 Binney Street, Cambridge, MA 02142-1031, United States
^l Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing–remitting MS who received DRF or DMF in EVOLVE-MS-2. Methods: A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work. Results: In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere ‘quite a bit’ or ‘extremely’ with regular daily activities [IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2–3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) versus DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF. Conclusions: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use. Trial registration: [ClinicalTrials.gov identifier: NCT03093324]. © The Author(s), 2021.

Author Keywords
clinical trial; diroximel fumarate; disease-modifying therapy; gastrointestinal; relapsing-remitting multiple sclerosis

Funding details
Biogen
AbbVie
Teva Pharmaceutical Industries
Biogen

Document Type: Article
Publication Stage: Final
Source: Scopus

“Modification of Glial Cell Activation through Dendritic Cell Vaccination: Promises for Treatment of Neurodegenerative Diseases” (2021) Journal of Molecular Neuroscience

Modification of Glial Cell Activation through Dendritic Cell Vaccination: Promises for Treatment of Neurodegenerative Diseases
(2021) Journal of Molecular Neuroscience, .

Sabahi, M.^a ^b , Joshaghanian, A.^a , Dolatshahi, M.^b ^c , Jabbari, P.^d ^e ^f , Rahmani, F.^b ^c ^g , Rezaei, N.^d ^e ^h

^a Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
^b Neuroimaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
^c Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
^d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
^e Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
^f Department of Genetics, Genomics and Bioinformatics, University of California, Riverside, United States
^g Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^h Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Children’s Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran

Abstract
Accumulation of misfolded tau, amyloid β (Aβ), and alpha-synuclein (α-syn) proteins is the fundamental contributor to many neurodegenerative diseases, namely Parkinson’s (PD) and AD. Such protein aggregations trigger activation of immune mechanisms in neuronal and glial, mainly M1-type microglia cells, leading to release of pro-inflammatory mediators, and subsequent neuronal dysfunction and apoptosis. Despite the described neurotoxic features for glial cells, recruitment of peripheral leukocytes to the brain and their conversion to neuroprotective M2-type microglia can mitigate neurodegeneration by clearing extracellular protein accumulations or residues. Based on these observations, it was speculated that Dendritic cell (DC)-based vaccination, by making use of DCs as natural adjuvants, could be used for treatment of neurodegenerative disorders. DCs potentiated by disease-specific antigens can also enhance T helper 2 (Th2)-specific immune response and by production of specific antibodies contribute to clearance of intracellular aggregations, as well as enhancing regulatory T cell response. Thus, enhancement of immune response by DC vaccine therapy can potentially augment glial polarization into the neuroprotective phenotype, enhance antibody production, and at the same time balance neuronal cells’ repair, renewal, and protection. The characteristic feature of this method of treatment is to maintain the equilibrium in the immune response rather than targeting a single mediator in the disease and their application in other neurodegenerative diseases should be addressed. However, the safety of these methods should be investigated by clinical trials. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Adjuvant therapy; Dendritic cell-based vaccination; Dendritic cells; Microglia; Neurodegenerative diseases

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

“Workup following retinal artery occlusion—experience from an outpatient retina clinic and the delay in workup” (2021) Graefe’s Archive for Clinical and Experimental Ophthalmology

Workup following retinal artery occlusion—experience from an outpatient retina clinic and the delay in workup
(2021) Graefe’s Archive for Clinical and Experimental Ophthalmology,.

Vangipuram, G.^a , Yang, L.^b , Weigle, M.P.^c , Blackorby, B.L.^a , Blinder, K.J.^a , Dang, S.^a , Shah, G.K.^a

^a The Retina Institute, 2201 S. Brentwood Blvd, St. Louis, MO 63144, United States
^b Washington University School of Medicine, St. Louis, MO, United States
^c St. Louis University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Acute retinal artery occlusion (RAO) is an urgent ophthalmic condition often indicative of future ischemic pathology. Patients diagnosed at an outpatient retina clinic must present to an emergency department (ED) or primary care clinic to obtain a systemic workup. We review the overall compliance and suspected delay in completing the required testing. Design: Retrospective cohort study Methods: Patients presenting with a symptomatic RAO from June 2009 to January 2019 at a vitreoretinal practice (The Retina Institute, St. Louis, MO) were included. Documentation of carotid vasculature and echocardiographic imaging was requested from the patient’s primary care physician (PCP), cardiologist, or neurologist. Time to workup (TTW) from RAO diagnosis to receiving appropriate workup and site of workup (ED vs. outpatient setting) were recorded. Results: One hundred forty-seven patients were included. A total of 132 (89.8%) patients were documented as having completed at least one type of cardiovascular or carotid imaging. Seventy-seven patients (52.3%) were documented to have completed both carotid and echocardiographic imaging. Following RAO diagnosis, 97 (66.0%) patients were referred to an outpatient facility while 35 (23.8%) were evaluated at an ED. Mean TTW through an ED setting vs. outpatient was 2.20 days (1.10 STDM, range 0–29) vs.13.6 days (2.23 STDM, range 0–149) respectively (p=0.003). Conclusion: Our study gives objective data to the delay suspected in referring patients with acute symptomatic RAO for outpatient workup. We recommend all outpatient ophthalmology and retina practices establish a relationship with a comprehensive or primary stroke center to facilitate urgent testing through an emergency department. [Figure not available: see fulltext.]. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Carotid disease; Echocardiography; Retinal artery occlusion; Systemic workup

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

“Closed-loop acoustic stimulation during sedation with dexmedetomidine (Class-d): Protocol for a within-subject, crossover, controlled, interventional trial with healthy volunteers” (2021) Nature and Science of Sleep

Closed-loop acoustic stimulation during sedation with dexmedetomidine (Class-d): Protocol for a within-subject, crossover, controlled, interventional trial with healthy volunteers
(2021) Nature and Science of Sleep, 13, pp. 303-313.

Guay, C.S.^a , Labonte, A.K.^a , Montana, M.C.^a , Landsness, E.C.^b , Lucey, B.P.^b , Kafashan, M.M.^a , Haroutounian, S.^a , Avidan, M.S.^a ^c , Brown, E.N.^d ^e , Palanca, B.J.A.^a ^c ^f ^g

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Division of Sleep Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
^e Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^f Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Introduction: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharma-cologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine. Methods: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volun-teers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation. Results: The primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep. Discussion: This investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation. © 2021 Guay et al.

Author Keywords
Acoustic stimulation; Anesthesia; Consciousness; Dexmedetomidine; Electroencephalography; Sleep

Funding details
National Institutes of HealthNIHP01-GM118629, R01 MH117063, R01AG057901

Document Type: Article
Publication Stage: Final
Source: Scopus

“Increased functional coupling between VTA and hippocampus during rest in first-episode psychosis” (2021) eNeuro

Increased functional coupling between VTA and hippocampus during rest in first-episode psychosis
(2021) eNeuro, 8 (2), art. no. ENEURO.0375-20.2021, pp. 1-8.

Gregory, D.F.^a , Rothrock, J.M.^a , Jalbrzikowski, M.^b , Foran, W.^b , Montez, D.F.^c , Luna, B.^b , Murty, V.P.^a

^a Department of Psychology, Temple University, Philadelphia, PA 19122, United States
^b Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Animal models suggest that interactions between the hippocampus and ventral tegmental area (VTA) underlie the onset and etiology of psychosis. While a large body of research has separately characterized alterations in hippocampal and VTA function in psychosis, alterations across the VTA and hippocampus have not been characterized in first-episode psychosis (FEP). As the phase of psychosis most proximal to conversion, studies specifically focused on FEP are valuable to psychosis research. Here, we characterize alterations in VTA-hippocampal interactions across male and female human participants experiencing their first episode of psychosis using resting state functional magnetic resonance imaging (rsfMRI). In comparison to age and sex matched healthy controls (HCs), FEP individuals had significantly greater VTA-hippocampal functional coupling but significantly less VTA-striatal functional coupling. Further, increased VTA-hippocampal functional coupling in FEP correlated with individual differences in psychosis-related symptoms. Together, these findings demonstrate alterations in mesolimbic-hippocampal circuits in FEP and extend prominent animal models of psychosis. © 2021 Gregory et al.

Author Keywords
Hippocampus; Psychosis; Resting state fMRI; Striatum; Ventral tegmental area

Funding details
Brain and Behavior Research FoundationBBRF
National Institutes of HealthNIHK01 MH112774, P50 MH103204, K01 MH111991, R21 DA043568
University of Pittsburgh

Document Type: Article
Publication Stage: Final
Source: Scopus

“Magnitude of blood pressure change and clinical outcomes after thrombectomy in stroke caused by large artery occlusion” (2021) European Journal of Neurology

Magnitude of blood pressure change and clinical outcomes after thrombectomy in stroke caused by large artery occlusion
(2021) European Journal of Neurology, .

Anadani, M.^a , Matusevicius, M.^b ^c , Tsivgoulis, G.^d , Peeters, A.^e , Nunes, A.P.^f , Mancuso, M.^g , Roffe, C.^h , de Havenon, A.ⁱ , Ahmed, N.^b ^j

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^c Department of Research and Education, Karolinska University Hospital, Stockholm, Sweden
^d Second Department of Neurology, National & Kapodistrian University of Athens, Athens, Greece
^e Cliniques Universitaires St Luc, Brussels, Belgium
^f Stroke Unit Centro Hospitalar Universitário de Lisboa Central – Hospital São José, Lisbon, Portugal
^g Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa and Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
^h Stroke Research in Stoke, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom
ⁱ Department of Neurology, University of Utah, Salt Lake City, UT, United States
^j Department of Neurovascular Disease, Karolinska University Hospital, Stockholm, Sweden

Abstract
Background: Extremes of both high and low systolic blood pressure (SBP) after mechanical thrombectomy (MT) in large artery occlusion stroke are known predictors of unfavorable outcome. However, the effect of SBP change (∆SBP) during the first 24 h on thrombectomy outcomes remains unclear. We aimed to investigate the association between ∆SBP at different time intervals and thrombectomy outcomes. Methods: We analyzed MT-treated patients registered in the SITS International Stroke Thrombectomy Registry from January 1, 2014 to September 3, 2019. Primary outcome was 3-month unfavorable outcome (modified Rankin scale scores 3–6). We defined ∆SBP as the mean SBP of a given time interval after MT (0–2, 2–4, 4–12, 12–24 h) minus admission SBP. Multivariable mixed logistic regression models were used to adjust for known confounders and center as random effect. Subgroup analyses were included to contrast specific subpopulations. Restricted cubic splines were used to model the associations. Results: The study population consisted of 5835 patients (mean age 70 years, 51% male, median NIHSS 16). Mean ∆SBP was −12.3, −15.7, −17.2, and −16.9 mmHg for the time intervals 0–2, 2–4, 4–12 h, and 12–24 h, respectively. Higher ∆SBP was associated with unfavorable outcome at 0–2 h (odds ratio 1.065, 95% confidence interval 1.014–1.118), 2–4 h (1.140, 1.081–1.203), 4–12 h (1.145, 1.087–1.203), and 12–24 h (1.145, 1.089–1.203), for every increase of 10 mmHg. Restricted cubic spline models suggested that increasing ∆SBP was associated with unfavorable outcome, with higher values showing increased risk of unfavorable outcome. Conclusion: SBP increase after thrombectomy in large artery occlusion stroke is associated with poor functional outcome. © 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology

Author Keywords
blood pressure; stroke; thrombectomy

Funding details
Karolinska InstitutetKI
K23NS105924
Regeneron Pharmaceuticals
AMAG Pharmaceuticals

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

“Laboratory monitoring of nusinersen safety” (2021) Muscle and Nerve

Laboratory monitoring of nusinersen safety
(2021) Muscle and Nerve, .

Goedeker, N.L.^a , Gibbons, J.L.^a , Varadhachary, A.S.^a , Connolly, A.M.^b , Zaidman, C.M.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, Neurology Division, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States

Abstract
Introduction: This retrospective study reports our tertiary care center’s experience with intrathecal nusinersen administration in children and adults with spinal muscular atrophy (SMA). Methods: We reviewed safety monitoring laboratory results and need for procedural sedation and fluoroscopy-guidance in all SMA patients receiving nusinersen between February 2017 and March 2020. Results: Fifty-eight patients ages 1 mo- 56 y received 494 nusinersen doses. There were 166 laboratory abnormalities in 45 patients. Most were either mild (145 [87.3%]) or were transient proteinuria (18 [10.8%]). None altered nusinersen treatment. Twenty-eight patients required either general anesthesia (75 doses) or anxiolysis with oral midazolam (133 doses, including 6 patients [23 doses] with SMA type I). Eight patients with complicated spines (45 doses) required fluoroscopic guidance. One treatment-related serious adverse event (emesis leading to intubation) occurred during general anesthesia. Two children had asymptomatic increased intracranial pressure. No patients discontinued treatment due to adverse events. Discussion: Intrathecal nusinersen is generally safe and well-tolerated, including in patients requiring oral anxiolysis, general sedation, and fluoroscopic guidance. Frequent serial laboratory monitoring did not identify any persistent significantly abnormal findings or alter treatment. © 2021 Wiley Periodicals LLC.

Author Keywords
antisense oligonucleotide; intrathecal; motor neuron disease; nusinersen; safety; spinal muscular atrophy

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

“Brain-Responsive Neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: A case series” (2021) Epilepsia Open

Brain-Responsive Neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: A case series
(2021) Epilepsia Open, .

McDermott, D.S.^a , Mirro, E.A.^b , Fetrow, K.^a , Burdette, D.E.^c , Chen, S.^d , Hopp, J.^d , Masel, T.^e , Johnson, E.A.^f , Elefant, F.M.K.^b , Le, S.^g , Patra, S.E.^c , Brown, M.-G.^a , Haneef, Z.^h

^a University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^b NeuroPace, Inc., Mountain View, CA, United States
^c Spectrum Health System, Grand RapidsMI, United States
^d University of Maryland Medical Center, Baltimore, MD, United States
^e University of Texas Medical Branch, Galveston, TX, United States
^f Washington University School of Medicine, St. Louis, MO, United States
^g Stanford University, Palo Alto, CA, United States
^h Baylor College of Medicine, Houston, TX, United States

Abstract
Objective: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. Methods: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc). Results: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. Significance: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation. © 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy

Author Keywords
refractory epilepsy; responsive neurostimulation; tuberous sclerosis complex

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

“Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response” (2021) Autophagy

Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response
(2021) Autophagy, .

Jeong, S.-J.^a , Stitham, J.^b , Evans, T.D.^a , Zhang, X.^a , Rodriguez-Velez, A.^a , Yeh, Y.-S.^a , Tao, J.^a , Takabatake, K.^a , Epelman, S.^c , J. Lodhi, I.^b , D. Schilling, J.^a ^d , J. Debosch, B.^e , Diwan, A.^a ^f , Razani, B.^a ^d ^f

^a Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Medicine, Division of Endocrinology, Lipid Research, Washington University School of Medicine, St. Louis, MO, United States
^c Cardiac Center, Ted Rogers Centre for Heart Failure Research, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON, Canada
^d Department of Pathology Immunology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^f John Cochran VA Medical Center, St. Louis, MO, United States

Abstract
The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system. Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Endocytosis; lysosome; MTORC1; TFEB; trehalose

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

“Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland” (2021) Human Genetics

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland
(2021) Human Genetics, .

Järvelä, I.^a , Määttä, T.^b , Acharya, A.^c , Leppälä, J.^d , Jhangiani, S.N.^e , Arvio, M.^f ^g ^h ⁱ , Siren, A.^j , Kankuri-Tammilehto, M.ⁱ ^k , Kokkonen, H.^l , Palomäki, M.^m , Varilo, T.^a , Fang, M.ⁿ , Hadley, T.D.ⁿ , Jolly, A.^o , Linnankivi, T.^p , Paetau, R.^p , Saarela, A.^q ^r , Kälviäinen, R.^q ^r , Olme, J.^s , Nouel-Saied, L.M.^c , Cornejo-Sanchez, D.M.^c , Llaci, L.^t , Lupski, J.R.^e ^o ^u ^v , Posey, J.E.^o , Leal, S.M.^c , Schrauwen, I.^c

^a Department of Medical Genetics, University of Helsinki, P.O. Box 720, Helsinki, 00251, Finland
^b Disability Services, Joint Authority for Kainuu, Kajaani, Finland
^c Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY, United States
^d Eskoo The Center for Disability Empowerment, Seinäjoki, Finland
^e Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, United States
^f KTO-Special Welfare District of Varsinais-Suomi, Paimio, Finland
^g Päijät-Häme Joint Municipal Authority, Lahti, Finland
^h PEDEGO, University of Oulu, Oulu, Finland
ⁱ Department of Clinical Genetics, Turku University Hospital, Turku, Finland
^j Kanta-Häme Central Hospital, Hämeenlinna, Finland
^k Department of Clinical Genetics, University of Turku, Turku, Finland
^l Northern Finland Laboratory Centre NordLab and Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
^m Department of Radiology, Helsinki University Hospital, Helsinki, Finland
ⁿ Baylor College of Medicine, Houston, TX 77030, United States
^o Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
^p Department of Child Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^q Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
^r Kuopio Epilepsy Center, Kuopio University Hospital, Neurocenter, Finland
^s Department of Child Neurology, Vaasa Central Hospital, Vaasa, Finland
^t Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63110, United States
^u Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
^v Texas Children’s Hospital, Houston, TX 77030, United States

Abstract
The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case. © 2021, The Author(s).

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

“Senses as capacities” (2020) Multisensory Research

Senses as capacities
(2020) Multisensory Research, 34 (3), pp. 233-259.

O’Callaghan, C.

Washington University in St. Louis, Philosophy Department, PNP Program, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
This paper presents an account of the senses and what differentiates them that is compatible with richly multisensory perception and consciousness. According to this proposal, senses are ways of perceiving. Each sense is a subfaculty that comprises a collection of perceptual capacities. What each sense shares and what differentiates one sense from another is the manner in which those capacities are exercised. Each way of perceiving involves a distinct type of information gathering, individuated by the information it functions to extract and the medium from which it does so. This approach distinguishes the project of characterizing and differentiating senses from that of attributing experiences to sensory modalities. Perceptual experiences are episodes in which perceptual capacities are exercised. Conscious perceptual episodes may be ascribed to distinct sensory modalities, according to the manners in which perceptual capacities are deployed on an occasion. According to this account, senses are not exclusive. First, their capacities may overlap. Second, perceptual episodes, including conscious experiences, may belong to multiple senses. Indeed, some episodes require the joint use of several senses. In this account, subjects have only limited first-person knowledge of the senses they employ. © Koninklijke Brill NV, Leiden, 2020

Author Keywords
Multisensory perception; Perceptual capacities; Sense individuation; The senses

Document Type: Article
Publication Stage: Final
Source: Scopus