Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator
(2024) Nature Communications, 15 (1), art. no. 3523, .
Jankowski, M.S.a , Griffith, D.b , Shastry, D.G.a , Pelham, J.F.a , Ginell, G.M.b , Thomas, J.a , Karande, P.c d , Holehouse, A.S.b e , Hurley, J.M.a d
a Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
b Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
d Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, United States
e Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ’s interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of transcriptional activity. Additionally, the microarray demonstrated an enrichment of FRH binding to FRQ peptides with a net positive charge. We found that positively charged residues occurred in significant “blocks” within the amino acid sequence of FRQ and that ablation of one of these blocks affected both core clock timing and physiological clock output. Finally, we found positive charge clusters were a commonly shared molecular feature in repressive circadian clock proteins. Overall, our study suggests a mechanistic purpose for positive charge blocks and yielded insights into repressive arm protein roles in clock function. © The Author(s) 2024.
Funding details
Longer Life FoundationLLF
University of WashingtonUW
National Science FoundationNSFDGE-2139839, DGE-1247271
National Institute of Biomedical Imaging and BioengineeringNIBIB2045674, R35GM128687, U01EB022546
National Institute of General Medical SciencesNIGMSGM067545
Human Frontier Science ProgramHFSPRGP0015/2022
Document Type: Article
Publication Stage: Final
Source: Scopus
Large-scale annotated dataset for cochlear hair cell detection and classification
(2024) Scientific Data, 11 (1), art. no. 416, .
Buswinka, C.J.a b c , Rosenberg, D.B.a b d , Simikyan, R.G.a , Osgood, R.T.a b e , Fernandez, K.f , Nitta, H.a , Hayashi, Y.a b , Liberman, L.W.a b , Nguyen, E.a , Yildiz, E.g , Kim, J.h i j , Jarysta, A.k , Renauld, J.l , Wesson, E.a , Wang, H.a b , Thapa, P.m , Bordiga, P.a b , McMurtry, N.n , Llamas, J.o p , Kitcher, S.R.e , López-Porras, A.I.q , Cui, R.r , Behnammanesh, G.s , Bird, J.E.s , Ballesteros, A.r , Vélez-Ortega, A.C.q , Edge, A.S.B.a b , Deans, M.R.t u , Gnedeva, K.o p , Shrestha, B.R.a b , Manor, U.d v , Zhao, B.n , Ricci, A.J.i w , Tarchini, B.k x y , Basch, M.L.l , Stepanyan, R.l z , Landegger, L.D.g j , Rutherford, M.A.aa , Liberman, M.C.a b c , Walters, B.J.m , Kros, C.J.e , Richardson, G.P.e , Cunningham, L.L.f , Indzhykulian, A.A.
a Eaton Peabody Laboratories, Mass Eye and Ear, Boston, MA 02114, United States
b Department of Otolaryngology, Head and Neck Surgery, Harvard Medical School, Boston, MA 02114, United States
c Speech and Hearing Biosciences and Technology graduate program, Harvard University, Cambridge, MA 02138, United States
d Department of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, United States
e Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United Kingdom
f Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20814, United States
g Department of Otolaryngology, Head and Neck Surgery, Vienna General Hospital and Medical University of Vienna, Vienna, 1090, Austria
h Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
j Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305, United States
k The Jackson Laboratory, Bar Harbor, ME 04609, United States
l Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States
m The University of Mississippi Medical Center, Department of Otolaryngology – Head and Neck Surgery, Jackson, MS 39216, United States
n Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
o Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90033, United States
p Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033, United States
q Department of Physiology, University of Kentucky, Lexington, KY 40536, United States
r Section on Sensory Physiology and Biophysics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20814, United States
s Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, United States
t Department of Neurobiology, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, UT 84112, United States
u Department of Otolaryngology – Head & amp; Neck Surgery, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, UT 84132, United States
v Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, United States
w Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, United States
x Tufts University School of Medicine, Boston, MA 02111, United States
y Graduate School of Biomedical Science and Engineering (GSBSE), University of Maine, Orono, ME 04469, United States
z Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States
aa Department of Otolaryngology, Washington University, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO 63110, United States
Abstract
Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5–15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease. © The Author(s) 2024.
Funding details
Chan Zuckerberg InitiativeCZI
Silicon Valley Community FoundationSVCF
David F. and Margaret T. Grohne Family Foundation
National Institutes of HealthNIHR01DC000188, R01DC020190, ZIA DC-000079, P50DC015857, T32 DC000038, R21DC020312, R01DC017166, R01DC016365, N00014-18-1-2716, R01DC018827
National Cancer InstituteNCIR01DC021075, CA014195
National Institute on Deafness and Other Communication DisordersNIDCDR01DC014712, R01DC021325, DIR DC000096
Document Type: Data Paper
Publication Stage: Final
Source: Scopus
A domain-oriented approach to characterizing movement-evoked pain
(2024) Pain Reports, 9 (3), p. E1158.
Crow, J.A.a , Joseph, V.b , Miao, G.c , Goodin, B.R.d , Sibille, K.T.a e , Cardoso, J.f , Bartley, E.J.g , Staud, R.h , Fillingim, R.B.a i , Booker, S.Q.a
a Pain Research & Intervention Center of Excellence, University of Florida, Gainesville, FL, United States
b College of Population Health, The University of New Mexico, Albuquerque, NM, United States
c Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL, United States
d Department of Anesthesiology, School of Medicine, Washington University, St. Louis, MO, United States
e Department of Physical Medicine & Rehabilitation, College of Medicine, University of Florida, Gainesville, FL, United States
f The Pennsylvania State University, University Park, PA, United States
g Department of Community Dentistry and Behavioral Science, College of Dentistry, University of Florida, Gainesville, FL, United States
h Department of Rheumatology, College of Medicine, University of Florida, Gainesville, FL, United States
i Department of Biobehavioral Nursing Science, College of Nursing, University of Florida, Gainesville, FL, United States
Abstract
Introduction:Movement-evoked pain (MEP) impacts a substantial proportion of US adults living with chronic pain. Evidence suggests that MEP is influenced by numerous biopsychosocial factors and mediated by mechanisms differing from those of spontaneous pain. However, both characteristic and mechanistic knowledge of MEP remain limited, hindering effective diagnosis and treatment.Objectives:We asked (1) can chronic pain, functional, psychosocial, and behavioral measures be grouped into descriptive domains that characterize MEP? and (2) what relationships exist between biopsychosocial factors across multiple domains of MEP?Methods:We formed 6 characteristic domains from 46 MEP-related variables in a secondary analysis of data from 178 individuals (aged 45-85 years) with knee pain. Ratings of pain during 3 functional activities (ie, Balance, Walking, Chair Stand) were used as primary MEP variables. Pearson correlations were calculated to show linear relationships between all individual domain variables. Relationships between variables were further investigated through weighted correlation network analysis.Results:We observed a unique combination of pain characteristics associated with MEP apart from general pain. Notably, minutes doing physical activity were inversely associated with multiple variables within 4 of the 6 domains. Weighted correlation network analysis largely supported our classification of MEP domains. Additional interdomain relationships were observed, with the strongest existing between MEP, Mechanical Pain, and Multiple Pain Characteristics and Symptoms. Additional relationships were observed both within and between other domains of the network.Conclusion:Our analyses bolster fundamental understanding of MEP by identifying relevant mechanistic domains and elucidating biopsychosocial and interdomain relationships. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
Chronic pain; Knee osteoarthritis; Movement-evoked pain; Quantitative sensory testing
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR37AG033906, R01AG054370
UL1TR001427, UL1TR001417
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSK23AR076463
National Center for Advancing Translational SciencesNCATSUL1 TR000064
Document Type: Article
Publication Stage: Final
Source: Scopus
Ethnic background and distribution of clinical phenotypes in patients with probable progressive supranuclear palsy (2024) Parkinsonism and Related Disorders, 123, art. no. 106955, .
Couto, B.a b , Di Luca, D.G.a c , Antwi, J.a , Bhakta, P.a , Fox, S.a h , Tartaglia, M.C.d h e h , Kovacs, G.G.a e f g h , Lang, A.E.a e h
a Edmond J. Safra Program in Parkinson’s Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada
b Instituto de Neurociencia Cognitiva y Traslacional (INCyT), INECO-CONICET-Favaloro, Buenos Aires, Argentina
c Department of Neurology, Washington University in St. LouisMO, United States
d Memory Clinic, Toronto Western Hospital, Toronto, ON, Canada
e Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
f Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada
g Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON, Canada
h Department of Medicine, Division of Neurology, University Health Network and the University of Toronto, Toronto, ON, Canada
Abstract
Background: Progressive Supranuclear Palsy (PSP) is a sporadic neurodegenerative disease without a clear geographic prevalence. Cohorts studied in the UK and India showed no higher prevalence of atypical parkinsonism in South Asian patients. We describe the ethnic and racial background of PSP patients in the Greater Toronto Area (GTA), Canada. Methods: A prospective observational study of patients with clinically probable PSP evaluated at the dedicated Rossy PSP program. Demographic and clinical data were collected at baseline including PSP phenotype. Results were compared with the latest demographic information from the greater Toronto area. Results: Of the 197 patients screened, 135 had probable PSP and resided within the GTA. The mean age at visit was 71.1 years, disease duration 4.4 years, and disease severity moderate. Compared to our catchment area, there was a higher proportion of patients with a South Asian origin and a lower proportion of patients from East and Southeastern Asia and Africa. A secondary analysis using population census data limited to individuals greater than 65 confirmed the significantly higher representation of South Asians in our clinic but found no differences for other racial and ethnic origins. Conclusion: Evaluation of this Toronto cohort found a greater than expected proportion of affected individuals with South Asian ethnic and racial origin. Despite limitations, our results suggest the possibility of a racial and ethnic predisposition to PSP. Further studies are needed to confirm and to address potential associated risk factors, and genome-environmental interactions. © 2024 Elsevier Ltd
Author Keywords
Diversity; Epidemiology; Ethnic; Progressive supranuclear palsy; Race
Funding details
Rossy FoundationRF
Document Type: Article
Publication Stage: Final
Source: Scopus
ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma
(2024) Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 42 (13), pp. 1542-1552.
Arrillaga-Romany, I.a , Gardner, S.L.b , Odia, Y.c , Aguilera, D.d , Allen, J.E.e , Batchelor, T.f , Butowski, N.g , Chen, C.h , Cloughesy, T.i , Cluster, A.j , de Groot, J.g , Dixit, K.S.k , Graber, J.J.l , Haggiagi, A.M.m , Harrison, R.A.n , Kheradpour, A.o , Kilburn, L.B.p , Kurz, S.C.q , Lu, G.r , MacDonald, T.J.d , Mehta, M.c , Melemed, A.S.e , Nghiemphu, P.L.i , Ramage, S.C.e , Shonka, N.s , Sumrall, A.t , Tarapore, R.S.e , Taylor, L.l , Umemura, Y.u , Wen, P.Y.f
a Massachusetts General Hospital, Boston, MA, United States
b New York University, Grossman School of Medicine, New York, NY
c Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, Puerto Rico
d Children’s Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, United States
e Chimerix, Inc, Durham, NC, United States
f Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, United States
g University of California, San Francisco, CA, United States
h University of Minnesota Medical Center, Minneapolis, MN, United States
i University of California, Los Angeles, CA, United States
j Washington University of St Louis, St Louis, MO, United States
k Northwestern Medical Lou and Jean Malnati Brain Tumor Institute, Chicago, IL, United States
l University of Washington Medical Center, Seattle, WA, United States
m Columbia University Irving Medical Center, New York, NY
n University of British Columbia, Vancouver, BC, Canada
o Loma Linda University, Loma Linda, CA, United States
p Children’s National HospitalWA, United States
q University Hospital Tuebingen, Tuebingen, Germany
r Oncoceutics Inc, Philadelphia, PA, United States
s University of Nebraska Medical Center, Omaha, NE, United States
t Levine Cancer Institute, Charlotte, NC
u University of Michigan, Ann Arbor, MI, United States
Abstract
PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
Document Type: Article
Publication Stage: Final
Source: Scopus
Living as a Survivor: Sleep Disturbance, Fatigue, Depressive Mood, and Cognitive Dysfunction after Breast Cancer Treatment
(2024) Cancer Nursing, 47 (3), pp. 221-228. Cited 4 times.
Wu, H.-S.a , Gao, F.b , Given, C.a
a College of Nursing, Michigan State University, East Lansing, United States
b Division of Public Health Sciences, Washington University, School of Medicine, St Louis, MO, United States
Abstract
Background Many cancer survivors endure multiple symptoms while striving to return to a normal life. Those symptoms often co-occur and exacerbate one another; however, their interplay is not fully understood. Objective This study aimed to examine the occurrence and concurrence of sleep disturbance, fatigue, depressive mood, and cognitive dysfunction in posttreatment breast cancer survivors. Methods The data for this descriptive analysis were collected as part of the screening for a clinical trial. The occurrences of sleep disturbance, depressive mood, and cognitive dysfunction were each determined by the cutoff scores of the Pittsburgh Sleep Quality Index, Center for Epidemiological Studies Depression Scale, and Montreal Cognitive Assessment, respectively; fatigue was determined by meeting the International Classification of Diseases cancer-related fatigue criteria. Results A convenience sample of 81 women completed chemotherapy or/and radiation for stage I-III breast cancer an average of 23.1 (±SD = 9.0) months ago. Sleep disturbance (85%) was most prevalent, followed by fatigue (67%), depressive mood (46%), and cognitive dysfunction (29%). Of the survivors, 80% reported 2 or more co-occurring symptoms. Worsened subjective sleep quality, sleep disturbance, and daytime dysfunction significantly increased the risk of fatigue by 5.3, 4.3, and 4.3 times (all P <.001) and depression by 2.0, 2.7, and 3.0 times (all P <.05), respectively. Conclusion Sleep disturbance significantly increased the risk of survivors’ fatigue and/or depressive mood after cancer treatment completion. Implication for Practice Effectively managing sleep disturbance and improving the individual’s sleep perception may subsequently reduce fatigue and/or depressive mood among breast cancer survivors. Nonpharmacological strategies for managing multiple posttreatment symptoms are needed. © Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
Cancer survivors; Cognitive dysfunction; Depression; Fatigue; Sleep; Symptom co-occurrence
Document Type: Article
Publication Stage: Final
Source: Scopus
Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
(2024) Science (New York, N.Y.), 384 (6694), p. eadf5489.
Dodd, D.O.a , Mechaussier, S.b , Yeyati, P.L.a , McPhie, F.a , Anderson, J.R.c , Khoo, C.J.d , Shoemark, A.e f , Gupta, D.K.g , Attard, T.h , Zariwala, M.A.i , Legendre, M.j k , Bracht, D.l , Wallmeier, J.l , Gui, M.c , Fassad, M.R.m n , Parry, D.A.a , Tennant, P.A.a , Meynert, A.a , Wheway, G.o , Fares-Taie, L.b , Black, H.A.p q , Mitri-Frangieh, R.r s , Faucon, C.r , Kaplan, J.b , Patel, M.m t , McKie, L.a , Megaw, R.a u , Gatsogiannis, C.v , Mohamed, M.A.m w , Aitken, S.a , Gautier, P.a , Reinholt, F.R.x , Hirst, R.A.y , O’Callaghan, C.y , Heimdal, K.z , Bottier, M.e , Escudier, E.k r , Crowley, S.aa , Descartes, M.ab , Jabs, E.W.ac ad , Kenia, P.ae , Amiel, J.af ag , Bacci, G.M.ah , Calogero, C.ai , Palazzo, V.aj , Tiberi, L.aj , Blümlein, U.ak , Rogers, A.f , Wambach, J.A.g , Wegner, D.J.g , Fulton, A.B.al , Kenna, M.am , Rosenfeld, M.an , Holm, I.A.ao ap , Quigley, A.aq , Hall, E.A.a , Murphy, L.C.a , Cassidy, D.M.e , von Kriegsheim, A.ar , Papon, J.-F.as , Pasquier, L.at , Murris, M.S.au , Chalmers, J.D.e , Hogg, C.f , Macleod, K.A.av , Urquhart, D.S.av aw , Unger, S.av aw , Aitman, T.J.p , Amselem, S.j k , Leigh, M.W.ax , Knowles, M.R.ay , Omran, H.l , Mitchison, H.M.m , Brown, A.c , Marsh, J.A.a , Welburn, J.P.I.h , Ti, S.-C.d , Horani, A.g az , Rozet, J.-M.b , Perrault, I.b , Mill, P.a , Scottish Genomes Partnership16ba , Genomics England Research Consortium45bb , Undiagnosed Diseases Network46bc
a MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom
b Laboratory of Genetics in Ophthalmology, Institute of Genetic Diseases, Institut Imagine, Université de Paris, Paris, 75015, France
c Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, United States
d School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
e Respiratory Research Group, Molecular and Cellular Medicine, University of Dundee, Dundee, DD1 9SY, United Kingdom
f Respiratory Paediatrics, Royal Brompton Hospital, London, SW3 6NP, United Kingdom
g Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130, United States
h Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom
i Department of Pathology and Laboratory Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States
j Molecular Genetics Laboratory, Sorbonne Université, Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Paris, 75012, France
k Sorbonne Université, INSERM, Childhood Genetic Disorders, Paris, 75012, France
l Department of General Pediatrics, University Children’s Hospital MünsterMünster 48149, Germany
m Genetics and Genomic Medicine Department, UCL Institute of Child Health, University College London, London, WC1N 1EH, United Kingdom
n Department of Human Genetics, Medical Research Institute, Alexandria UniversityAlexandria 21561, Egypt
o Faculty of Medicine, University of SouthamptonSouthampton SO16 6YD, United Kingdom
p Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom
q South East of Scotland Genetics Service, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom
r Department of Anatomy, Cytology and Pathology, Hôpital Intercommuncal de Créteil, Créteil 94000, France
s Biomechanics and Respiratory Apparatus, IMRB, U955 INSERM – Université Paris Est Créteil, CNRS ERL 7000, Créteil 94000, France
t MRC Prion Unit, Institute of Prion Diseases, University College London, London W1W 7FF, United Kingdom
u Princess Alexandra Eye Pavilion, Edinburgh, EH3 9HA, United Kingdom
v Center for Soft Nanoscience and Institute of Medical Physics and BiophysicsMünster 48149, Germany
w Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Ash Sharqiyah, 44519, Egypt
x Core Facility for Electron Microscopy, Department of Pathology, Oslo University Hospital-RikshospitaletOslo 0372, Norway
y Centre for PCD Diagnosis and Research, Department of Respiratory Sciences, University of Leicester, Leicester, LE1 9HN, United Kingdom
z Department of Medical Genetics, Oslo University HospitalOslo 0407, Norway
aa Paediatric Department of Allergy and Lung Diseases, Oslo University HospitalOslo 0407, Norway
ab Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA
ac Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029-6504, New York, USA
ad Department of Clinical Genomics, Mayo Clinic, Rochester, NY 55905, USA
ae Department of Paediatric Respiratory Medicine, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, B15 2TG, United Kingdom
af Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, 75015, France
ag Laboratory of Embryology and Genetics of Human Malformations, INSERM UMR 1163, Institut Imagine, Université de Paris, Paris, 75015, France
ah Pediatric Ophthalmology Unit, Meyer Children’s Hospital IRCCS, Florence, 50139, Italy
ai Pediatric Pulmonary Unit, Meyer Children’s Hospital IRCCS, Florence, 50139, Italy
aj Medical Genetics Unit, Meyer Children’s Hospital IRCCS, Florence, 50139, Italy
ak Carl-Thiem-Klinikum Cottbus, Cottbus, 03048, Germany
al Department of Ophthalmology, Boston Children’s Hospital, Boston, MA 02115, United States
am Department of Otolaryngology, Boston Children’s Hospital, Boston, MA 02115, United States
an Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Research Institute, Seattle, WA 98015, USA
ao Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children’s Hospital, Boston, MA 02115, United States
ap Department of Pediatrics, Harvard Medical School, Boston
aq Department of Paediatric Radiology, Royal Hospital for Children and Young People, Edinburgh, EH16 4TJ, United Kingdom
ar Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom
as ENT Department, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris-Saclay University, France
at Medical Genetics Department, CHU Pontchaillou, Rennes, 35033, France
au Department of Pulmonology, Transplantation, Cystic Fibrosis Centre, Larrey Hospital, Toulouse, 31400, France
av Department of Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children and Young People, Edinburgh, EH16 4TJ, United Kingdom
aw Department of Child Life and Health, University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom
ax Department of Pediatrics, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States
ay Department of Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States
az Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.
Document Type: Article
Publication Stage: Final
Source: Scopus
Schöbi, N.a , Sanchez, C.b , Welzel, T.b c , Bamford, A.d e , Webb, K.f , Rojo, P.g , Tremoulet, A.h , Atkinson, A.b i , Schlapbach, L.J.j k , Bielicki, J.A.b l , Swissped-RECOVERY trial groupm
a Paediatrics, Inselspital, Bern University Hospital, University of BernBern, Switzerland
b Paediatric Research Centre, University Children’s Hospital Basel, University of Basel, Basel, Switzerland
c Pediatric Rheumatology, University Children’s Hospital Basel, University of Basel, Basel, Switzerland
d Paediatric Infectious Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
e Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
f Division of Paediatric Rheumatology, School of Child and Adolescent Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa
g Pediatrics, Hospital Universitario Doce de Octubre. Universidad Complutense. Instituto de Investigación 12 OctubreMadrid, Spain
h Paediatrics, University of California San Diego, Rady Children’s Hospital San Diego, San Diego, CA, United States
i Infectious Diseases, Washington University in St. Louis School of Medicine, St. Louis, St Louis, Missouri, USA
j Department of Intensive Care and Neonatalogy, Children’s Research Center, University Children’s Hospital ZürichZurich, Switzerland
k Child Health Research Centre, University of Queensland, Paediatric Intensive Care Unit, Queensland Children’s HospitalQLD, Australia
l Centre for Neonatal and Paediatric Infection, St George’s University, London, United Kingdom
Abstract
OBJECTIVES: In trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of trial findings. Swissped-RECOVERY was set up as one of the first randomised controlled trials worldwide, investigating the comparative effectiveness of anti-inflammatory treatment with intravenous methylprednisolone or intravenous immunoglobulins in children and adolescents with Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We present one approach towards improving the interpretation of non-randomised treatment in a randomised controlled trial. DESIGN: This is a pre-planned ancillary analysis of the Swissped-RECOVERY trial, a randomised multicentre open-label two-arm trial. SETTING: 10 Swiss paediatric hospitals (secondary and tertiary care) participated. PARTICIPANTS: Paediatric patients hospitalised with PIMS-TS. INTERVENTIONS: All patient-first intercurrent events, if applicable, were presented to an independent adjudication committee consisting of four international paediatric COVID-19 experts to provide independent clinical adjudication to a set of standardised questions relating to whether additional non-randomised treatments were clinically indicated and disease classification at the time of the intercurrent event. RESULTS: Of 41 treatments in 75 participants (24/41 (59%) and 17/41 (41%) in the intravenous methylprednisolone and immunoglobulin arms of the trial, respectively), two-thirds were considered indicated. The most common treatment (oral glucocorticoids, 14/41, 35%) was mostly considered not indicated (11/14, 79%), although in line with local guidelines. Intercurrent events among patients with Shock-like PIMS-TS at baseline were mostly considered indicated. A significant proportion of patients with undifferentiated PIMS-TS at baseline were not attributed to the same group at the time of the intercurrent event (6/12 unchanged, 4/12 Kawasaki disease-like, 2/12 Shock-like). CONCLUSION: The masked adjudication of intercurrent events contributes to the interpretation of results in open-label trials and should be incorporated in the future. TRIAL REGISTRATION NUMBERS: SNCTP000004720 and NCT04826588. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
paediatric infectious disease & immunisation; paediatric intensive & critical care; post-infectious disorders; randomized controlled trial; SARS-CoV-2 infection
Document Type: Article
Publication Stage: Final
Source: Scopus
Heterogeneous Forgetting Rates and Greedy Allocation in Slot-Based Memory Networks Promotes Signal Retention
(2024) Neural Computation, 36 (5), pp. 1022-1040.
Jones, B.a , Snyder, L.b , Ching, S.a
a Department of Electrical and Systems Science, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
A key question in the neuroscience of memory encoding pertains to the mechanisms by which afferent stimuli are allocated within memory networks. This issue is especially pronounced in the domain of working memory, where capacity is finite. Presumably the brain must embed some “policy” by which to allocate these mnemonic resources in an online manner in order to maximally represent and store afferent information for as long as possible and without interference from subsequent stimuli. Here, we engage this question through a top-down theoretical modeling framework. We formally optimize a gating mechanism that projects afferent stimuli onto a finite number of memory slots within a recurrent network architecture. In the absence of external input, the activity in each slot attenuates over time (i.e., a process of gradual forgetting). It turns out that the optimal gating policy consists of a direct projection from sensory activity to memory slots, alongside an activity-dependent lateral inhibition. Interestingly, allocating resources myopically (greedily with respect to the current stimulus) leads to efficient utilization of slots over time. In other words, later-arriving stimuli are distributed across slots in such a way that the network state is minimally shifted and so prior signals are minimally “overwritten.” Further, networks with heterogeneity in the timescales of their forgetting rates retain stimuli better than those that are more homogeneous. Our results suggest how online, recurrent networks working on temporally localized objectives without high-level supervision can nonetheless implement efficient allocation of memory resources over time. © 2024 Massachusetts Institute of Technology.
Document Type: Article
Publication Stage: Final
Source: Scopus
An executive-functions-based reading training enhances sensory-motor systems integration during reading fluency in children with dyslexia
(2024) Cerebral Cortex, 34 (4), art. no. bhae166, .
Farah, R.a b , Dworetsky, A.c , Coalson, R.S.c , Petersen, S.E.d , Schlaggar, B.L.e f , Rosch, K.S.e g , Horowitz-Kraus, T.a b e g
a Educational Neuroimaging Group, Faculty of Education in Science and Technology, Technion, Haifa, Israel
b Faculty of Biomedical Engineering, Technion, Haifa, 3200003, Israel
c Neurology and Radiology at Washington University Medical School, St Louis, MO, United States
d Department of Neurology, Washington University Medical School, 1 Brookings Dr, St. Louis, MO 63130, United States
e Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, United States
f Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, United States
g Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, United States
Abstract
The Simple View of Reading model suggests that intact language processing and word decoding lead to proficient reading comprehension, with recent studies pointing at executive functions as an important component contributing to reading proficiency. Here, we aimed to determine the underlying mechanism(s) for these changes. Participants include 120 8-to 12-year-old children (n = 55 with dyslexia, n = 65 typical readers) trained on an executive functions-based reading program, including pre/postfunctional MRI and behavioral data collection. Across groups, improved word reading was related to stronger functional connections within executive functions and sensory networks. In children with dyslexia, faster and more accurate word reading was related to stronger functional connections within and between sensory networks. These results suggest greater synchronization of brain systems after the intervention, consistent with the “neural noise”hypothesis in children with dyslexia and support the consideration of including executive functions as part of the Simple View of Reading model. © 2024 The Author(s). Published by Oxford University Press. All rights reserved.
Author Keywords
dyslexia; executive functions; functional connectivity; intervention; neural noise
Document Type: Article
Publication Stage: Final
Source: Scopus
Exome sequencing of 1190 non-syndromic clubfoot cases reveals HOXD12 as a novel disease gene
(2024) Journal of Medical Genetics, art. no. jmg-2024-109846, .
Charng, W.-L.a , Nikolov, M.a , Shrestha, I.a , Seeley, M.A.b , Josyula, N.S.c , Justice, A.E.c , Dobbs, M.B.d , Gurnett, C.A.a
a Department of Neurology, Washington University in Saint Louis, School of Medicine, Saint Louis, MO, United States
b Department of Orthopaedics, Geisinger Medical Center, Danville, PA, United States
c Department of Population Health Sciences, Geisinger, Danville, PA, United States
d Paley Orthopedic & Spine Institute, West Palm Beach, FL, United States
Abstract
Background: Clubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants in known clubfoot disease genes account for only a small portion of the heritability. Methods: Exome sequence data were generated from 1190 non-syndromic clubfoot cases and their family members from multiple ethnicities. Ultra-rare variant burden analysis was performed comparing 857 unrelated clubfoot cases with European ancestry with two independent ethnicity-matched control groups (1043 in-house and 56 885 gnomAD controls). Additional variants in prioritised genes were identified in a larger cohort, including probands with non-European ancestry. Segregation analysis was performed in multiplex families when available. Results: Rare variants in 29 genes were enriched in clubfoot cases, including PITX1 (a known clubfoot disease gene), HOXD12, COL12A1, COL9A3 and LMX1B. In addition, rare variants in posterior HOX genes (HOX9-13) were enriched overall in clubfoot cases. In total, variants in these genes were present in 8.4% (100/1190) of clubfoot cases with both European and non-European ancestry. Among these, 3 are de novo and 22 show variable penetrance, including 4 HOXD12 variants that segregate with clubfoot. Conclusion: We report HOXD12 as a novel clubfoot disease gene and demonstrate a phenotypic expansion of known disease genes (myopathy gene COL12A1, Ehlers-Danlos syndrome gene COL9A3 and nail-patella syndrome gene LMX1B) to include isolated clubfoot. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
exome sequencing; genetic diseases, inborn; genetic research; orthopedics; sequence analysis, DNA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Early automated cerebral edema assessment following endovascular therapy: impact on stroke outcome
(2024) Journal of NeuroInterventional Surgery, art. no. 021641, .
Guasch-Jiménez, M.a b , Dhar, R.c , Kumar, A.c , Cifarelli, J.c , Ezcurra-Díaz, G.a d , Lambea-Gil, A.a d , Ramos-Pachón, A.a d , Martínez-Domeño, A.a d , Prats-Sánchez, L.a d , Guisado-Alonso, D.a d , Fernández-Cadenas, I.a d , Aguilera-Simón, A.a d , Marín, R.a d , Martínez-González, J.P.e , Ortega-Quintanilla, J.f , Fernández-Pérez, I.g , Avellaneda-Gómez, C.g , Rodríguez-Pardo, J.h , De Celis, E.h , Moniche, F.i , Freijo, M.D.M.j , Cortijo, E.k , Trillo, S.l , Camps-Renom, P.a d , Martí-Fábregas, J.a d
a Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
b Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
c Neurology, Washington University, St Louis School of Medicine, St Louis, MO, United States
d Stroke Unit, Institut de Recerca Sant Pau (IIB-SANT PAU), Barcelona, Spain
e Neurointerventional Radiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
f Neurointerventional Radiology, Virgen Del Rocio University Hospital, Seville, Spain
g Neurology, Hospital Del Mar, Barcelona, Spain
h Neurology, La Paz University Hospital, Madrid, Spain
i Neurology, Hospital Universitario Virgen Del Rocio, Seville, Spain
j Neurology, Cruces University Hospital, Barakaldo, Spain
k Neurology, Valladolid University Hospital, Valladolid, Spain
l Neurology, Hospital Universitario de la Princesa, Madrid, Spain
Abstract
Background: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome. Methods: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis. Results: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32). Conclusions: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated δCSF, was associated with worse outcomes. © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
Stroke; Thrombectomy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Identifying the Unmet Needs of People Living With Amyotrophic Lateral Sclerosis: A National Survey to Inform Interdisciplinary Palliative Care
(2024) American Journal of Hospice and Palliative Medicine, .
Washington, K.T.a , Mechling, C.A.b , Pitzer, K.A.a , Maiser, S.c d , Mehta, A.K.e f
a Division of Palliative Medicine, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Program in Occupational Therapy, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology and Internal Medicine, Hennepin Healthcare, Minneapolis, MN, United States
d Department of Neurology and Internal Medicine, University of Minnesota Medical School, Minneapolis, MN, United States
e Department of Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
Abstract
Introduction/Aims: This national survey builds on previous qualitative research examining potential palliative care needs among people living with ALS (pALS) by quantifying and investigating relationships among pALS’ stage of illness progression; physical, emotional, social, spiritual, and intimacy-related concerns; advance care planning behaviors; perceptions of feeling heard and understood by healthcare providers; and overall quality of life. Methods: Researchers partnered with national organizations to recruit pALS to participate in a one-time survey comprising items from validated instruments (eg, the ALS Specific Quality of Life Instrument-Revised) and researcher-generated measures. Data were analyzed using logistic and linear regression. Results: Among pALS (n = 112), many respondents indicated they had discussed their wishes for end-of-life care with family or friends, shared their wishes with providers, and documented their wishes in writing (79.5%, 49.1%, and 63.4%, respectively). Mean (M) quality of life scores were moderate (M ≈ 6 of 10). Illness stage was associated with documentation of end-of-life care wishes but not with having discussed these wishes with others or with overall quality of life. Reported emotional intimacy received was comparable to that desired (difference =.01 of 10); however, a greater desire for physical intimacy relative to that received was indicated (difference = 1.75 of 10). Discussion: Interdisciplinary palliative care teams may enhance ALS care by promoting advance care planning behaviors (particularly discussing one’s wishes with healthcare providers), providing interventions to improve quality of life, and supporting pALS in navigating challenges related to physical intimacy. © The Author(s) 2024.
Author Keywords
amyotrophic lateral sclerosis; interdisciplinary; intimacy; neuropalliative care; palliative care; survey
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
ALSUntangled #75: Portable neuromodulation stimulator therapy
(2024) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, .
Officer, L.a , Armon, C.b , Barkhaus, P.c , Beauchamp, M.d , Benatar, M.e , Bertorini, T.f , Bowser, R.g , Bromberg, M.h , Brown, A.e , Carbunar, O.M.e , Carter, G.T.i , Crayle, J.j , Denson, K.k , Feldman, E.l , Fullam, T.a , Heiman-Patterson, T.m , Jackson, C.n , Jhooty, S.o , Levinson, D.p , Li, X.q , Linares, A.p , Mallon, E.r , Mascias Cadavid, J.s , Mcdermott, C.t , Mushannen, T.q , Ostrow, L.m , Patel, R.a , Pattee, G.u , Ratner, D.v , Sun, Y.a , Sladky, J.a , Wicks, P.w , Bedlack, R.q
a Department of Neurology, University of Kentucky, Lexington, KY, United States
b Department of Neurology, Shamir Medical Center, Tzrifin, Israel
c Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States
d UNC Neuroscience Clinical Trials Unit, Chapel Hill, NC, United States
e Department of Neurology, University of Miami, Miami, FL, United States
f Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, United States
g Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
h Department of Neurology, University of Utah, Salt Lake City, UT, United States
i Department of Rehabilitation, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
j Department of Neurology, Washington University, St. Louis, MO, United States
k Department of Neurology, Houston Methodist Hospital, Houston, TX, United States
l Department of Neurology, University of Michigan, Ann Arbor, MI, United States
m Department of Neurology, Temple Health, Philadelphia, PA, United States
n Department of Neurology, UT Health San Antonio, San Antonio, TX, United States
o Department of Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
p Medical School, Duke University, Durham, NC, United States
q Department of Neurology, Duke University, Durham, NC, United States
r Undergraduate, Duke University, Durham, NC, United States
s ALS Unit, Neurology Department, Hospital La Paz Institute for Health Research, Madrid, Spain
t Department of Neuroscience, University of Sheffield, South Yorkshire, Sheffield, United Kingdom
u Department of Neurology, University of Nebraska Medical Center, Omaha, NE, United States
v Undergraduate, Tulane University, New Orleans, LA, United States
w Independent Consultant, England, Lichfield, United Kingdom
Abstract
Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment. © 2024 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.
Author Keywords
Electrical stimulation; neuromodulation; PoNS™ Device
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer’s disease late in the disease course and dependent on Lewy pathology burden
(2024) Alzheimer’s and Dementia, .
Levin, J.a b c , Baiardi, S.d , Quadalti, C.e , Rossi, M.e , Mammana, A.e , Vöglein, J.a b , Bernhardt, A.a b , Perrin, R.J.f g , Jucker, M.h i , Preische, O.h i , Hofmann, A.h i , Höglinger, G.U.a b c , Cairns, N.J.j , Franklin, E.E.f g , Chrem, P.k , Cruchaga, C.l , Berman, S.B.m , Chhatwal, J.P.n , Daniels, A.g , Day, G.S.o , Ryan, N.S.p q , Goate, A.M.r , Gordon, B.A.g , Huey, E.D.s , Ibanez, L.l , Karch, C.M.l , Lee, J.-H.t , Llibre-Guerra, J.g , Lopera, F.u , Masters, C.L.v , Morris, J.C.g , Noble, J.M.w , Renton, A.E.x , Roh, J.H.y , Frosch, M.P.z , Keene, C.D.aa , McLean, C.ab , Sanchez-Valle, R.ac , Schofield, P.R.ad ae , Supnet-Bell, C.g , Xiong, C.af , Giese, A.ag , Hansson, O.ah ai , Bateman, R.J.g , McDade, E.g , Parchi, P.d e
a Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
b German Center for Neurodegenerative Diseases, Munich, Germany
c Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
d Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
e IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
f Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
g Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
h German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
i Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
j Living Systems Institute, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
k FLENI, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina
l Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
m University of Pittsburgh Neurology, Pittsburgh, PA, United States
n Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
o Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
p Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
q UK Dementia Research Institute at UCL, London, United Kingdom
r Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
s Butler Hospital, Brown Center for Alzheimer’s Disease Research, Alpert Medical School of Brown University, Providence, RI, United States
t Department of Neurology, Asan Medical Center, Seoul, South Korea
u Grupo de Neurosciencias de Antioquia, Sede de Investigación Universitaria SIU, Medellín, Colombia
v Florey Institute and The University of Melbourne, Melbourne, VIC, Australia
w Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and GH Sergievsky Center, Columbia University, New York, NY, United States
x Department of Genetics and Genomic Sciences and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
y Departments of Neurology and Physiology, Korea University College of Medicine, Seoul, South Korea
z MassGeneral Institute for Neurodegenerative Diseases, Neuropathology Service, Massachusetts General Hospital, Boston, MA, United States
aa Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
ab Department of Anatomical Pathology, AlfredHealth, Melbourne, VIC, Australia
ac Alzheimer’s Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clinic de Barcelona, FRCB-IDIBAPS, Barcelona, Spain
ad Neuroscience Research Australia, Sydney, NSW, Australia
ae School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
af Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
ag Modag GmbH, Wendelsheim, Germany
ah Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
ai Memory Clinic, Skåne University Hospital, Lund, Sweden
Abstract
INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer’s disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer’s disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
alpha-synuclein seed amplification assay; Dominantly Inherited Alzheimer Network; Lewy body pathology; real-time quaking-induced conversion
Funding details
Alzheimer’s AssociationAA
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Instituto de Salud Carlos IIIISCIII
Fleni
Fonds de Recherche du Québec – SantéFRQS
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Ministero dell’Istruzione, dell’Università e della RicercaMIUR
Canadian Institutes of Health ResearchCIHR
National Institute on AgingNIA
Ministry of HealthMOH
National Institutes of HealthNIHP30 AG066444, P01AG003991, P01AG026276
Korea Dementia Research CenterKDRCHU21C0066
U19AG032438, PE0000006
Bundesministerium für Bildung und ForschungBMBFFKZ161L0214C CLINSPECT‐M, FKZ161L0214B
Deutsche ForschungsgemeinschaftDFG390857198
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Plasma miRNA expression profile in pediatric pineal pure germinomas
(2024) Frontiers in Oncology, 14, art. no. 1219796, .
Fakhry, M.a , Elayadi, M.a b , Elzayat, M.G.c , Samir, O.c , Maher, E.d , Taha, H.e , El-Beltagy, M.f , Refaat, A.g , Zamzam, M.a b , Abdelbaki, M.S.h , Sayed, A.A.c i , Kieran, M.a , Elhaddad, A.a
a Department of Pediatric Oncology, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
b Department of Pediatric Oncology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
c Genomics and Epigenomics Program, Research Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
d Clinical Research Department, Children’s Cancer Hospital Egypt (CCHE-57357), Cairo, Egypt
e Department of Pathology, National Cancer Institute (NCI), Cairo University and Children Cancer Hospital (CCHE-57357), Cairo, Egypt
f Department of Neurosurgery, Children’s Cancer Hospital Egypt (CCHE-57357), Faculty of Medicine, Cairo University, Cairo, Egypt
g Radio-Diagnosis Department, National Cancer Institute (NCI), Cairo University, Children Cancer Hospital (CCHE-57357), Cairo, Egypt
h The Division of Hematology and Oncology, St. Louis Children’s Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
i Faculty of Science, Ain Shams University, Cairo, Egypt
Abstract
Background: Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs (miRNA) have emerged as potential non-invasive biomarkers for germ cell tumors and may facilitate the non-invasive diagnosis of pure pineal germinomas. Material and methods: A retrospective chart review was performed on all patients treated at the Children’s Cancer Hospital Egypt diagnosed with a pineal region tumor between June 2013 and March 2021 for whom a research blood sample was available. Plasma samples were profiled for miRNA expression, and DESeq2 was used to compare between pure germinoma and other tumor types. Differentially expressed miRNAs were identified. The area under the curve of the receive;r operating characteristic curve was constructed to evaluate diagnostic performance. Results: Samples from 39 pediatric patients were available consisting of 12 pure germinomas and 27 pineal region tumors of other pathologies, including pineal origin tumors [n = 17; pineoblastoma (n = 13) and pineal parenchymal tumors of intermediate differentiation (n = 4)] and others [n = 10; low-grade glioma (n = 6) and atypical teratoid rhabdoid tumor (n = 4)]. Using an adjusted p-value <0.05, three miRNAs showed differential expression (miR-143-3p, miR-320c, miR-320d; adjusted p = 0.0058, p = 0.0478, and p = 0.0366, respectively) and good discriminatory power between the two groups (AUC 90.7%, p < 0.001) with a sensitivity of 25% and a specificity of 100%. Conclusion: Our results suggest that a three-plasma miRNA signature has the potential to non-invasively identify pineal body pure germinomas which may allow selected patients to avoid the potential surgical complications. Copyright © 2024 Fakhry, Elayadi, Elzayat, Samir, Maher, Taha, El-Beltagy, Refaat, Zamzam, Abdelbaki, Sayed, Kieran and Elhaddad.
Author Keywords
germinoma; liquid biopsy; miRNA; pineal body tumors; plasma biomarkers
Document Type: Article
Publication Stage: Final
Source: Scopus
Variables associated with days of school missed following concussion: results from the Sport Concussion Outcomes in PEdiatrics (SCOPE) study
(2024) Physician and Sportsmedicine, .
Roberts, J.a , Wilson, J.C.a , Halstead, M.E.b , Miller, S.M.c , Santana, J.A.d , Valovich McLeod, T.C.e , Zaslow, T.L.f , Master, C.L.g , Grady, M.F.g , Snedden, T.R.h , Fazekas, M.L.i , Coel, R.A.j , Howell, D.R.a
a Sports Medicine Center, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
b School of Medicine, Departments of Orthopedics and Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
c Scottish Rite for Children and UT Southwestern Medical Center, Dallas, TX, United States
d Children’s Hospital Los Angeles and Keck School of Medicine of USC, Los Angeles, CA, United States
e Athletic Training Program, A.T. Still University, Mesa, AZ, United States
f Cedars Sinai Kerlan Jobe Institute, Los Angeles, CA, United States
g Center for Injury Research and Prevention, Children’s Hospital of Philadelphia, and University of Pennsylvania Perelman, School of Medicine, Philadelphia, PA, United States
h University of Wisconsin-Madison School of Nursing, Madison, WI, United States
i Joe DiMaggio Children’s Hospital, Hollywood, FL, United States
j Kapi’olani Medical Center for Women and Children, University of Hawai‘i John A. Burns School of Medicine, Honolulu, HI, United States
Abstract
Objective: To understand factors associated with missed academic time after concussion to improve support for patients. Our goal was to assess patient-specific predictors of total school time lost after pediatric/adolescent concussion. Study Design: We performed a prospective cohort study of children and adolescents (8–18 years of age) seen within 14 days of concussion from seven pediatric medical centers across the United States. We collected outcomes via the Concussion Learning Assessment & School Survey (CLASS) and constructed a multivariable predictive model evaluating patient factors associated with school time loss. Results: 167 patients participated (mean age = 14.5 ± 2.2 years; 46% female). Patients were assessed initially at 5.0 ± 3.0 days post-injury and had a final follow-up assessment 24.5 ± 20.0 days post-concussion. Participants missed a median of 2 days of school (IQR = 0.5–4), and 21% reported their grades dropped after concussion. Higher initial symptom severity rating (β = 0.06, 95% CI = 0.03–0.08, p < 0.001) and perception of grades dropping after concussion (β = 1.37, 95% CI = 0.28–2.45, p = 0.01) were significantly associated with more days of school time missed after concussion. Those who reported their grades dropping reported missing significantly more school (mean = 5.0, SD = 4.7 days missed of school) than those who reported their grades did not drop (mean = 2.2, SD = 2.6 days missed of school; p < 0.001; Cohen’s d = 0.87). Conclusions: Children and adolescents reported missing a median of 2 days of school following concussion, and more missed school time after a concussion was associated with more severe concussion symptoms and perception of grades dropping. These findings may support recommendations for minimal delays in return-to-learn after concussion. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
academic adjustments; Concussion; grades; mild traumatic brain injury; return-to-learn; return-to-school
Funding details
American College of Sports MedicineACSM
Children’s Hospital of PhiladelphiaCHOP
Chuck Noll Foundation for Brain Injury Research
Taisei Foundation
Colorado Clinical and Translational Sciences InstituteCCTSIUL1 TR002535‐05
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD108133, R03HD094560
Centers for Disease Control and PreventionCDC1U01CE003479-01-00
National Institute of Neurological Disorders and StrokeNINDSR43NS108823, R01NS100952, 5R01NS097549–06
U.S. Department of DefenseDODW81XWH2210590, W81XWH21C0103
National Eye InstituteNEI1R34EY030582-01A1, 2R01EY023261–06
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS1R13AR080451
National Institute of Nursing ResearchNINR5R01NR018425–03
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Burden of delirium on mortality and healthcare resource utilization in geriatric patients hospitalized for inflammatory bowel disease
(2024) Baylor University Medical Center Proceedings, .
Aldiabat, M.a b , Aleyadeh, W.c , Rana, T.d , Ta’ani, O.A.d , Alahmad, M.e , Ayoub, M.b , Jaber, F.f , Obeidat, A.g , Numan, L.h , Manvar, A.i , Alhuneafat, L.j
a Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
b Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Medicine, Akron General Hospital, Akron, OH, United States
d Department of Medicine, Allegheny Health Network, Pittsburgh, PA, United States
e Department of Medicine, University of Missouri–Columbia, Columbia, MO, United States
f Department of Medicine, University of Missouri–Kansas City, Kansas City, MO, United States
g Presbyterian Health System, Albuquerque, NM, United States
h Division of Gastroenterology, SSM Health Saint Louis University Hospital, St. Louis, MO, United States
i Division of Gastroenterology, NYU Langone Health, Mineola, NY, United States
j Department of Cardiovascular Disease, University of Minnesota, Minneapolis, MN, United States
Abstract
Background: Delirium is prevalent in elderly patients, linked to elevated mortality rates, heightened healthcare resource use, and caregiver burden. Inflammatory bowel disease (IBD) poses various delirium risk factors, yet the impact on geriatric IBD patient outcomes remains unexplored. Methods: Using 2016–2019 National Inpatient Sample data, we identified ≥65-year-old patients admitted for IBD (Crohn’s, ulcerative colitis) management stratified by delirium presence as a secondary diagnosis. The study aimed to assess delirium’s impact on geriatric IBD patient outcomes. Results: Among 67,534 elderly IBD admissions, 0.7% (470) developed delirium. The delirium group had a 4.8-fold increase in in-hospital mortality risk (odds ratio 4.80, P < 0.001, 95% confidence interval [CI] 1.94–11.8). IBD patients with delirium experienced prolonged length of stay (adjusted mean difference 5.15 days, 95% CI 3.24–7.06, P < 0.001) and increased care costs (adjusted mean difference $48,328, 95% CI $26,485–$70,171, P < 0.001) compared to those without delirium. Conclusion: Elderly IBD patients with delirium face higher mortality risk, prolonged hospitalization, and increased healthcare costs. Clinicians should recognize delirium’s detrimental effects in this vulnerable group and adhere to preventive protocols for improved care. © Copyright © 2024 Baylor University Medical Center.
Author Keywords
Geriatrics; inflammatory bowel disease; outcomes research
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Apparent Diffusion Coefficient of the Optic Nerve Head in Idiopathic Intracranial Hypertension
(2024) Neuro-Ophthalmology, .
Lama, C.a , Derakhshan, J.a b , Wilson, B.c , Snyder, D.c , Tang, Y.a , Van Stavern, G.c
a Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Radiology, Abington Hospital, Jefferson Health, Abington, PA, United States
c Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Idiopathic Intracranial Hypertension (IIH) is a condition in which patients have elevated intracranial pressure which does not have an apparent cause. To diagnose IIH, evaluation excluding other causes of elevated pressure must be performed. This typically includes magnetic resonance imaging (MRI) of the brain and venous sinuses. Despite there being known radiographic signs suggestive of IIH on MRI, there currently are no established correlations between radiographic findings and visual outcomes. Previous work revealed diffusion weighted imaging (DWI), a qualitative measurement on MRI, correlated with clinical findings (i.e presence and grade of papilloedema), but not visual outcomes. We hypothesized that the apparent diffusion coefficient (ADC), a quantitative value obtained during clinical MRI, may correlate with visual outcomes. We conducted a retrospective chart review to correlate findings on the ADC sequence on routine brain MRIs in patients with papilloedema with visual outcomes. In 49 patients with IIH, this study shows the ADC in the retrobulbar optic nerve to be 1,487 ± 559 × 10−6 mm2 /s, 15% lower than reported value of 1744 ± 413 in healthy controls. This suggests that there is true restricted diffusion in patients with IIH and papilloedema, as previously reported visually by MRI. However, there was no significant correlation with clinical outcomes of papilloedema grade, mean deviation on standard perimetry, and retinal nerve fibre layer (RNFL) on optical coherence tomography (OCT). We discuss reasons why the ADC measurement may be confounded by motion and partial volume and propose methods that may reduce these confounders for future studies. © 2024 Taylor & Francis Group, LLC.
Author Keywords
apparent diffusion coefficient; diffusion weighted imaging; Idiopathic intracranial hypertension; Papilledema; pseudotumor cerebri
Funding details
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Article in Press
Source: Scopus