“Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease” (2021) Alzheimer’s Research and Therapy
Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease
(2021) Alzheimer’s Research and Therapy, 13 (1), art. no. 153, .
Hassenstab, J.a b , Nicosia, J.a , LaRose, M.a , Aschenbrenner, A.J.a , Gordon, B.A.b c , Benzinger, T.L.S.c , Xiong, C.a d , Morris, J.C.a
a Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. Methods: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. Results: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007). Conclusions: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset. © 2021, The Author(s).
Author Keywords
Alzheimer disease; Cognitive assessment; Cognitive decline
Funding details
National Institutes of HealthNIHP30 AG008017, P30 AG008051, P30 AG010124, P30 AG010129, P30 AG010133, P30 AG010161, P30 AG012300, P30 AG013846, P30 AG013854, P30 AG019610, P30 AG028383, P30 AG035982, P30 AG049638, P30 AG053760, P50 AG005131, P50 AG005133, P50 AG005134, P50 AG005136, P50 AG005138, P50 AG005142, P50 AG005146, P50 AG008702, P50 AG016573, P50 AG016574, P50 AG023501, P50 AG025688, P50 AG033514, P50 AG047266, P50 AG047270, P50 AG047366, U24 AG072122
National Institute on AgingNIAK01AG053474, P01AG026276, P01AG03991, P30AG066444
Document Type: Article
Publication Stage: Final
Source: Scopus
“Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults” (2021) Scientific Reports
Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults
(2021) Scientific Reports, 11 (1), art. no. 17980, .
Yudkovicz, J.J.a , Minster, R.L.b , Barinas-Mitchell, E.a , Christensen, K.c , Feitosa, M.d , Barker, M.S.e , Newman, A.B.a , Kuipers, A.L.a
a Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Epidemiology, Biostatistics and Biodemography, Danish Aging Research Center, University of Southern Denmark, Odense C, Denmark
d Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Columbia University, New York, NY, United States
Abstract
Cardiovacular disease (CVD) is the leading cause of death among older adults and is often accompanied by functional decline. It is unclear what is driving this co-occurrence, but it may be behavioral, environmental and/or genetic. We used a family-based study to estimate the phenotypic and shared genetic correlation between CVD risk factors and physical and cognitive functional measures. Participants (n = 1,881) were from the Long Life Family Study, which enrolled families based on their exceptional longevity (sample mean age = 69.4 years, 44% female). Cardiovascular disease risk factors included carotid vessel measures [intima-media thickness and inter-adventitial diameter], obesity [body mass index (BMI) and waist circumference], and hypertension [systolic and diastolic blood pressures]. Function was measured in the physical [gait speed, grip strength, chair stand] and cognitive [digital symbol substitution test, retained and working memory, semantic fluency, and trail making tests] domains. We used SOLAR to estimate the genetic, environmental, and phenotypic correlation between each pair adjusting for age, age2, sex, field center, smoking, height, and weight. There were significant phenotypic correlations (range |0.05–0.22|) between CVD risk factors and physical and cognitive function (all P < 0.05). Most significant genetic correlations (range |0.21–0.62|) were between CVD risk factorsand cognitive function, although BMI and waist circumference had significant genetic correlation with gait speed and chair stand time (range |0.29–0.53|; all P < 0.05). These results suggest that CVD risk factors may share a common genetic-and thus, biologic-basis with both cognitive and physical function. This is particularly informative for research into the genetic determinants of chronic disease. © 2021, The Author(s).
Funding details
National Institute on AgingNIAU01AG023712, U01AG023744, U01AG023746, U01AG023749, U01AG023755, U19AG063893
National Heart, Lung, and Blood InstituteNHLBIK01HL125658
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neuropathology of blepharospasm” (2021) Experimental Neurology
Neuropathology of blepharospasm
(2021) Experimental Neurology, 346, art. no. 113855, .
Fagan, M.a , Scorr, L.a , Bernhardt, D.a , Hess, E.J.b , Perlmutter, J.S.c , Pardo, C.A.d , Jinnah, H.A.e
a Department of Neurology, Emory University, Atlanta, GA, United States
b Departments of Pharmacology and Neurology, Emory University, Atlanta, GA, United States
c Departments of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. LouisMO, United States
d Departments of Neurology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Departments of Neurology, Human Genetics and Pediatrics, Emory University, Atlanta, GA, United States
Abstract
Background: The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is affected, leading to excessive eye blinking and spasms of muscles around the eyes. The pathogenesis of blepharospasm is not well understood, but several imaging studies have implied subtle structural defects in several brain regions, including the cerebellum. Objective: To delineate cerebellar pathology in brains collected at autopsy from 7 human subjects with blepharospasm and 9 matched controls. Methods: Sections from 3 cerebellar regions were sampled and processed using Nissl and silver impregnation stains. Purkinje neurons were the focus of the evaluation, along with as several other subtle pathological features of cerebellar dysfunction such as Purkinje neuron axonal swellings (torpedo bodies), proliferation of basket cell processes around Purkinje neurons (hairy baskets), empty baskets (missing Purkinje neurons), and displacement of cell soma from their usual location (ectopic Purkinje neurons). Results: The results revealed a significant reduction in Purkinje neuron and torpedo body density, but no changes in any of the other measures. Conclusions: These findings demonstrate subtle neuropathological changes similar to those reported for subjects with cervical dystonia. These findings may underly some of the subtle imaging changes reported for blepharospasm. © 2021 Elsevier Inc.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIANS075321
National Institute of Neurological Disorders and StrokeNINDSNS119831
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA
Alzheimer’s Disease Research Center, Emory UniversityADRC
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish Hospital
Benign Essential Blepharospasm Research FoundationBEBRF
Dystonia CoalitionNS065701, NS116025, TR001456
Document Type: Article
Publication Stage: Final
Source: Scopus
“Multi-parametric MRI phenotype with trustworthy machine learning for differentiating CNS demyelinating diseases” (2021) Journal of Translational Medicine
Multi-parametric MRI phenotype with trustworthy machine learning for differentiating CNS demyelinating diseases
(2021) Journal of Translational Medicine, 19 (1), art. no. 377, .
Huang, J.a c , Xin, B.b , Wang, X.b , Qi, Z.a c , Dong, H.d , Li, K.a c , Zhou, Y.e , Lu, J.a c
a Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xuanwu District, Beijing, 100053, China
b School of Computer Science, The University of Sydney, Building J12/1 Cleveland Street, Sydney, NSW 2006, Australia
c Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Capital Medical University, Beijing, China
d Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
e Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
Abstract
Background: Misdiagnosis of multiple sclerosis (MS) and neuromyelitis optica (NMO) may delay the treatment, resulting in poor prognosis. However, the precise identification of these two diseases is still challenging in clinical practice. We aimed to evaluate the value of quantitative radiomic features extracted from the brain white matter lesions for differential diagnosis of MS and NMO. Methods: We recruited 116 CNS demyelinating patients including 78 MS, and 38 NMO. Three neuroradiologists performed visual differential diagnosis based on brain MRI for comparison purpose. A multi-level scheme was designed to harness the selection of discriminative and stable radiomics features extracted from brain while mater lesions in T1-MPRAGE, T2 sequences and clinical factors. Based on the imaging phenotype composed of the selected radiomic and clinical features, Multi-parametric Multivariate Random Forest (MM-RF) model was constructed and verified with both 10-fold cross-validation and independent testing. Result interpretation was provided to build trust in diagnostic decisions. Results: Eighty-six patients were randomly selected to form the training set while the rest 30 patients for independent testing. On the training set, our MM-RF model achieved accuracy 0.849 and AUC 0.826 in 10-fold cross-validation, which were significantly higher than clinical visual analysis (0.709 and 0.683, p < 0.05). In the independent testing, the MM-RF model achieved AUC 0.902, accuracy 0.871, sensitivity 0.873, specificity 0.869, respectively. Furthermore, age, sex and EDSS were found mildly correlated with the radiomic features (p of all < 0.05). Conclusions: Multi-parametric radiomic features have potential as practical quantitative imaging biomarkers for differentiating MS from NMO. © 2021, The Author(s).
Author Keywords
Machine learning; MRI; Multiple sclerosis; Neuromyelitis optica; Radiomics
Document Type: Article
Publication Stage: Final
Source: Scopus
“Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy” (2021) BMC Ophthalmology
Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy
(2021) BMC Ophthalmology, 21 (1), art. no. 327, .
Dana, R.a , Farid, M.b , Gupta, P.K.c , Hamrah, P.d , Karpecki, P.e , McCabe, C.M.f , Nijm, L.g h , Pepose, J.S.i j , Pflugfelder, S.k , Rapuano, C.J.l , Saini, A.m , Gibbs, S.N.n , Broder, M.S.n
a Massachusetts Eye and Ear, Harvard Medical School Department of Ophthalmology, Boston, MA 02114, United States
b University of California, Irvine School of Medicine, 850 Health Sciences Rd, Irvine, CA 92697, United States
c Duke University Eye Center, 4709 Creekstone Drive, Suite 100, Durham, NC 27703, United States
d Tufts Medical Center, Tufts University School of Medicine, 800 Washington St, Boston, MA 02111, United States
e UPike College of Optometry/Kentucky Eye Institute, 147 Sycamore Street, Pikeville, KY 41501, United States
f The Eye Associates, 2111 Bee Ridge Rd, Sarasota, FL 34239, United States
g Warrenville EyeCare and LASIK, 2S631 Illinois Route 59, Suite A, Warrenville, IL 60555, United States
h University of Illinois Eye and Ear Infirmary, 1855 W Taylor St, Chicago, IL 60612, United States
i Pepose Vision Institute, 1815 Clarkson Rd, Chesterfield, MO 63017, United States
j Washington University School of Medicine, Department of Ophthalmology and Visual Science, 660 Euclid Avenue, St. Louis, MO 63110, United States
k Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin St, NC-505, Houston, TX 77030, United States
l Wills Eye Hospital, 840 Walnut St, Philadelphia, PA 19107, United States
m Integrity Eye, 1955 Citracado Parkway, Escondido, CA 92029, United States
n Partnership for Health Analytic Research (PHAR), LLC, 280 S Beverly Dr Suite 404, Beverly Hills, CA 90212, United States
Abstract
Background: Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. Methods: An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. Results: There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. Conclusions: These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK. © 2021, The Author(s).
Author Keywords
Consensus; Corneal diseases; Corneal epithelium; Keratitis; Trigeminal nerve diseases
Funding details
National Institutes of HealthNIH
GlaxoSmithKlineGSK
Novartis
Allergan
Catholic Medical CenterCMC
Document Type: Article
Publication Stage: Final
Source: Scopus
“Bcl6 controls meningeal Th17-B cell interaction in murine neuroinflammation” (2021) Proceedings of the National Academy of Sciences of the United States of America
Bcl6 controls meningeal Th17-B cell interaction in murine neuroinflammation
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (36), art. no. e2023174118, .
Hartlehnert, M.a , Börsch, A.-L.a , Li, X.a , Burmeister, M.b c , Gerwien, H.b c , Schafflick, D.a , Heming, M.a , Lu, I.-N.a , Narayanan, V.a , Strecker, J.-K.a , Kolz, A.d , Peters, A.d e , Wu, G.F.f , Wiendl, H.a c , Sorokin, L.b c , zu Horste, G.M.a
a Department of Neurology, Institute of Translational Neurology, University Hospital Münster, Münster, 48149, Germany
b Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, 48149, Germany
c Cells in Motion Interfaculty Centre, University of Münster, Münster, 48149, Germany
d Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians University Munich, Munich, 81377, Germany
e Biomedical Center, Faculty of Medicine, Ludwig-Maximilians University Munich, Munich, 81377, Germany
f Department of Neurology, Washington University in St. Louis, St. Louis, MO 63108, United States
Abstract
Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in-depth characterization of meningeal versus parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells that is required in other T cell lineages to induce isotype class switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class switching in the cerebrospinal fluid. We thus identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a mechanism controlling compartment specificity in neuroinflammation. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Bcl6; CNS meninges; Ectopic lymphoid tissue; Single-cell RNA-seq; Th17
Funding details
MzH3/020/20, SEED/016/21
PE2681/1-1, RG-1802-30253
National Institutes of HealthNIHR01 NS106289
National Multiple Sclerosis Society
Deutsche ForschungsgemeinschaftDFGE-Rare-3, EXC1009, ME4050/12-1, ME4050/13-1, ME4050/4-1, ME4050/8-1, SFB1009 A02, TR128 B03
Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMIWF-NRW
Document Type: Article
Publication Stage: Final
Source: Scopus
“Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients” (2021) Journal of Neuro-Ophthalmology: the Official Journal of the North American Neuro-Ophthalmology Society
Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients
(2021) Journal of Neuro-Ophthalmology: the Official Journal of the North American Neuro-Ophthalmology Society, 41 (3), pp. 375-378.
Margolis, M.S., DeBusk, A.A., Moster, M.L., Falardeau, J.M., Eggenberger, E.R., Sergott, R.C., Van Stavern, G.P.
Department of Ophthalmology and Visual Sciences (MSM), Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois; Department of Ophthalmology and Visual Sciences (GVS), Washington University School of Medicine, St. Louis, Missouri; Department of Neuro-Ophthalmology (AD, MLM, RCS), Wills Eye Hospital; Department of Ophthalmology (JF), Oregon Health and Science University; and Department of Neurology (EE), Mayo Clinic, Jacksonville, Florida
Abstract
BACKGROUND: Patients with typical features of pseudotumor cerebri syndrome (PTCS) must undergo lumbar puncture (LP) to demonstrate elevated opening pressure and cerebrospinal fluid (CSF) analysis to rule out alternative diagnoses. As LP may be associated with significant morbidity, this study aims to determine its necessity in diagnosing typical PTCS. METHODS: Retrospective chart review at 3 university-based neuro-ophthalmology practices included women aged 18-45 years with body mass index >25, papilledema, negative neuroimaging, and who met criteria for PTCS or probable PTCS. RESULTS: One hundred fifty-six patients were enrolled. Seven (4.5%) had clinically insignificant CSF abnormalities. No diagnoses or management changed based on LP/CSF results. CONCLUSION: LP may not be routinely required in the initial evaluation of typical patients with PTCS evaluated by experienced clinicians We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes. Copyright © 2021 by North American Neuro-Ophthalmology Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Pitch and rhythm perception and verbal short-term memory in acute traumatic brain injury” (2021) Brain Sciences
Pitch and rhythm perception and verbal short-term memory in acute traumatic brain injury
(2021) Brain Sciences, 11 (9), art. no. 1173, .
Anderson, K.S.a b c , Gosselin, N.a c , Sadikot, A.F.d , Laguë-Beauvais, M.d e , Kang, E.S.H.f , Fogarty, A.E.g , Marcoux, J.d e , Dagher, J.b e , de Guise, E.a b h
a Psychology Department, University of Montreal, Montreal, QC H2V 2S9, Canada
b Centre de Recherche Interdisciplinaire en Réadaptation du Montréal Métropolitain (CRIR), Montreal, QC H3S 1M9, Canada
c International Laboratory for Brain, Music and Sound Research (BRAMS), and Centre for Research on Brain, Language, and Music (CRBLM), Montreal, QC H2V2S9, Canada
d Neurology and Neurosurgery Department, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
e Traumatic Brain Injury Program, McGill University Health Centre, Montreal, QC H3G 1A4, Canada
f Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
g Department of Neurology, Division of Physical Medicine and Rehabilitation, Washington University School of Medicine, St. Louis, MO 63110, United States
h Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
Abstract
Music perception deficits are common following acquired brain injury due to stroke, epilepsy surgeries, and aneurysmal clipping. Few studies have examined these deficits following traumatic brain injury (TBI), resulting in an under-diagnosis in this population. We aimed to (1) compare TBI patients to controls on pitch and rhythm perception during the acute phase; (2) determine whether pitch and rhythm perception disorders co-occur; (3) examine lateralization of injury in the context of pitch and rhythm perception; and (4) determine the relationship between verbal short-term memory (STM) and pitch and rhythm perception. Music perception was examined using the Scale and Rhythm tests of the Montreal Battery of Evaluation of Amusia, in association with CT scans to identify lesion laterality. Verbal short-term memory was examined using Digit Span Forward. TBI patients had greater impairment than controls, with 43% demonstrating deficits in pitch perception, and 40% in rhythm perception. Deficits were greater with right hemisphere damage than left. Pitch and rhythm deficits co-occurred 31% of the time, suggesting partly dissociable networks. There was a dissociation between performance on verbal STM and pitch and rhythm perception 39 to 42% of the time (respectively), with most individuals (92%) demonstrating intact verbal STM, with impaired pitch or rhythm perception. The clinical implications of music perception deficits following TBI are discussed. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Music perception; Pitch; Rhythm; Traumatic brain injury; Verbal short-term memory
Funding details
32548
Canadian Institutes of Health ResearchCIHRMOP-142324
Fonds de Recherche du Québec – SantéFRQS
Document Type: Article
Publication Stage: Final
Source: Scopus
“Glioblastoma signature in the DNA of blood-derived cells” (2021) PLoS ONE
Glioblastoma signature in the DNA of blood-derived cells
(2021) PLoS ONE, 16 (9 September), art. no. e0256831, .
Jain, S.a , Mazaheri, B.b , Raviv, N.c , Bruck, J.a
a Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, United States
b Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, United States
c Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Current approach for the detection of cancer is based on identifying genetic mutations typical to tumor cells. This approach is effective only when cancer has already emerged, however, it might be in a stage too advanced for effective treatment. Cancer is caused by the continuous accumulation of mutations; is it possible to measure the time-dependent information of mutation accumulation and predict the emergence of cancer? We hypothesize that the mutation history derived from the tandem repeat regions in blood-derived DNA carries information about the accumulation of the cancer driver mutations in other tissues. To validate our hypothesis, we computed the mutation histories from the tandem repeat regions in blood-derived exomic DNA of 3874 TCGA patients with different cancer types and found a statistically significant signal with specificity ranging from 66% to 93% differentiating Glioblastoma patients from other cancer patients. Our approach and findings offer a new direction for future cancer prediction and early cancer detection based on information derived from blood-derived DNA. © 2021 Jain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Evaluating Neurotrophin Signaling Using MicroRNA Perilymph Profiling in Cochlear Implant Patients With and Without Residual Hearing” (2021) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and) European Academy of Otology and Neurotology
Evaluating Neurotrophin Signaling Using MicroRNA Perilymph Profiling in Cochlear Implant Patients With and Without Residual Hearing
(2021) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and )European Academy of Otology and Neurotology, 42 (8), pp. e1125-e1133.
Shew, M.a , Wichova, H.b , Warnecke, A.c d , Lenarz, T.c d , Staecker, H.b
a Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, KS, United States
c Department of Otolaryngology, Medizinische Hochschule Hannover, Hannover, Germany
d Cluster of Excellence “Hearing4all” of the German Research Foundation (EXC 1077), Germany
Abstract
HYPOTHESIS: MicroRNAs predicted to regulate neurotrophin signaling can be found in human perilymph. BACKGROUND: Animal and human temporal bone studies suggest that spiral ganglion health can affect cochlear implant (CI) outcomes. Neurotrophins have been identified as a key factor in the maintenance of spiral ganglion health. Changes in miRNAs may regulate neurotrophin signaling and may reflect neurotrophin expression levels. METHODS: Perilymph sampling was carried out in 18 patients undergoing cochlear implantation or stapedotomy. Expression of miRNAs in perilymph was evaluated using an Agilent miRNA gene chip. Using ingenuity pathway analysis (IPA) software, miRNAs targeting neurotrophin signaling pathway genes present in a cochlear cDNA library were annotated. Expression levels of miRNAs in perilymph were correlated to the patients’ preoperative pure-tone average. RESULTS: Expression of mRNAs coding for neurotrophins and their receptors were identified in tissue obtained from normal human cochlea during skull base surgery. We identified miRNAs predicted to regulate these signaling cascades, including miR-1207-5p, miR-4651, miR-103-3p, miR-100-5p, miR-221-3p, miR-200-3p. There was a correlation between poor preoperative hearing and lower expression of miR-1207 (predicted to regulate NTR3) and miR-4651 (predicted to regulate NTR2). Additionally, miR-3960, miR-4481, and miR-675 showed significant differences in expression level when comparing mild and profound hearing loss patients. CONCLUSIONS: Expression of some miRNAs that are predicted to regulate neurotrophin signaling in the perilymph of cochlear implant patients vary with the patient’s level of residual hearing. These miRNAs may serve as biomarkers for changes in neurotrophin signaling. Copyright © 2021, Otology & Neurotology, Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases” (2021) Nature Communications
Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
(2021) Nature Communications, 12 (1), p. 5071.
Kapoor, M.a , Chao, M.J.a , Johnson, E.C.b , Novikova, G.a , Lai, D.c , Meyers, J.L.d , Schulman, J.a , Nurnberger, J.I., Jre , Porjesz, B.d , Liu, Y.c , Foroud, T.c e , Edenberg, H.J.c f , Marcora, E.a , Agrawal, A.b , Goate, A.a , Collaborative Study on the Genetics of Alcoholism (COGA)g
a Departments of Genetics and Genomic Sciences and Neuroscience, Icahn School of Medicine at Mount Sinai, NY, NY, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
c Department of Medical and Molecular Genetics, Indiana University School of Medicine, IN, Indianapolis, United States
d Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
e Department of Psychiatry, Indiana University School of Medicine, IN, Indianapolis, United States
f Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, IN, Indianapolis, United States
Abstract
Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies. © 2021. The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
“Children’s Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma” (2021) Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Children’s Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma
(2021) Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 39 (24), pp. 2685-2697.
Michalski, J.M.a , Janss, A.J.b , Vezina, L.G.c , Smith, K.S.d , Billups, C.A.e , Burger, P.C.f , Embry, L.M.g , Cullen, P.L.h , Hardy, K.K.i , Pomeroy, S.L.j , Bass, J.K.k , Perkins, S.M.a , Merchant, T.E.l , Colte, P.D.m , Fitzgerald, T.J.n , Booth, T.N.o , Cherlow, J.M.p , Muraszko, K.M.q , Hadley, J.d , Kumar, R.d , Han, Y.e , Tarbell, N.J.r , Fouladi, M.s , Pollack, I.F.t , Packer, R.J.u , Li, Y.e , Gajjar, A.v , Northcott, P.A.d
a Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO
b Department of Pediatrics, Emory University School of Medicine, Atlanta, United States
c Division of Diagnostic Imaging and Radiology, Children’s National Medical Center, DCWA
d Department of Developmental Neurobiology, St Jude Children’s Research Hospital, TN, Memphis, United States
e Department of Biostatistics, St Jude Children’s Research Hospital, TN, Memphis, United States
f Department of Neuropathology, Johns Hopkins University, MD, Baltimore, United States
g Department of Pediatrics, University of Texas Health Science Center at San Antonio, TX, San Antonio, Mexico
h Loretto Heights School of Nursing, Regis University, CO, Denver, United States
i Division of Neuropsychology, Children’s National Medical Center, DCWA
j Department of Neurology, Harvard Medical School, MA, Boston
k Department of Rehabilitation Services, St Jude’s Children’s Research Hospital, TN, Memphis, United States
l Department of Radiation Oncology, St Jude’s Children’s Research Hospital, TN, Memphis, United States
m Division of Hematology/Oncology/BMT, Primary Children’s Hospital, CO, Aurora, United States
n Image and Radiation Oncology Core-Rhode Island, Lincoln, RI
o Department of Radiology, UT Southwestern/Simmons Cancer Center, TX, Dallas, United States
p Department of Radiation Oncology, Miller Children’s and Women’s Hospital Long Beach, Long Beach, CA, Italy
q Department of Neurosurgery, University of Michigan, MI, Ann Arbor, United States
r Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, MA, Boston
s Department of Pediatrics, University of Cincinnati, Cincinnati, OH
t Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, PA, Pittsburgh, United States
u Center for Neuroscience and Behavioral Medicine, Children’s National Medical Center, DCWA
v Department of Oncology, St Jude’s Children’s Research Hospital, TN, Memphis, United States
Abstract
PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Endovascular Thrombectomy Treatment: Beyond Early Time Windows and Small Core” (2021) Topics in Magnetic Resonance Imaging: TMRI
Endovascular Thrombectomy Treatment: Beyond Early Time Windows and Small Core
(2021) Topics in Magnetic Resonance Imaging: TMRI, 30 (4), pp. 173-180.
Lavie, J.a , Vellimana, A.K.b , Chatterjee, A.R.c
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
b Department of Neurological Surgery, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
c Departments of Neurosurgery and Neurology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
Abstract
ABSTRACT: Tremendous advancements in the treatment of acute ischemic stroke in the last 25 years have been based on the principle of reperfusion in early time windows and identification of small core infarct for intravenous thrombolysis and mechanical thrombectomy. Advances in neuroimaging have made possible the safe treatment of patients with acute ischemic stroke in longer time windows and with more specific selection of patients with salvageable brain tissue. In this review, we discuss the history of endovascular stroke thrombectomy trials and highlight the neuroimaging-based trials that validated mechanical thrombectomy techniques in the extended time window with assessment of penumbral tissue. We conclude with a survey of currently open trials that seek to safely expand eligibility for this highly efficacious treatment. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial” (2021) Neurocritical Care
Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial
(2021) Neurocritical Care, .
Hergenroeder, G.W.a b , Yokobori, S.c , Choi, H.A.a b , Schmitt, K.a b , Detry, M.A.d , Schmitt, L.H.a b , McGlothlin, A.d , Puccio, A.M.e , Jagid, J.f , Kuroda, Y.g , Nakamura, Y.h , Suehiro, E.i , Ahmad, F.j , Viele, K.d , Wilde, E.A.k , McCauley, S.R.k , Kitagawa, R.S.a b , Temkin, N.R.l , Timmons, S.D.m , Diringer, M.N.n , Dash, P.K.a o , Bullock, R.f , Okonkwo, D.O.e , Berry, D.A.d , Kim, D.H.a b
a The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 7.156, Houston, TX 77030, United States
b Memorial Hermann Hospital, Texas Medical Center, Houston, TX, United States
c Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, Tokyo, Japan
d Statistical and Software Team, Berry Consultants, Austin, TX, United States
e Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
f Department of Neurological Surgery, Jackson Memorial Hospital, University of Miami, Miami, FL, United States
g Department of Emergency, Disaster, and Critical Care Medicine, Kagawa University Hospital, Kagawa Prefecture, Japan
h Emergency and Critical Care Medicine, Kurume University Hospital, Fukuoka, Japan
i Department of Neurosurgery, Yamaguchi University Hospital, Yamaguchi, Japan
j Department of Neurological Surgery, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, GA, United States
k H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, United States
l Departments of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, United States
m Department of Neurological Surgery, Indiana University Health, Indiana University School of Medicine, Indianapolis, IN, United States
n Departments of Neurology, Neurological Surgery, Anesthesiology, and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
o Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
Abstract
Background: Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p =.35). Plasma levels of glial fibrillary acidic protein (p =.036), but not ubiquitin C-terminal hydrolase L1 (p =.26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups. © 2021, The Author(s).
Author Keywords
Brain injuries (traumatic); Hematoma (subdural); Hypothermia (induced)
Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATSUL1 TR000371, UL1 TR000445, UL1 TR001105
Japan Society for the Promotion of ScienceKAKENJP26293386
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms” (2021) Molecular Genetics and Genomic Medicine
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms
(2021) Molecular Genetics and Genomic Medicine, .
Yabumoto, M.a b , Kianmahd, J.c , Singh, M.a b , Palafox, M.F.a b , Wei, A.b , Elliott, K.b , Goodloe, D.H.d , Dean, S.J.d , Gooch, C.e , Murray, B.K.f , Swartz, E.f , Schrier Vergano, S.A.f , Towne, M.C.g , Nugent, K.h i , Roeder, E.R.h i , Kresge, C.j , Pletcher, B.A.j , Grand, K.k , Graham, J.M., Jr.k , Gates, R.l , Gomez-Ospina, N.l , Ramanathan, S.m , Clark, R.D.m , Glaser, K.n , Benke, P.J.n , Cohen, J.S.o p , Fatemi, A.o p , Mu, W.q , Baranano, K.W.p , Madden, J.A.r s , Gubbels, C.S.r , Yu, T.W.r , Agrawal, P.B.r s t , Chambers, M.-K.u , Phornphutkul, C.u , Pugh, J.A.v , Tauber, K.A.w , Azova, S.x , Smith, J.R.x , O’Donnell-Luria, A.r , Medsker, H.y , Srivastava, S.y , Krakow, D.a z , Schweitzer, D.N.c , Arboleda, V.A.a b
a Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
b Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
c Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
d Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
e Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, United States
g Ambry Genetics Corp, Aliso Viejo, CA, United States
h Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, United States
i Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
j Department of Pediatrics, Division of Clinical Genetics, Rutgers New Jersey Medical School, Newark, NJ, United States
k Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, United States
l Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, United States
m Department of Pediatrics, Division of Medical Genetics, Loma Linda University Children’s Hospital, Loma Linda, CA, United States
n Division of Genetics, Joe DiMaggio Children’s Hospital, Hollywood, FL, United States
o Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
p Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
q Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
r Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
s The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, United States
t Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
u Division of Human Genetics, Warren Alpert Medical School of Brown University, Hasbro Children’s Hospital/Rhode Island Hospital, Providence, RI, United States
v Division of Child Neurology, Department of Neurology, Albany Medical Center, Albany, NY, United States
w Division of Neonatology, Department of Pediatrics, Albany Medical Center, Bernard and Millie Duker Children’s Hospital, Albany, NY, United States
x Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
y Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
z Department of Obstetrics and Gynecology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
Abstract
The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders. © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC
Author Keywords
CRISPR; Genitopatellar syndrome; KAT6B-related disorders; phenotypic spectrum; Say-Barber-Biesecker-Young-Simpson syndrome; variable expressivity, rare genetic diagnosis
Funding details
National Institutes of HealthNIHDP5OD024579
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Contributions of gains and losses to attentional capture and disengagement: evidence from the gap paradigm” (2021) Experimental Brain Research
Contributions of gains and losses to attentional capture and disengagement: evidence from the gap paradigm
(2021) Experimental Brain Research, .
Zhuang, R.a , Tu, Y.a , Wang, X.a , Ren, Y.a , Abrams, R.A.b
a School of Psychology, Shandong Normal University, No. 1 Daxue Road, Changqing District, Jinan, 250358, China
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, United States
Abstract
It is known that movements of visual attention are influenced by features in a scene, such as colors, that are associated with value or with loss. The present study examined the detailed nature of these attentional effects by employing the gap paradigm—a technique that has been used to separately reveal changes in attentional capture and shifting, and changes in attentional disengagement. In four experiments, participants either looked toward or away from stimuli with colors that had been associated either with gains or with losses. We found that participants were faster to look to colors associated with gains and slower to look away from them, revealing effects of gains on both attentional capture and attentional disengagement. On the other hand, participants were both slower to look to features associated with loss, and faster to look away from such features. The pattern of results suggested, however, that the latter finding was not due to more rapid disengagement from loss-associated colors, but instead to more rapid shifting of attention away from such colors. Taken together, the results reveal a complex pattern of effects of gains and losses on the disengagement, capture, and shifting of visual attention, revealing a remarkable flexibility of the attention system. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
Attentional capture; Attentional disengagement; Gains; Gap paradigm; Losses
Funding details
2017190
2018GSF118090
Natural Science Foundation of Shandong ProvinceZR2017MC058
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Development and Validation of a Model to Predict Posttraumatic Stress Disorder and Major Depression after a Motor Vehicle Collision” (2021) JAMA Psychiatry,
Development and Validation of a Model to Predict Posttraumatic Stress Disorder and Major Depression after a Motor Vehicle Collision
(2021) JAMA Psychiatry, .
Ziobrowski, H.N.a , Kennedy, C.J.b , Ustun, B.c , House, S.L.d , Beaudoin, F.L.e , An, X.f , Zeng, D.g , Bollen, K.A.h , Petukhova, M.a , Sampson, N.A.a , Puac-Polanco, V.a i , Lee, S.a , Koenen, K.C.j , Ressler, K.J.k l , McLean, S.A.f m , Kessler, R.C.a , Stevens, J.S.n , Neylan, T.C.o , Clifford, G.D.p q , Jovanovic, T.r , Linnstaedt, S.D.f , Germine, L.T.k s t , Rauch, S.L.k s u , Haran, J.P.v , Storrow, A.B.w , Lewandowski, C.x , Musey, P.I., Jry , Hendry, P.L.z , Sheikh, S.z , Jones, C.W.aa , Punches, B.E.ab ac ad , Lyons, M.S.ab ad , Murty, V.P.ae , McGrath, M.E.af , Pascual, J.L.ag ah , Seamon, M.J.ag , Datner, E.M.ai aj , Chang, A.M.ak , Pearson, C.al , Peak, D.A.am , Jambaulikar, G.an , Merchant, R.C.an , Domeier, R.M.ao , Rathlev, N.K.ap , O’Neil, B.J.al , Sergot, P.aq , Sanchez, L.D.ar as , Bruce, S.E.at , Pietrzak, R.H.au av , Joormann, J.aw , Barch, D.M.ax , Pizzagalli, D.A.k l ay , Sheridan, J.F.az ba , Harte, S.E.bb bc , Elliott, J.M.bd be bf , Van Rooij, S.J.H.n
a Department of Health Care Policy, Harvard Medical School, 180 Longwood Ave, Boston, MA 02115, United States
b Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
c Halicioǧlu Data Science Institute, University of California, San Diego, United States
d Department of Emergency Medicine, Washington University, School of Medicine, St Louis, MO, United States
e Department of Emergency Medicine, Department of Health Services, Policy, and Practice, Alpert Medical School of Brown University, Rhode Island Hospital, Miriam Hospital, Providence, RI, United States
f Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, United States
g Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, United States
h Department of Psychology and Neuroscience, Department of Sociology, University of North Carolina at Chapel Hill, United States
i Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
j Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, United States
k Department of Psychiatry, Harvard Medical School, Boston, MA, United States
l Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
m Department of Emergency Medicine, University of North Carolina at Chapel Hill, United States
n Department of Psychiatry and Behavioral Sciences, Emory University, School of Medicine, Atlanta, GA, United States
o Departments of Psychiatry and Neurology, University of California, San Francisco, United States
p Department of Biomedical Informatics, Emory University, School of Medicine, Atlanta, GA, United States
q Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, United States
r Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
s Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
t Many Brains Project, Belmont, MA, United States
u Department of Psychiatry, McLean Hospital, Belmont, MA, United States
v Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, United States
w Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
x Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
y Department of Emergency Medicine, Indiana University, School of Medicine, Indianapolis, United States
z Department of Emergency Medicine, University of Florida, College of Medicine, Jacksonville, United States
aa Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
ab Department of Emergency Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
ac College of Nursing, University of Cincinnati, Cincinnati, OH, United States
ad Center for Addiction Research, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
ae Department of Psychology, Temple University, Philadelphia, PA, United States
af Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
ag Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
ah Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
ai Department of Emergency Medicine, Einstein Healthcare Network, Philadelphia, PA, United States
aj Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
ak Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
al Department of Emergency Medicine, Wayne State University, Detroit, MI, United States
am Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
an Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ao Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
ap Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, United States
aq McGovern Medical School, University of Texas, Health Science Center, Houston, United States
ar Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
as Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
at Department of Psychological Sciences, University of Missouri, St Louis, United States
au National Center for PTSD, Clinical Neurosciences Division, Veterans Affairs Connecticut Healthcare System, West Haven, United States
av Department of Psychiatry, Yale School of Medicine, West Haven, CT, United States
aw Department of Psychology, Yale University, West Haven, CT, United States
ax Department of Psychological and Brain Sciences, Washington University, St Louis, MO, United States
ay Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, United States
az Department of Biosciences and Neuroscience, Wexner Medical Center, Ohio State University, Columbus, United States
ba Institute for Behavioral Medicine Research, Wexner Medical Center, Ohio State University, Columbus, United States
bb Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, United States
bc Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, United States
bd Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
be Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health DistrictNSW, Australia
bf Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Abstract
Importance: A substantial proportion of the 40 million people in the US who present to emergency departments (EDs) each year after traumatic events develop posttraumatic stress disorder (PTSD) or major depressive episode (MDE). Accurately identifying patients at high risk in the ED would facilitate the targeting of preventive interventions. Objectives: To develop and validate a prediction tool based on ED reports after a motor vehicle collision to predict PTSD or MDE 3 months later. Design, Setting, and Participants: The Advancing Understanding of Recovery After Trauma (AURORA) study is a longitudinal study that examined adverse posttraumatic neuropsychiatric sequalae among patients who presented to 28 US urban EDs in the immediate aftermath of a traumatic experience. Enrollment began on September 25, 2017. The 1003 patients considered in this diagnostic/prognostic report completed 3-month assessments by January 31, 2020. Each patient received a baseline ED assessment along with follow-up self-report surveys 2 weeks, 8 weeks, and 3 months later. An ensemble machine learning method was used to predict 3-month PTSD or MDE from baseline information. Data analysis was performed from November 1, 2020, to May 31, 2021. Main Outcomes and Measures: The PTSD Checklist for DSM-5 was used to assess PTSD and the Patient Reported Outcomes Measurement Information System Depression Short-Form 8b to assess MDE. Results: A total of 1003 patients (median [interquartile range] age, 34.5 [24-43] years; 715 [weighted 67.9%] female; 100 [weighted 10.7%] Hispanic, 537 [weighted 52.7%] non-Hispanic Black, 324 [weighted 32.2%] non-Hispanic White, and 42 [weighted 4.4%] of non-Hispanic other race or ethnicity were included in this study. A total of 274 patients (weighted 26.6%) met criteria for 3-month PTSD or MDE. An ensemble machine learning model restricted to 30 predictors estimated in a training sample (patients from the Northeast or Midwest) had good prediction accuracy (mean [SE] area under the curve [AUC], 0.815 [0.031]) and calibration (mean [SE] integrated calibration index, 0.040 [0.002]; mean [SE] expected calibration error, 0.039 [0.002]) in an independent test sample (patients from the South). Patients in the top 30% of predicted risk accounted for 65% of all 3-month PTSD or MDE, with a mean (SE) positive predictive value of 58.2% (6.4%) among these patients at high risk. The model had good consistency across regions of the country in terms of both AUC (mean [SE], 0.789 [0.025] using the Northeast as the test sample and 0.809 [0.023] using the Midwest as the test sample) and calibration (mean [SE] integrated calibration index, 0.048 [0.003] using the Northeast as the test sample and 0.024 [0.001] using the Midwest as the test sample; mean [SE] expected calibration error, 0.034 [0.003] using the Northeast as the test sample and 0.025 [0.001] using the Midwest as the test sample). The most important predictors in terms of Shapley Additive Explanations values were symptoms of anxiety sensitivity and depressive disposition, psychological distress in the 30 days before motor vehicle collision, and peritraumatic psychosomatic symptoms. Conclusions and Relevance: The results of this study suggest that a short set of questions feasible to administer in an ED can predict 3-month PTSD or MDE with good AUC, calibration, and geographic consistency. Patients at high risk can be identified in the ED for targeting if cost-effective preventive interventions are developed. © 2021 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Comprehensive medical evaluation of pediatric bilateral sensorineural hearing loss” (2021) Laryngoscope Investigative Otolaryngology
Comprehensive medical evaluation of pediatric bilateral sensorineural hearing loss
(2021) Laryngoscope Investigative Otolaryngology, .
Kılıç, S.a , Bouzaher, M.H.a , Cohen, M.S.b , Lieu, J.E.C.c , Kenna, M.d , Anne, S.a
a Head and Neck Institute, Cleveland Clinic, Cleveland, OH, United States
b Department of Otolaryngology, Head and Neck Surgery, Harvard Medical School, Boston, MA, United States
c Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis, St. Louis, MO, United States
d Department of Otolaryngology and Communication Enhancement, Boston Children’s Hospital, Boston, MA, United States
Abstract
Children with bilateral sensorineural hearing loss (SNHL) should undergo a comprehensive medical evaluation to determine the underlying etiology and help guide treatment and counseling. In this article, we review the indications and rationale for medical evaluation of pediatric bilateral SNHL, including history and physical examination, imaging, genetic testing, specialist referrals, cytomegalovirus (CMV) testing, and other laboratory tests. Workup begins with a history and physical examination, which can provide clues to the etiology of SNHL, particularly with syndromic causes. If SNHL is diagnosed within the first 3 weeks of life, CMV testing should be performed to identify patients that may benefit from antiviral treatment. If SNHL is diagnosed after 3 weeks, testing can be done using dried blood spots samples, if testing capability is available. Genetic testing is oftentimes successful in identifying causes of hearing loss as a result of recent technological advances in testing and an ever-increasing number of identified genes and genetic mutations. Therefore, where available, genetic testing should be performed, ideally with next generation sequencing techniques. Ophthalmological evaluation must be done on all children with SNHL. Imaging (high-resolution computed tomography and/or magnetic resonance imaging) should be performed to assess for anatomic causes of hearing loss and to determine candidacy for cochlear implantation when indicated. Laboratory testing is indicated for certain etiologies, but should not be ordered indiscriminately since the yield overall is low. © 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.
Author Keywords
bilateral sensorineural hearing loss; EKG; genetic testing; imaging; medical evaluation; medical workup; pediatric sensorineural hearing loss; SNHL
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Pharmacophore-Based Design of Phenyl-(hydroxycyclohexyl) Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity” (2021) Journal of Medicinal Chemistry
Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity
(2021) Journal of Medicinal Chemistry, .
Dang, X.a b , Williams, S.B.c , Devanathan, S.c , Franco, A.b , Fu, L.d , Bernstein, P.R.e , Walters, D.f , Dorn, G.W.b c
a Department of Cardiology, The First Affiliated Hospital of xi’An Jiao Tong University, Shaanxi, Xi’an, 710061, China
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Mitochondria in Motion, Inc., 4340 Duncan Avenue, Suite 216, St. Louis, MO 63110, United States
d WuXi AppTec Co., Ltd., 666 Gaoxin Road, East Lake High-tech Development Zone, Hubei, Wuhan, 430075, China
e PharmaB LLC, 50 S. 16th Street, Unit 5201, Philadelphia, PA 19102, United States
f Crystal Pharmatech Inc., 3000 Eastpark Blvd., Ste 500B, Cranbury, NJ 08512, United States
Abstract
Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro, promising a novel therapeutic approach. The first-in-class mitofusin activator, 2, has a short plasma t1/2 and limited neurological system bioavailability, conferring “burst activation”. Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5, improved plasma and brain t1/2, increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a “heavy atom”, 14A and 14B, showed that 5 biological activity resides in the trans-R/R configuration, 5B. Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation. © 2021 American Chemical Society.
Funding details
National Institutes of HealthNIH628906, R35135736, R41NS113642, R41NS115184
Muscular Dystrophy AssociationMDA
China Scholarship CouncilCSC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus