An fMRI protocol for administering liquid incentives to human participants
(2022) STAR Protocols, 3 (4), art. no. 101707, .
Yee, D.M.a b , Crawford, J.L.b , Braver, T.S.b
a Cognitive Linguistics, and Psychological Sciences, Brown University, Providence, RI 02912, United States
b Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
This protocol describes the materials and approaches for administering liquid incentives to human participants during fMRI scanning. We first describe preparation of the liquid solutions (e.g., neutral solution and saltwater) and liquid delivery setups. We then detail steps to connect the setups to the computer-controlled syringe pump in the MRI control room, followed by procedures for testing the syringe pump dispensing a liquid bolus during the task. Description of custom software and required adapters for implementing the liquid setup are included. For complete details on the use and execution of this protocol, please refer to Yee et al. (2021). © 2022
Author Keywords
Behavior; Clinical protocol; Cognitive neuroscience; Neuroscience
Funding details
National Institutes of HealthNIHR21-AG058206, R21-AG067295, R24-AG054355
McDonnell Center for Systems NeuroscienceF31-DA042574, T32-AG000030, T32-MH126388, T32-NS073547, T32-NS115672
Document Type: Article
Publication Stage: Final
Source: Scopus
An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
(2022) Nature Communications, 13 (1), art. no. 6784, .
Zhang, G.a , Xu, X.b c d e , Jia, Z.f g , Geng, Y.h , Liang, H.a , Shi, J.a , Marras, M.a , Abella, C.a , Magleby, K.L.h , Silva, J.R.a , Chen, J.f g , Zou, X.b c d e , Cui, J.a
a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, United States
b Dalton Cardiovascular Research Center, University of Missouri – Columbia, Columbia, MO, United States
c Department of Physics and Astronomy, University of Missouri – Columbia, Columbia, MO, United States
d Department of Biochemistry, University of Missouri – Columbia, Columbia, MO, United States
e Institute for Data Science and Informatics, University of Missouri – Columbia, Columbia, MO, United States
f Department of Chemistry, University of Massachusetts, Amherst, MA, United States
g Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, United States
h Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, United States
Abstract
BK type Ca2+-activated K+ channels activate in response to both voltage and Ca2+. The membrane-spanning voltage sensor domain (VSD) activation and Ca2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca2+ binding to pore opening are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca2+ dependent activation mechanism. BC5 activates the channel in the absence of Ca2+ binding but Ca2+ binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca2+ binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation. © 2022, The Author(s).
Funding details
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Tuning landscapes of the ventral stream
(2022) Cell Reports, 41 (6), art. no. 111595, .
Wang, B.a b , Ponce, C.R.b
a Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurobiology, Harvard Medical School, Boston, MA, United States
Abstract
A goal in visual neuroscience is to explain how neurons respond to natural scenes. However, neurons are generally tested using simpler stimuli, often because they can be transformed smoothly, allowing the measurement of tuning functions (i.e., response peaks and slopes). Here, we test the idea that all classic tuning curves can be viewed as slices of a higher-dimensional tuning landscape. We use activation-maximizing stimuli (“prototypes”) as landmarks in a generative image space and map tuning functions around these peaks. We find that neurons show smooth bell-shaped tuning consistent with radial basis functions, spanning a vast image transformation range, with systematic differences in landscape geometry from V1 to inferotemporal cortex. By modeling these trends, we infer that neurons in the higher visual cortex have higher intrinsic feature dimensionality. Overall, these results suggest that visual neurons are better viewed as signaling distances to prototypes on an image manifold. © 2022 The Author(s)
Author Keywords
CP: Neuroscience; generative image model; geometry; inferotemporal cortex; intrinsic dimensionality; natural image manifold; neural tuning; neuron-guided image synthesis; radial basis function; tuning; V1; V4; vision; visual cortex; visual hierarchy
Funding details
David and Lucile Packard FoundationDLPF2020-71377
E. Matilda Ziegler Foundation for the Blind
Document Type: Article
Publication Stage: Final
Source: Scopus
Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience
(2022) Diabetes Care, 45 (11), pp. 2653-2661.
White, N.H.a , Pan, Q.b , Knowler, W.C.c , Schroeder, E.B.d , Dabelea, D.e , Chew, E.Y.f , Blodi, B.g , Goldberg, R.B.h , Pi-Sunyer, X.i , Darwin, C.j , Schlogl, M.k , Nathan, D.M.l
a Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b The Biostatistics Center, Milken Institute School of Public Health, George Washington University, Rockville, MD, United States
c National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States
d Parkview Health, Fort Wayne, IN, United States
e Colorado School of Public Health, Anschutz Medical Campus, Aurora, CO, United States
f Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, United States
g Wisconsin Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
h Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
i Columbia University Irving Medical Center, New York, NY, United States
j Department of Medicine/Endocrinology Diabetes, , , David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
k University Clinic for Acute Geriatric Care, City Hospital Waid Zurich, Zurich, Switzerland
l Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
Abstract
OBJECTIVE To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS By DPPOS year 16 (20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hyper-tension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20–0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46–1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D. © 2022 by the American Diabetes Association.
Funding details
National Institutes of HealthNIHU01 DK048339, U01 DK048349, U01 DK048375, U01 DK048377, U01 DK048380, U01 DK048381, U01 DK048387, U01 DK048397, U01 DK048400, U01 DK048404, U01 DK048406, U01 DK048407, U01 DK048411, U01 DK048412, U01 DK048413, U01 DK048434, U01 DK048437, U01 DK048443, U01 DK048468, U01 DK048485, U01 DK048489, U01 DK048514
Centers for Disease Control and PreventionCDC
American Diabetes AssociationADA
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBI
National Eye InstituteNEI
National Cancer InstituteNCI
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Institute of Child Health and Human DevelopmentNICHD
National Center for Research ResourcesNCRR
Office of Research on Women’s HealthORWH
U.S. Department of Veterans AffairsVA
Indian Health ServiceIHS
National Institute on Minority Health and Health DisparitiesNIMHD
Document Type: Article
Publication Stage: Final
Source: Scopus
Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm
(2022) Neurosurgical Focus, 53 (5), art. no. E8, .
Li, Y.D.a , Coxon, A.T.a , Huang, J.b d , Abraham, C.D.b d , Dowling, J.L.a b d , Leuthardt, E.C.a b d , Dunn, G.P.c , Kim, A.H.a b d , Dacey, R.G.a b d , Zipfel, G.J.a b d , Evans, J.a , Filiput, E.A.a b , Chicoine, M.R.a b d e
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, United States
b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Harvard Medical School, Boston, MA, United States
d The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, United States
e Department of Neurosurgery, University of Missouri, Columbia, MO, United States
Abstract
OBJECTIVE For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor “seeding” away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32–84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS. © AANS 2022, except where prohibited by US copyright law
Author Keywords
Brain metastasis; Neoadjuvant stereotactic radiosurgery; Preoperative; Resection
Funding details
National Cancer InstituteNCIP30 CA091842
National Institute of Neurological Disorders and StrokeNINDS
Alvin J. Siteman Cancer Center
Head for the Cure FoundationHFTC
Document Type: Article
Publication Stage: Final
Source: Scopus
Reconstructing neural circuits using multiresolution correlated light and electron microscopy
(2022) Frontiers in Neural Circuits, 16, art. no. 753496, .
Friedrichsen, K.a b c , Ramakrishna, P.a b c , Hsiang, J.-C.a b c , Valkova, K.a b c , Kerschensteiner, D.a b c , Morgan, J.L.a b c
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. LouisMO, United States
b Department of Neuroscience, Washington University in St. Louis, St. LouisMO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. LouisMO, United States
Abstract
Correlated light and electron microscopy (CLEM) can be used to combine functional and molecular characterizations of neurons with detailed anatomical maps of their synaptic organization. Here we describe a multiresolution approach to CLEM (mrCLEM) that efficiently targets electron microscopy (EM) imaging to optically characterized cells while maintaining optimal tissue preparation for high-throughput EM reconstruction. This approach hinges on the ease with which arrays of sections collected on a solid substrate can be repeatedly imaged at different scales using scanning electron microscopy. We match this multiresolution EM imaging with multiresolution confocal mapping of the aldehyde-fixed tissue. Features visible in lower resolution EM correspond well to features visible in densely labeled optical maps of fixed tissue. Iterative feature matching, starting with gross anatomical correspondences and ending with subcellular structure, can then be used to target high-resolution EM image acquisition and annotation to cells of interest. To demonstrate this technique and range of images used to link live optical imaging to EM reconstructions, we provide a walkthrough of a mouse retinal light to EM experiment as well as some examples from mouse brain slices. Copyright © 2022 Friedrichsen, Ramakrishna, Hsiang, Valkova, Kerschensteiner and Morgan.
Author Keywords
confocal 3D microscopy; connectomics; correlated light and electron microscopy (CLEM); electron microscopy; neural circuit; synapse; tissue mapping
Funding details
National Institutes of HealthNIHEY023341, EY026978, EY027411, EY029313, EYE030623
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
Amphiphilic stilbene derivatives attenuate the neurotoxicity of soluble Aβ42 oligomers by controlling their interactions with cell membranes
(2022) Chemical Science, 297 (5580), .
Yu, Z.a , Guo, W.b , Patel, S.a , Cho, H.-J.a , Sun, L.a , Mirica, L.M.a c
a Department of Chemistry, Beckman Institute for Advanced Science and Technology, The Neuroscience Program, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
b Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer’s disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit selective binding toward Aβ oligomers. These amphiphilic compounds can also label the Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu2+-Aβ induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target Aβ oligomers and modulate the Aβ oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics. © 2022 The Royal Society of Chemistry.
Funding details
National Institutes of HealthNIHR01GM114588
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluation of noise regression techniques in resting-state fMRI studies using data of 434 older adults
(2022) Frontiers in Neuroscience, 16, art. no. 1006056, .
Scheel, N.a , Keller, J.N.b , Binder, E.F.c , Vidoni, E.D.d , Burns, J.M.d , Thomas, B.P.e , Stowe, A.M.f , Hynan, L.S.e , Kerwin, D.R.g , Vongpatanasin, W.e , Rossetti, H.e , Cullum, C.M.e , Zhang, R.e g , Zhu, D.C.a
a Department of Radiology, Michigan State University, East Lansing, MI, United States
b Pennington Biomedical Research Center, Baton RougeLA, United States
c Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, United States
d Alzheimer’s Disease Center, University of Kansas, Fairway, KS, United States
e UT Southwestern Medical Center, Dallas, TX, United States
f Department of Neurology, University of Kentucky, Lexington, KY, United States
g Texas Health Presbyterian Hospital, Dallas, TX, United States
Abstract
Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the “Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts” (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer’s Disease (rrAD) trial included hypertensive older adults (60–84 years old) at elevated risk of developing Alzheimer’s Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults. Copyright © 2022 Scheel, Keller, Binder, Vidoni, Burns, Thomas, Stowe, Hynan, Kerwin, Vongpatanasin, Rossetti, Cullum, Zhang and Zhu.
Author Keywords
aging; multi-site studies; noise regression; preprocessing; resting-state fMRI
Funding details
National Institutes of HealthNIHR01AG049749, R56AG074613
Document Type: Article
Publication Stage: Final
Source: Scopus
Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease
(2022) Annals of Clinical and Translational Neurology, .
Tarawneh, R.a b , Kasper, R.S.a , Sanford, J.c d , Phuah, C.-L.d e , Hassenstab, J.f , Cruchaga, C.c d
a Department of Neurology, University of New Mexico, Albuquerque, NM, United States
b Center for Memory and Aging, University of New Mexico, Albuquerque, NM, United States
c Department of Psychiatry, Washington University in St Louis, St. Louis, MO, United States
d NeuroGenomics and Informatics Center, Washington University in St LouisMO, United States
e Department of Neurology, Washington University in St Louis, St. Louis, MO, United States
f Department of Psychology, Washington University in St Louis, St. Louis, MO, United States
Abstract
Objective: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Methods: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer’s Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. Results: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Interpretation: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
P30NS048056
National Institutes of HealthNIHP20AG068077, R21AG067755‐01A1
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSK23 NS110927, P01AG03991, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922
Foundation for Barnes-Jewish HospitalFBJH3962
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZIP01AG026276, P30AG066444, P50AG05681
Centene CorporationP19‐00559
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neurologic injury after spinopelvic dissociation: Incidence, outcome, and predictors
(2022) Injury, .
Morris, C.A.a , Moo Young, J.P.a , Savakus, J.C.a , Obey, M.R.b , Pereira, D.E.b , Hills, J.M.a , McKane, A.c , Babcock, S.N.c , Miller, A.N.b , Stephens, B.F.a , Mitchell, P.M.a
a Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
c Department of Orthopaedic Surgery and Rehabilitation, Wake Forest University School of Medicine, Winston-Salem, NC, United States
Abstract
Background: Traumatic spinopelvic dissociation is a rare injury pattern resulting in discontinuity between the spine and bony pelvis. This injury is associated with a known risk of neurologic compromise which can impact the clinical outcome of these patients. We sought to determine incidence and characteristics of neurologic injury, outcomes following treatment, and predictive factors for neurologic recovery. Methods: We reviewed the clinical documentation and imaging of 270 patients with spinopelvic dissociation from three Level-1 trauma centers treated over a 20-year period. From this cohort, 137 patients fulfilled inclusion criteria with appropriate follow-up. Details surrounding patient presentation, incidence of neurologic injury, and outcome variables were collected for each injury. Neurologic injuries were categorized using the Gibbons criteria. Multivariate analysis was performed to assess for patient and injury factors predictive of neurologic injury and recovery. Results: The overall incidence of neurologic injury in spinopelvic dissociation injuries was 33% (45/137), with bowel and/or bladder dysfunction (n=16) being the most common presentation. Complete neurologic recovery was seen in 26 cases (58%) and two patients (4%) improved at least one Gibbon stage in clinical follow-up. The most common long-term neurologic sequela at final follow-up was radiculopathy (n=12, 9%). Increased kyphosis was found to be associated with neurologic injury (p=0.002), while location of transverse limb and Roy-Camille type were not predictive of neurologic injury (p=0.31 and p=0.07, respectively). There were no factors found to be predictive of neurologic recovery in this cohort. Conclusion: Neurologic injury is commonly seen in patients with spinopelvic dissociation and complete neurologic recovery was seen in the majority of patients at final follow-up. When present, long term neurologic dysfunction is most commonly characterized by radiculopathy. While increasing kyphosis was shown to be associated with neurologic injury, no patient or injury factors were predictive of neurologic recovery. © 2022
Author Keywords
Neurologic injury; Pelvic trauma; Sacral fracture; Spinopelvic dissociation; U-shaped sacral fracture
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Radiotherapy for elderly patients with glioblastoma: an assessment of hypofractionation and modern treatment techniques
(2022) Chinese Clinical Oncology, 11 (5), p. 38.
Matsui, J.K.a , Perlow, H.K.b , Facer, B.D.b , McCalla, A.c , Marrazzo, L.d , Detti, B.e , Scorsetti, M.f , Clerici, E.f , Scoccianti, S.e , Navarria, P.f , Trifiletti, D.M.g , Gondi, V.h , Bovi, J.i , Huang, J.j , Brown, P.D.k , Palmer, J.D.b
a Ohio State University College of Medicine, Columbus, OH, United States
b Department of Radiation Oncology, Ohio State University Wexner Medical Center, Columbus, OH, United States
c Central Michigan University, College of Medicine, Mt. PleasantMI, United States
d Department of Medical Physics, Azienda Ospedaliera Universitaria, Florence, Italy
e Department of Radiation Oncology, Azienda Ospedaliera Universitaria, Florence, Italy
f Radiotherapy and Radiosurgery Department, IRCCS Humanitas Research Hospital, Milan, Italy
g Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, United States
h Department of Radiation Oncology, Northwestern Medicine Cancer Center and Proton Center, Warrenville, IL, United States
i Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
j Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
k Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States
Abstract
Glioblastoma (GBM) is a disease with a poor prognosis. For decades, radiotherapy has played a critical role in the management of GBM. The standard of care radiation prescription is 60 Gy in 30 fractions, but landmark trials have historically excluded patients older than 70 years. Currently, there is considerable variation in the management of elderly patients with GBM. Shortened radiation treatment (hypofractionated) regimens have been explored since conventional treatment schedules are lengthy and many elderly patients have functional, cognitive, and social limitations. Clinical trials have demonstrated the effectiveness of hypofractionated radiotherapy (40 Gy in 15 fractions) to treat elderly or frail patients with GBM. Although previous studies have suggested these unique hypofractionation prescriptions effectively treat these patients, there are many avenues for improvement in this patient population. Herein, we describe the unique tumor biology of glioblastoma, key hypofractionated radiotherapy studies, and health-related quality of life (HRQOL) studies for elderly patients with GBM. Hypofractionated radiation has emerged as a shortened alternative and retrospective studies have suggested survival outcomes are similar for elderly patients with GBM. Prospective studies comparing hypofractionation with conventional treatment regiments are warranted. In addition to evaluating survival outcomes, HRQOL endpoints should be incorporated into future studies.
Author Keywords
Elderly; glioblastoma; hypofractionation; radiation
Document Type: Article
Publication Stage: Final
Source: Scopus
APOE ɛ4 allele and TOMM40-APOC1 variants jointly contribute to survival to older ages
(2022) Aging Cell, .
Kulminski, A.M.a , Jain-Washburn, E.a , Philipp, I.a , He, L.a , Loika, Y.a , Loiko, E.a , Bagley, O.a , Ukraintseva, S.a , Yashin, A.a , Arbeev, K.a , Stallard, E.a , Feitosa, M.F.b , Schupf, N.c , Christensen, K.d , Culminskaya, I.a
a Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, United States
b Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
c Gertrude H. Sergievsky Center, Columbia University Irving Medical Center, New York, NY, United States
d Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, Southern Denmark University, Odense, Denmark
Abstract
Age-related diseases characteristic of post-reproductive life, aging, and life span are the examples of polygenic non-Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer’s disease (AD), compared with non-carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non-carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid- and immunity-related mechanisms, whereas the AD risk, can be driven by the AD-biomarker-related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care. © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Author Keywords
aging; Alzheimer’s disease; apolipoprotein E polymorphism; haplotypes; linkage disequilibrium
Funding details
National Institute on AgingNIAR01AG061853, R01AG065477, R01AG070488, U01AG023712, U01AG023744, U01AG023746, U01AG023749, U01AG023755, U19AG063893
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Cognitive Assessment in Elderly Cochlear Implant Recipients: Long-Term Analysis
(2022) Laryngoscope, .
Herzog, J.A., Buchman, C.A., Kallogjeri, D., Chen, S., Wick, C., Durakovic, N., Shew, M.A.
Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Objectives: To examine long-term speech and cognition outcomes in older adult cochlear implant (CI) recipients. First, by evaluating if CI performance was maintained over an extended follow-up period regardless of preoperative cognitive status. Secondly, by evaluating if there was a difference in the rate of cognitive decline between preoperative mild and normal cognition following CI over an extended period of time. Study Design and Setting: Retrospective cohort study. Methods: CI recipients ≥65 years of age implanted between 2009 and 2014 with 4+ years follow up. Pre- and postoperative audiometric and speech outcome assessments were collected. Cognitive status was measured using the mini mental status examination (MMSE) at numerous time points. Results: Fifty-three patients met inclusion. Patients were divided into two groups based on preoperative MMSE with scores considered normal (28–30) and those with mildly impaired cognition (MIC, scores 25–27). Audiometric and speech performance improved significantly at one-year post implantation and this was maintained without significant change at 4+ years, regardless of cognitive status. Mixed modeling analysis controlling for age demonstrated no significant difference in the rate of cognitive decline at 4+ years post implantation between the normal cognition cohort (1.74; 95%CI 0.89–2.6) and MIC (2.9; 95%1.91–3.88). Conclusion: Speech performance was significantly improved and sustained after CI in both normal cognition and MIC patients. The rate of cognitive decline in older adult CI patients appears to be similar regardless of preoperative cognitive status. Although results demonstrate rates of cognitive decline following CI did not differ between cognition groups over 4+ years, future studies will need to further investigate this over extended time periods with a more comprehensive cognitive testing battery. Level of Evidence: Level 4 Laryngoscope, 2022. © 2022 The American Laryngological, Rhinological and Otological Society, Inc.
Author Keywords
Cochlear implant; cognition; elderly; hearing loss; mini mental status examination
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations between social COVID-19 exposure and psychological functioning
(2022) Journal of Behavioral Medicine, .
Lewicka, M.a , Hamilton, J.G.a , Waters, E.A.b , Orom, H.c , Schofield, E.a , Kiviniemi, M.T.d , Kanetsky, P.A.e , Hay, J.L.a
a Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave, New York, NY 10022, United States
b Division of Public Health Sciences, Washington University in St. Louis, 4590 Children’s Place, Suite 9600, St. Louis, MO 63110, United States
c Department of Community Health and Health Behavior, University at Buffalo, 304 Kimball, Buffalo, NY 14214, United States
d Department of Health, Behavior and Society, University of Kentucky, 1000 S. Limestone, Lexington, KY 40536, United States
e Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, United States
Abstract
The negative consequences of the COVID-19 pandemic on mental health have been widely reported, but less is known about how the impact of COVID-19 on others in one’s social circle shapes these high distress levels. This study examines associations between social COVID-19 exposure—knowing someone who had a COVID-19 infection—and psychological functioning, as well as whether socio-demographic factors moderate these relationships. In June 2020, respondents (N = 343) from clinics in Tampa, Florida, U.S.A. reported whether they had social COVID-19 exposure, anxiety, depression, and stress, and other COVID-19-related concerns. Social COVID-19 exposure was associated with increased anxiety, stress, and concerns about a family member getting sick, and concerns about drinking and substance use. Several associations between exposure and psychological functioning were stronger in women, younger people, and people with lower income, implying these groups face elevated psychological risks due to the pandemic, and should be prioritized in mental health recovery efforts. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
COVID-19; COVID-19 concerns; Exploratory factor analysis (EFA); Moderation analyses; Psychological functioning; Social factors
Funding details
P30-CA076292
U54 CA163068
American Cancer SocietyACSRSG-14-162-01-CPHPS
National Cancer InstituteNCIP30 CA008748
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Optimistic children engage in more constructive risk-taking behaviors
(2022) International Journal of Behavioral Development, .
Lu, M.S., Hennefield, L., Tillman, R., Markson, L.
Washington University in St. Louis, United States
Abstract
Optimism is linked to persistence and resilience in adults; however, how optimism might relate to children’s evaluations of potentially challenging situations and risk-taking behaviors is unknown. This study examined the role of optimism in 4- to 8-year-old children’s (N = 121) perceptions of and willingness to engage in physical activities that ranged from low to high risk. Overall, children perceived activities with more risky elements as more dangerous and were less willing to try them, with this pattern strongest in older children. Moreover, children higher in optimism were (1) more willing to engage in moderate-risk activities relative to children lower in optimism, but (2) less willing to engage in the highest-risk activities—even though they perceived those highest-risk activities as less dangerous than children lower in optimism. These findings support the possibility that optimism motivates children to engage in beneficial moderately challenging activities and protects them from engaging in severe injury-inflicting activities. © The Author(s) 2022.
Author Keywords
children; motivation; Optimism; resilience; risk factors; risk-taking
Funding details
National Institute of Mental HealthNIMH32 MH100019
University of WashingtonUW
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD21 HD095490, 32 HD093273
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Ownership psychology as a cognitive adaptation: A minimalist model
(2022) Behavioral and Brain Sciences, .
Boyer, P.a b
a Department of Anthropology and Psychology & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Washington University in St. Louis One, CB 1125, Brookings Drive, St. Louis, MO 63130, United States
Abstract
Short Abstract Ownership is universal and ubiquitous in human societies, yet the underlying psychology is still poorly understood. The proposed model derives intuitions about ownership from the interaction of two evolved cognitive systems. One of these handles competitive interactions for the possession of resources. The other handles the level of expected mutually beneficial cooperation between agents. Together, these systems account for the variety and flexibility of people’s intuitions in the domain. This computational model explains not just standard cases of property but also the ease with which people apply ownership to novel domains. Long Abstract Ownership is universal and ubiquitous in human societies, yet the psychology underpinning ownership intuitions is generally not described in a coherent and computationally tractable manner. Ownership intuitions are commonly assumed to derive from culturally transmitted social norms, or from a mentally represented implicit theory. While the social norms account is entirely ad hoc, the mental theory requires prior assumptions about possession and ownership that must be explained. Here I propose such an explanation, arguing that the intuitions result from the interaction of two cognitive systems. One of these handles competitive interactions for the possession of resources observed in many species including humans. The other handles mutually beneficial cooperation between agents, as observed in communal sharing, collective action and trade. Together, these systems attend to specific cues in the environment, and produce definite intuitions such as “this is hers”, “that is not mine”. This computational model provides an explanation for ownership intuitions, not just in straightforward cases of property, but also in disputed ownership (squatters, indigenous rights), historical changes (abolition of slavery), as well as apparently marginal cases, such as the questions, whether people own their seats on the bus, or their places in a queue, and how people understand “cultural appropriation” and slavery. In contrast to some previous theories, the model is empirically testable and free of ad hoc stipulations. © 2022 Cambridge University Press. All rights reserved.
Author Keywords
Cooperation; Evolutionary Psychology; Hawk-Dove; Ownership; Property; Social norms
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
White matter alterations associated with lifetime and current depression in adolescents: Evidence for cingulum disruptions
(2022) Depression and Anxiety, .
Barch, D.M.a b c , Hua, X.d , Kandala, S.b , Harms, M.P.b , Sanders, A.b , Brady, R.b , Tillman, R.b , Luby, J.L.b
a Departments of Psychological & Brain Sciences, Psychiatry, and Radiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychological & Brain Sciences, Imaging Sciences Program, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Introduction: Compared to research on adults with depression, relatively little work has examined white matter microstructure differences in depression arising earlier in life. Here we tested hypotheses about disruptions to white matter structure in adolescents with current and past depression, with an a priori focus on the cingulum bundles, uncinate fasciculi, corpus collosum, and superior longitudinal fasciculus.Methods: One hundred thirty-one children from the Preschool Depression Study were assessed using a Human Connectome Project style diffusion imaging sequence which was processed with HCP pipelines and TRACULA to generate estimates of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD).Results: We found that reduced FA, reduced AD, and increased RD in the dorsal cingulum bundle were associated with a lifetime diagnosis of major depression and greater cumulative and current depression severity. Reduced FA, reduced AD, and increased RD in the ventral cingulum were associated with greater cumulative depression severity.Conclusion: These findings support the emergence of white matter differences detected in adolescence associated with earlier life and concurrent depression. They also highlight the importance of connections of the cingulate to other brain regions in association with depression, potentially relevant to understanding emotion dysregulation and functional connectivity differences in depression. © 2022 Wiley Periodicals LLC.
Author Keywords
adolescence; brain development; cingulum; depression; white matter
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord
(2022) Clinical Genetics, .
Wongkittichote, P.a , Choi, T.-I.b c , Kim, O.-H.b c , Riley, K.d , Koeberl, D.d e , Narayanan, V.f , Ramsey, K.f , Balak, C.f , Schwartz, C.E.g , Cueto-Gonzalez, A.M.h i , Casadesus, F.M.j , Kim, C.-H.b , Shinawi, M.S.a
a Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biology, Chungnam National University, Daejeon, South Korea
c Zebrafish Center for Disease Modeling, Daejeon, South Korea
d Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, NC, United States
e Department of Molecular Genetics and Microbiology, Duke UniversityNC, United States
f Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, United States
g Greenwood Genetic Center, Greenwood, SC, United States
h Department of Clinical and Molecular Genetics, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
i Medicine Genetics Group, Vall Hebron Research Institute (VHIR), Autonomous University of Barcelona, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
j Department of Pediatric Neurology, Hospital Vall d’Hebron, Barcelona, Spain
Abstract
ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants. © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Author Keywords
arthrogryposis; tethered cord; Wieacker-Wolff syndrome; X-linked disorder; ZC4H2; ZC4H2-related disorder; zebrafish model
Funding details
Ministry of Science, ICT and Future PlanningMSIP2018M3A9B8021980
National Research Foundation of KoreaNRF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Derivation and Validation of a Brief Emergency Department-Based Prediction Tool for Posttraumatic Stress After Motor Vehicle Collision
(2022) Annals of Emergency Medicine, .
Jones, C.W.a , An, X.b , Ji, Y.c , Liu, M.c , Zeng, D.c , House, S.L.d , Beaudoin, F.L.e , Stevens, J.S.f , Neylan, T.C.g , Clifford, G.D.h , Jovanovic, T.i , Linnstaedt, S.D.b , Germine, L.T.j k l , Bollen, K.A.m , Rauch, S.L.j l n , Haran, J.P.o , Storrow, A.B.p , Lewandowski, C.q , Musey, P.I., Jr.r , Hendry, P.L.r , Sheikh, S.s t , Punches, B.E.s , Lyons, M.S.u , Kurz, M.C.v , Swor, R.A.w , McGrath, M.E.x , Hudak, L.A.y z , Pascual, J.L.z aa , Seamon, M.J.ab , Datner, E.M.ac , Harris, E.ad , Chang, A.M.ae , Pearson, C.af , Peak, D.A.ag , Merchant, R.C.ah , Domeier, R.M.ai , Rathlev, N.K.aj , O’Neil, B.J.ak , Sergot, P.al , Sanchez, L.D.ag am , Bruce, S.E.an , Miller, M.W.ao ap , Pietrzak, R.H.aq , Joormann, J.ar , Barch, D.M.as , Pizzagalli, D.A.l at , Sheridan, J.F.au , Smoller, J.W.av , Harte, S.E.aw , Elliott, J.M.ax , Koenen, K.C.ay , Ressler, K.J.l as , Kessler, R.C.az , McLean, S.A.ba
a Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
b Department of Anesthesiology, Department of Psychiatry, Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c Department of Biostatistics, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, United States
d Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
e Department of Emergency Medicine and Department of Health Services, Policy, and Practice, The Alpert Medical School of Brown University, Rhode Island Hospital and The Miriam Hospital, Providence, RI, United States
f Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
g Department of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
h Department of Biomedical Informatics, Emory University School of Medicine and Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
i Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
j Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
k The Many Brains Project, Belmont, MA, United States
l Department of Psychiatry, Harvard Medical School, Boston, MA, United States
m Department of Psychology and Neuroscience and Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
n Department of Psychiatry, McLean Hospital, Belmont, MA, United States
o Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, United States
p Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
q Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
r Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
s Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, United States
t Department of Emergency Medicine, University of Cincinnati College of Medicine, and College of Nursing, University of Cincinnati, Cincinnati, OH, United States
u College of Nursing, University of Cincinnati, Cincinnati, OH, United States
v Department of Emergency Medicine, Division of Acute Care Surgery, Department of Surgery, University of Alabama School of Medicine, and Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States
w Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
x Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
y Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
z Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Pennsylvania, PA, United States
aa Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, United States
ab Division of Traumatology, Department of Surgery, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Pennsylvania, PA, United States
ac Department of Emergency Medicine, Einstein Healthcare Network, and the Sidney Kimmel Medical College, Thomas Jefferson University, Pennsylvania, PA, United States
ad Einstein Medical Center, Philadelphia, PA, United States
ae Department of Emergency Medicine, Jefferson University Hospitals, Pennsylvania, PA, United States
af Department of Emergency Medicine, Wayne State University, Ascension St John Hospital, Detroit, MI, United States
ag Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
ah Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ai Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
aj Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
ak Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
al Department of Emergency Medicine, McGovern Medical School, University of Texas Health, Houston, TX, United States
am Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
an Department of Psychological Sciences, University of Missouri – St Louis, St Louis, MO, United States
ao National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, and Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
ap Clinical Neurosciences Division, National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, United States
aq Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
ar Department of Psychology, Yale School of Medicine, New Haven, CT, United States
as Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
at Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
au Department of Biosciences, and the Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, United States
av Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
aw Department of Anesthesiology, Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
ax Kolling Institute of Medical Research, University of Sydney, St Leonards, and Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, New South Wales, Australia, and Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
ay Department of Epidemiology, Harvard T H Chan School of Public Health, Harvard University, Boston, MA, United States
az Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
ba Departments of Emergency Medicine and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Abstract
Study objective: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision. Methods: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration. Results: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort. Conclusion: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery. © 2022 American College of Emergency Physicians
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The effect of temperature on fish swimming and schooling is context dependent
(2022) Oikos, .
Kuruvilla, M.a b , Dell, A.c e g , Olson, A.R.d , Knouft, J.e , Grady, J.M.c , Forbes, J.c f , Berdahl, A.M.a b
a Quantitative Ecology and Resource Management Program, Univ. of Washington, Seattle, WA, United States
b School of Aquatic and Fishery Sciences, Univ. of Washington, Seattle, WA, United States
c National Great Rivers Research and Education Center, One Confluence Way, East Alton, IL, United States
d School of Science, Psychology and Sport, Federation Univ. Australia, Churchill, VIC, Australia
e Dept of Biology, Saint Louis Univ., St. Louis, MO, United States
f Dept of Biological Sciences, Southern Illinois Univ. Edwardsville, Edwardsville, IL, United States
g Dept of Biology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Temperature is highly influential on the physiology and behaviour of ectotherms. In fish, temperature affects social interactions such as schooling behaviour, a common defence against predation. However, the effect of temperature on the ability of schooling fish to collectively respond to a predator is unknown. Here we used a loom stimulus to simulate an approaching predator that elicited a fleeing response in schooling fish over a range of water temperatures (9–29°C) and group sizes (1–16 fish). While speed and acceleration always exhibited a positive curvilinear response to temperature, the optimal temperature at which performance peaked was different during the predation threat versus when they were unperturbed. Similarly, group-level metrics were sensitive to temperature immediately after a loom stimulus but showed no response to temperature during unperturbed swimming. The time taken for fish to respond to the loom stimulus was minimal at 20°C. The proportion of fish that startled, during a loom, peaked at 13°C – around the same temperature at which speed, and acceleration was maximum. Taken together, our results suggest that ectothermic fish may be able to compensate for their slower swim speeds at lower temperatures during unperturbed swimming by increasing their sensitivity to startle in response to a predation threat. More generally, we show that in ectotherms the qualitative and quantitative effect of temperature on a behavioural trait may be dependent on the context. © 2022 Nordic Society Oikos. Published by John Wiley & Sons Ltd.
Author Keywords
behavioral ecology; collective behavior; golden shiners; predation; thermal ecology
Funding details
NGRREC‐IP2019‐18
National Science FoundationNSFDEB‐1838346
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
cGAS-STING pathway targeted therapies and their applications in the treatment of high-grade glioma
(2022) F1000Research, 11, p. 1010.
Tripathi, S.a b , Najem, H.a b , Mahajan, A.S.b c , Zhang, P.a b , Low, J.T.d , Stegh, A.H.e , Curran, M.A.f , Ashley, D.M.d , James, C.D.a b , Heimberger, A.B.a b
a Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
b Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
c Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
d Department of Neurological Surgery, Preston Robert Tisch Brain Tumor Center, Duke University Medical School, Durham, NC 27710, United States
e Department of Neurological Surgery, Brain Tumor Center, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
Abstract
Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas. Copyright: © 2022 Tripathi S et al.
Author Keywords
cGAS-STING; glioblastoma; immune cells; immune therapies; myeloid cells; STING Agonist; T cells; tumor microenvironment
Document Type: Review
Publication Stage: Final
Source: Scopus
Quantifying latent social motivation and its associations with joint attention and language in infants at high and low likelihood for autism spectrum disorder
(2022) Developmental Science, .
Stallworthy, I.C.a , Berry, D.a , Davis, S.b , Wolff, J.J.c , Burrows, C.A.d , Swanson, M.R.e , Grzadzinski, R.L.f , Botteron, K.b , Dager, S.R.g , Estes, A.M.h , Schultz, R.T.i , Piven, J.f , Elison, J.T.a d , Pruett, J.R., Jr.b , Marrus, N.b , for The IBIS Networkj
a Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St Louis, MO, United States
c Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
d Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
e School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States
f Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
g Departments of Radiology and Bioengineering, University of Washington, Seattle, WA, United States
h Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
i Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Social motivation—the psychobiological predisposition for social orienting, seeking social contact, and maintaining social interaction—manifests in early infancy and is hypothesized to be foundational for social communication development in typical and atypical populations. However, the lack of infant social-motivation measures has hindered delineation of associations between infant social motivation, other early-arising social abilities such as joint attention, and language outcomes. To investigate how infant social motivation contributes to joint attention and language, this study utilizes a mixed longitudinal sample of 741 infants at high (HL = 515) and low (LL = 226) likelihood for ASD. Using moderated nonlinear factor analysis (MNLFA), we incorporated items from parent-report measures to establish a novel latent factor model of infant social motivation that exhibits measurement invariance by age, sex, and familial ASD likelihood. We then examined developmental associations between 6- and 12-month social motivation, joint attention at 12–15 months, and language at 24 months of age. On average, greater social-motivation growth from 6–12 months was associated with greater initiating joint attention (IJA) and trend-level increases in sophistication of responding to joint attention (RJA). IJA and RJA were both positively associated with 24-month language abilities. There were no additional associations between social motivation and future language in our path model. These findings substantiate a novel, theoretically driven approach to modeling social motivation and suggest a developmental cascade through which social motivation impacts other foundational skills. These findings have implications for the timing and nature of intervention targets to support social communication development in infancy. Highlights: We describe a novel, theoretically based model of infant social motivation wherein multiple parent-reported indicators contribute to a unitary latent social-motivation factor. Analyses revealed social-motivation factor scores exhibited measurement invariance for a longitudinal sample of infants at high and low familial ASD likelihood. Social-motivation growth from ages 6–12 months is associated with better 12−15-month joint attention abilities, which in turn are associated with greater 24-month language skills. Findings inform timing and targets of potential interventions to support healthy social communication in the first year of life. © 2022 The Authors. Developmental Science published by John Wiley & Sons Ltd.
Author Keywords
autism; infancy; joint attention; language; social motivation
Funding details
00074041
National Science FoundationNSF
National Institutes of HealthNIHMH118362‐02S1, R01 HD055741, R01 MH104324
National Institute of Mental HealthNIMHK08MH112891
Autism SpeaksAS6020
Simons FoundationSF140209, HD079124, HD087011
University of WashingtonUWHD083091, HD86984
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The effects of passive dehydration on motor unit firing rates of the vastus lateralis in males
(2022) Sport Sciences for Health, .
Reece, T.M.a , Hatcher, M.L.b , Emerson, D.M.c , Herda, T.J.b
a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Department of Health, Sport and Exercise Sciences, University of Kansas, Lawrence, KS, United States
c Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS, United States
Abstract
Purpose: The purpose of the present study was to examine the effects of dehydration on strength and motor unit (MU) firing rates of the vastus lateralis (VL) during submaximal contractions. Methods: Eight resistance trained, healthy males (mean ± SD; age = 27.6 ± 3.2 years, mass = 98.7 ± 15.1 kg, stature = 181.0 ± 3.8 cm) performed submaximal leg extension contractions at 70% of maximal voluntary contraction (MVC) before and after a passive dehydration protocol to a 5% loss in body weight. Surface EMG signals of the VL were collected and decomposed into their constituent MU action potential trains and linear mean firing rate (pps) vs. recruitment threshold [expressed as a percentage of MVC (%MVC)] relationships were analyzed for each subject and hydration condition. Results: The MVC torque was higher during euhydration (269.3 ± 58.9 Nm) than during hypohydration (242.8 ± 60.8 Nm) while there were no differences between the slopes (euhydrated = -0.43 ± 0.23 pps/%MVC; hypohydrated = -0.50 ± 0.28 pps/%MVC; p = 0.23) or the y-intercepts (euhydrated = 30.43 ± 10.47 pps; hypohydrated = 35.22 ± 14.58 pps; p = 0.078) between conditions. Conclusion: The 9.8% decrease in strength during hypohydration might be caused by a decrease in the contractile force of the active muscle fibers rather than decreased activation of the MU pool. © 2022, The Author(s), under exclusive licence to Springer-Verlag Italia S.r.l., part of Springer Nature.
Author Keywords
Electromyography; Firing rates; Hypohydration; Motor unit; Muscle activation; Muscle fibers
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer’s Disease
(2022) Journal of Prevention of Alzheimer’s Disease, .
Petersen, K.K.a , Ezzati, A.a , Lipton, R.B.a , Gordon, B.A.b , Hassenstab, J.b , Morris, J.C.b , Grober, E.a
a Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, 1225 Morris Park Avenue, Bronx, NY 10461, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. Methods: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of β-amyloid (Aβ42/Aβ40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. Results: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aβ42/Aβ40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. Conclusion: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology. © 2022, Serdi.
Author Keywords
APOE e4; biomarkers; cerebrospinal fluid; cognition; SOMI
Funding details
National Institutes of HealthNIH30 AG066444, P01 AG026276, P01AG003991, U19 AG024904, U19 AG032438
National Institute on AgingNIA2PO1 AG003949, K23 AG063993
Alzheimer’s AssociationAA2019-AACSF-641329
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Development and Psychometric Validation of the Olfactory Dysfunction Outcomes Rating
(2022) JAMA Otolaryngology – Head and Neck Surgery, . Cited 1 time.
Lee, J.J.a , Mahadev, A.a b , Kallogjeri, D.a c , Peterson, A.M.a , Gupta, S.a d , Khan, A.M.a , Jiramongkolchai, P.a , Schneider, J.S.e , Piccirillo, J.F.a f
a Clinical Outcomes Research Office, Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine, St Louis, MO, United States
b University of Missouri, School of Medicine, Kansas City, United States
c JAMA Otolaryngology-Head & Neck Surgery, United States
d Medical College of Georgia, Augusta, United States
e Department of Otolaryngology-Head and Neck Surgery, Washington University, School of Medicine, St Louis, MO, United States
f JAMA Otolaryngology-Head & Neck Surgery, United States
Abstract
Importance: Olfactory dysfunction (OD) is an increasingly common and morbid condition, especially given the ongoing COVID-19 pandemic. Thus, the ability to reproducibly measure smell loss-associated quality of life (QOL) and its response to treatment is paramount. Objective: To develop and validate a concise and visually appealing smell loss-associated QOL patient-reported outcome measure for OD. Design, Setting, and Participants: A secondary analysis of comments to an online survey by 1000 patients with olfactory dysfunction published in 2013 was used as the primary source to generate items of the Olfactory Dysfunction Outcomes Rating (ODOR). In addition, 30 patients with OD enrolled in 2 clinical studies at a tertiary care medical center (Washington University) were asked to identify their main concerns associated with smell loss. And finally, 4 otolaryngologists reviewed the items generated from the online survey and the patients’ interviews to identify any additional items. Prospective study design was used for data collection from the 30 patients and 4 otolaryngologists. Prospective study design was used for survey validation. Validation of the ODOR was performed with 283 patients enrolled in several prospective studies at a single institution that completed the ODOR as an outcome measure. Main Outcomes and Measures: Item generation and selection were the outcomes of ODOR development. The psychometric and clinimetric measures evaluated for validation were internal consistency, test-retest reliability, face and content validity, concurrent validity, and discriminant validity. Minimal clinically important difference was also determined. Results: The ODOR is a 28-item instrument with each item scored as either no difficulty or very rarely bothered (0) to complete difficulty or very frequently bothered (4) with a total instrument score range of 0 to 112 points. Higher scores indicate higher degree of dysfunction and limitation. Validation in the cohort of 283 patients (mean [SD] age, 47.0 [14.4] years; 198 female participants [73%]; 179 White participants [80%]) revealed that the instrument has high internal consistency (Cronbach α = 0.968), test-retest reliability (r = 0.90 [95% CI, 0.81-0.95]), face validity, content validity, concurrent validity (r = 0.87 [95% CI, 0.80-0.91] compared with the Questionnaire of Olfactory Disorders-Negative Statements; ρ = -0.76 [95% CI, -0.81 to -0.71] compared with a patient-reported symptom severity scale), and divergent validity (mean score difference, -33.9 [95% CI, -38.3 to -29.6] between normosmic patients and hyposmic/anosmic patients). The minimal clinically important difference was 15 points. The estimated time for survey completion was approximately 5 minutes. Conclusions and Relevance: In this survey creation and validation study, the ODOR was shown to be a novel, concise, reliable, and valid patient-reported outcome measure of OD-associated QOL. It can be used to measure physical problems, functional limitations, and emotional consequences associated with OD and how they change after a given intervention, which is clinically applicable and particularly pertinent given the growing burden of OD associated with COVID-19. © 2022 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis
(2022) Molecular Psychiatry, .
Tielbeek, J.J.a , Uffelmann, E.a , Williams, B.S.b , Colodro-Conde, L.c , Gagnon, É.d , Mallard, T.T.e , Levitt, B.E.f , Jansen, P.R.a , Johansson, A.g , Sallis, H.M.h , Pistis, G.i , Saunders, G.R.B.j , Allegrini, A.G.k , Rimfeld, K.k , Konte, B.l , Klein, M.m , Hartmann, A.M.l , Salvatore, J.E.n , Nolte, I.M.o , Demontis, D.p , Malmberg, A.L.K.q , Burt, S.A.r , Savage, J.E.a , Sugden, K.b , Poulton, R.s , Harris, K.M.t , Vrieze, S.j , McGue, M.j , Iacono, W.G.j , Mota, N.R.m , Mill, J.u , Viana, J.F.v , Mitchell, B.L.w , Morosoli, J.J.c , Andlauer, T.F.M.x , Ouellet-Morin, I.y , Tremblay, R.E.z , Côté, S.M.aa , Gouin, J.-P.ab , Brendgen, M.R.ac , Dionne, G.d , Vitaro, F.ad , Lupton, M.K.w , Martin, N.G.w , Porjesz, B.at , Hesselbrock, V.au , Foroud, T.av , Agrawal, A.aw , Edenberg, H.J.ax , Liu, Y.ay , Plawecki, M.H.az , Kuperman, S.ba , Kramer, J.R.ba , Meyers, J.M.at , Kamarajan, C.at , Pandey, A.at , Bierut, L.aw , Rice, J.aw , Bucholz, K.K.aw , Schuckit, M.A.bb , Tischfield, J.bc , Hart, R.bd , Almasy, L.be , Goate, A.bf , Slesinger, P.bg , Scott, D.bh , Castelao, E.i , Räikkönen, K.q , Eriksson, J.G.ae , Lahti, J.q , Hartman, C.A.af , Oldehinkel, A.J.af , Snieder, H.o , Liu, H.ag , Preisig, M.i , Whipp, A.ah , Vuoksimaa, E.ah , Lu, Y.ai , Jern, P.g , Rujescu, D.l , Giegling, I.l , Palviainen, T.ah , Kaprio, J.ah , Harden, K.P.aj , Munafò, M.R.h , Morneau-Vaillancourt, G.d , Plomin, R.k , Viding, E.ak , Boutwell, B.B.al , Aliev, F.am , Dick, D.M.am , Popma, A.an , Faraone, S.V.ao , Børglum, A.D.p , Medland, S.E.c , Franke, B.ap , Boivin, M.d , Pingault, J.-B.aq , Glennon, J.C.ar , Barnes, J.C.ag , Fisher, S.E.as , Moffitt, T.E.b , Caspi, A.b , Polderman, T.J.C.an , Posthuma, D.a , COGA Consortiumbi , Spit for Science Working Groupbj
a Center for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, De Boelelaan 1105, Amsterdam, 1081 HV, Netherlands
b Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University, 2020 West Main Street, Durham, NC 27705, United States
c Psychiatric Genetics, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
d Research Unit on Children’s Psychosocial Maladjustment, École de psychologie, Université Laval, 2523 Allée des Bibliothèques, Quebec City, QC G1V 0A6, Canada
e Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
f Carolina Population Center, University of North Carolina at Chapel Hill, 123 Franklin St, Chapel Hill, NC 27516, United States
g Department of Psychology, Faculty of Arts, Psychology, and Theology, Åbo Akademi University, Tuomiokirkontori 3, Turku, FI-20500, Finland
h MRC Integrative Epidemiology Unit, University of Bristol, Oakfield Road, Bristol, BS8 2BN, United Kingdom
i Center for Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Route de Cery 25, Prilly, Vaud, CH-1008, Switzerland
j Department of Psychology, University of Minnesota, 75 E. River Road, Minneapolis, MN 55455, United States
k Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, DeCrespigny Park, Denmark Hill, London, SE5 8AF, United Kingdom
l Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria
m Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Groteplein 10, Nijmegen, 6500 HB, Netherlands
n Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
o Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9700 RB, Netherlands
p iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, 8000, Aarhus C, Denmark
q Department of Psychology and Logopedics, University of Helsinki, Haartmaninkatu 3, Helsinki, 00014, Finland
r Michigan State University, East Lansing, MI, United States
s Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, Dunedin, New Zealand
t Department of Sociology, University of North Carolina at Chapel Hill, CB# 3210, 201 Hamilton Hall, Chapel Hill, NC 27599, United States
u University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
v The Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, Birmingham, United Kingdom
w Genetic Epidemiology, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
x Department of Neurology, Technical University of Munich, 22 Ismaninger St., Munich, 81675, Germany
y Research Unit on Children’s Psychosocial Maladjustment, École de criminologie, Université of Montreal, 3150 Rue Jean-Brillant, Montreal, QC H3T 1N8, Canada
z Research Unit on Children’s Psychosocial Maladjustment, Département de pédiatrie et de psychologie, University of Montreal, 90 Avenue Vincent d’Indy, Montreal, QC H2V 2S9, Canada
aa Research Unit on Children’s Psychosocial Maladjustment, CHU Ste-Justine Research Center and Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC H3T 1C5, Canada
ab Department of Psychology, Concordia University, 7141 Sherbrooke St. West, Montreal, QC H4B 1R6, Canada
ac Research Unit on Children’s Psychosocial Maladjustment, Département de psychologie, Université du Québec à Montréal, CP 8888 succursale Centre-ville, Montreal, QC H3C 3P8, Canada
ad Research Unit on Children’s Psychosocial Maladjustment, CHU Sainte-Justine Research Center and University of Montreal, 3175 Chemin de la Côte Ste-Catherine, Montreal, QC H3T 1C5, Canada
ae Department of General Practice and Primary Health Care, University of Helsinki, Tukholmankatu 8 B, Helsinki, Finland
af Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9700 RB, Netherlands
ag School of Criminal Justice, University of Cincinnati, 2840 Bearcat Way, Cincinnati, OH 45221, United States
ah Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, PO Box 4, (Yliopistonkatu 3), Helsinki, 00014, Finland
ai Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels Väg 12A, Stockholm, 171 77, Sweden
aj Department of Psychology and Population Research Center, University of Texas at Austin, 108 E Dean Keeton Stop #A8000, Austin, TX 78712, United States
ak Division of Psychology and Language Sciences, University College London, London, United Kingdom
al School of Applied Sciences, University of Mississippi, John D. Bower School of Population Health, University of Mississippi Medical Center, 84 Dormitory Row West, University, MS 38677, United States
am Department of Psychology, Virginia Commonwealth University, Box 842018, 806W Franklin St, Richmond, VA 23284, United States
an Amsterdam UMC, VKC Psyche, Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam, Netherlands
ao Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, United States
ap Department of Human Genetics, Donders Institute for Brain, Cognition and Behaivour, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 GA, Netherlands
aq Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom
ar Conway Institute of Biomolecular and Biomedical Sciences, School of Medicine, University College Dublin, Dublin, Ireland
as Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, Nijmegen, 6525 XD, Netherlands
at Department of Psychiatry and Behavioral Sciences, State University of New York Health Sciences University, Brooklyn, NY, United States
au Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
av Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
aw Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ax Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, United States
ay Departments of Medical and Molecular Genetics, Biostatistics, and BioHealth Informatics, Indiana University, Indianapolis, IN, United States
az Department of Psychiatry, Indiana University, Indianapolis, IN, United States
ba Department of Psychiatry, University of Iowa, Iowa City, IA, United States
bb Department of Psychiatry, University of California San Diego Medical School, San Diego, CA, United States
bc Department of Genetics, Rutgers University, Piscataway, NJ, United States
bd Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
be The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
bf Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
bg Departments of Neuroscience and Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
bh Department of Pediatrics, Howard University, Washington, DC, United States
Abstract
Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10−10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
263278, 265240
R01 AA028064, R25 AA027402, R34 AA027347, U10 AA008401
400-17-602
728018, 847879
667302
45219212
National Institutes of HealthNIHP50 AA022537, R01 AA015416
National Institute of Mental HealthNIMH1U01MH109514-01
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAAR01 DA050721
Fonds de Recherche du Québec-Société et CultureFRQSC
Yrjö Jahnssonin Säätiö
Jalmari ja Rauha Ahokkaan Säätiö
Seventh Framework ProgrammeFP7602768
University Hospitals Bristol NHS Foundation TrustUHBW
National Institute for Health and Care ResearchNIHR
University of Bristol
National Health and Medical Research CouncilNHMRC274521, 284385, 319403, APP1140441, APP1172917, APP1172990
Canada Research Chairs
Academy of FinlandAKA
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
LundbeckfondenR102-A9118, R155-2014-1724, R248-2017-2003
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Seventh Framework ProgrammeFP7602805
Sigrid Juséliuksen Säätiö
Suomen Tiedeseura
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy: A Systematic Review and Meta-analysis
(2022) JAMA Neurology, .
Srivastava, S.a , Lewis, S.A.b c d e f , Cohen, J.S.g h , Zhang, B.a , Aravamuthan, B.R.i , Chopra, M.a , Sahin, M.a , Kruer, M.C.b c d e f , Poduri, A.a j
a Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
b Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
c Department of Child Health, Program in Genetics, University of Arizona, College of Medicine, Phoenix, United States
d Department of Neurology, Program in Genetics, University of Arizona, College of Medicine, Phoenix, United States
e Department of Cellular & Molecular Medicine, Program in Genetics, University of Arizona, College of Medicine, Phoenix, United States
f Department of Program in Genetics, University of Arizona, College of Medicine, Phoenix, United States
g Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
h Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
i Department of Neurology, Washington University in St Louis, St Louis, MO, United States
j Department of Epilepsy, Boston Children’s Hospital, Boston, MA, United States
Abstract
Importance: There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA). Objective: To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA. Data Sources: Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022). Study Selection: Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer. Main Outcomes and Measures: A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies. Results: In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%). Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.. © 2022 American Medical Association. All rights reserved.
Document Type: Review
Publication Stage: Article in Press
Source: Scopus