Arts & Sciences Brown School Engineering & Applied Science Medicine Weekly Publications

WashU weekly Neuroscience publications

“Examining the Role of Cone-expressed RPE65 in Mouse Cone Function” (2018) Scientific Reports

Examining the Role of Cone-expressed RPE65 in Mouse Cone Function
(2018) Scientific Reports, 8 (1), art. no. 14201, . 

Kolesnikov, A.V.a , Tang, P.H.b c , Kefalov, V.J.a

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States
c Byers Eye Institute, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94303, United States

Abstract
Efficient chromophore supply is paramount for the continuous function of vertebrate cone photoreceptors. It is well established that isomerization of all-trans- to 11-cis- retinoid in the retinal pigmented epithelium by RPE65 is a key reaction in this process. Mutations in RPE65 result in a disrupted chromophore supply, retinal degeneration, and blindness. Interestingly, RPE65 has recently been found to also be expressed in cone photoreceptors in several species, including mouse and human. However, the functional role of cone-expressed RPE65 has remained unknown. Here, we used loss and gain of function approaches to investigate this issue. First, we compared the function of cones from control and RPE65-deficient mice. Although we found that deletion of RPE65 partially suppressed cone dark adaptation, the interpretation of this result was complicated by the abnormal cone structure and function caused by the chromophore deficiency in the absence of RPE65 in the pigmented epithelium. As an alternative approach, we generated transgenic mice to express human RPE65 in the cones of mice where RPE65 expression is normally restricted to the pigmented epithelium. Comparison of control (RPE65-deficient) and transgenic (RPE65-expressing) cones revealed no morphological or functional changes, with only a slight delay in dark adaptation, possibly caused by the buffering of retinoids by RPE65. Together, our results do not provide any evidence for a functional role of RPE65 in mouse cones. Future studies will have to determine whether cone-expressed RPE65 plays a role in maintaining the long-term homeostasis of retinoids in cones and their function and survival, particularly in humans. © 2018, The Author(s).

Document Type: Article
Source: Scopus

“The Power of Collaboration and Data Aggregation” (2018) Biological Psychiatry

The Power of Collaboration and Data Aggregation
(2018) Biological Psychiatry, 84 (9), pp. 626-628. 

Barch, D.M.

Departments of Psychological and Brain Sciences, Psychiatry, and Radiology, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Source: Scopus

“Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1” (2018) Cell Reports

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1
(2018) Cell Reports, 25 (1), pp. 1-9.e5. 

Lananna, B.V.a , Nadarajah, C.J.a , Izumo, M.b , Cedeño, M.R.a , Xiong, D.D.a , Dimitry, J.a , Tso, C.F.c , McKee, C.A.a , Griffin, P.a , Sheehan, P.W.a , Haspel, J.A.d , Barres, B.A.e , Liddelow, S.A.f g , Takahashi, J.S.b h , Karatsoreos, I.N.i , Musiek, E.S.a

a Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
c Department of Biology, Washington University, St. Louis, MO, United States
d Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, United States
f Neuroscience Institute, Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY, United States
g Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
h Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States
i Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA, United States

Abstract
Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease. Lananna et al. show that the circadian clock protein BMAL1 regulates astrocyte activation via a cell-autonomous mechanism involving diminished glutathione-S-transferase signaling. This finding elucidates a function of the core circadian clock in astrocytes and reveals BMAL1 as a modulator of astrogliosis. © 2018 The Author(s)

Author Keywords
astrocyte;  astrogliosis;  Bmal1;  circadian;  glutathione;  neuroinflammation;  rhythm

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

“Is a reduction in access to prescription opioids the cure for the current opioid crisis?” (2018) American Journal of Public Health

Is a reduction in access to prescription opioids the cure for the current opioid crisis?
(2018) American Journal of Public Health, 108 (10), pp. 1322-1323. 

Cicero, T.J.

Department of Psychiatry, School of Medicine, Washington University, Box 8134, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Document Type: Review
Source: Scopus

“The identity and function of microglia in neurodegeneration” (2018) Nature Immunology

The identity and function of microglia in neurodegeneration
(2018) Nature Immunology, 19 (10), pp. 1048-1058. 

Song, W.M., Colonna, M.

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, morphology and function in similar ways; thus, these activated cells have been called ‘degeneration- or disease-associated microglia’ (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

Document Type: Review
Source: Scopus

“Media-Related Education in Psychiatry Residency Programs” (2018) Academic Psychiatry

Media-Related Education in Psychiatry Residency Programs
(2018) Academic Psychiatry, 42 (5), pp. 679-685. 

Morris, N.P.a , Johansen, S.L.a , May, M.a , Gold, J.A.b

a Stanford University School of MedicineCA, United States
b Washington University School of Medicine, St. Louis, MO, United States

Document Type: Article
Source: Scopus

“Audience segmentation to disseminate behavioral health evidence to legislators: An empirical clustering analysis” (2018) Implementation Science

Audience segmentation to disseminate behavioral health evidence to legislators: An empirical clustering analysis
(2018) Implementation Science, 13 (1), art. no. 121, . 

Purtle, J.a , Lê-Scherban, F.b , Wang, X.b , Shattuck, P.T.a c , Proctor, E.K.d , Brownson, R.C.e f

a Drexel University, Department of Health Management and Policy, Dornsife School of Public Health, 3215 Market St., Philadelphia, PA 19104, United States
b Drexel University, Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Philadelphia, PA, United States
c Drexel University, A.J. Drexel Autism Institute, Philadelphia, PA, United States
d Washington University in St. Louis, Center for Mental Health Services Research, Brown School of Social Work, St. Louis, MO, United States
e Washington University in St. Louis, Prevention Research Center in St. Louis, Brown School of Social Work, St. Louis, MO, United States
f Washington University in St. Louis, Division of Public Health Sciences and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Elected officials (e.g., legislators) are an important but understudied population in dissemination research. Audience segmentation is essential in developing dissemination strategies that are tailored for legislators with different characteristics, but sophisticated audience segmentation analyses have not been conducted with this population. An empirical clustering audience segmentation study was conducted to (1) identify behavioral health (i.e., mental health and substance abuse) audience segments among US state legislators, (2) identify legislator characteristics that are predictive of segment membership, and (3) determine whether segment membership is predictive of support for state behavioral health parity laws. Methods: Latent class analysis (LCA) was used. Data were from a multi-modal (post-mail, e-mail, telephone) survey of state legislators fielded in 2017 (N=475). Nine variables were included in the LCA (e.g., perceptions of behavioral health treatment effectiveness, mental illness stigma). Binary logistic regression tested associations between legislator characteristics (e.g., political party, gender, ideology) and segment membership. Multi-level logistic regression assessed the predictive validity of segment membership on support for parity laws. A name was developed for each segment that captured its most salient features. Results: Three audience segments were identified. Budget-oriented skeptics with stigma (47% of legislators) had the least faith in behavioral health treatment effectiveness, had the most mental illness stigma, and were most influenced by budget impact. This segment was predominantly male, Republican, and ideologically conservative. Action-oriented supporters (24%) were most likely to have introduced a behavioral health bill, most likely to identify behavioral health issues as policy priorities, and most influenced by research evidence. This was the most politically and ideologically diverse segment. Passive supporters (29%) had the greatest faith in treatment effectiveness and the least stigma, but were also least likely to have introduced a behavioral health bill. Segment membership was a stronger predictor of support for parity laws than almost all other legislator characteristics. Conclusions: State legislators are a heterogeneous audience when it comes to behavioral health. There is a need to develop and test behavioral health evidence dissemination strategies that are tailored for legislators in different audience segments. Empirical clustering approaches to audience segmentation are a potentially valuable tool for dissemination science. © 2018 The Author(s).

Author Keywords
Audience segmentation;  Dissemination;  Latent class analysis;  Policymaker;  State legislators;  United States

Document Type: Article
Source: Scopus

“Chemogenetic isolation reveals synaptic contribution of δ GABAA receptors in mouse dentate granule neurons” (2018) Journal of Neuroscience

Chemogenetic isolation reveals synaptic contribution of δ GABAA receptors in mouse dentate granule neurons
(2018) Journal of Neuroscience, 38 (38), pp. 8128-8145. 

Sun, M.-Y.a , Shu, H.-J.a , Benz, A.a , Bracamontes, J.c , Akk, G.c d , Zorumski, C.F.a b d , Steinbach, J.H.c d , Mennerick, S.J.a b d

a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Two major GABAA receptor classes mediate ionotropic GABA signaling, those containing a δ subunit and those with a γ2 subunit. The classical viewpoint equates γ2-containing receptors with IPSCs and δ-containing receptors with tonic inhibition because of differences in receptor localization, but significant questions remain because the populations cannot be pharmacologically separated. We removed this barrier using gene editing to confer a point mutation on the δ subunit in mice, rendering receptors containing the subunit picrotoxin resistant. By pharmacologically isolating δ-containing receptors, our results demonstrate their contribution to IPSCs in dentate granule neurons and weaker contributions to thalamocortical IPSCs. Despite documented extrasynaptic localization, we found that receptor localization does not preclude participation in isolated IPSCs, including mIPSCs. Further, phasic inhibition from δ subunit-containing receptors strongly inhibited summation of EPSPs, whereas tonic activity had little impact. In addition to any role that δ-containing receptors may play in canonical tonic inhibition, our results highlight a previously underestimated contribution of δ-containing receptors to phasic inhibition. © 2018 the authors.

Author Keywords
GABA;  Hippocampus;  Inhibition;  IPSC;  Picrotoxin;  Tonic

Document Type: Article
Source: Scopus

“Intracellular GPCRs Play Key Roles in Synaptic Plasticity” (2018) ACS Chemical Neuroscience

Intracellular GPCRs Play Key Roles in Synaptic Plasticity
(2018) ACS Chemical Neuroscience, 9 (9), pp. 2162-2172. 

Jong, Y.-J.I., Harmon, S.K., O’Malley, K.L.

Department of Neuroscience, Washington University, School of Medicine, Saint Louis, MO 63110, United States

Abstract
The trillions of synaptic connections within the human brain are shaped by experience and neuronal activity, both of which underlie synaptic plasticity and ultimately learning and memory. G protein-coupled receptors (GPCRs) play key roles in synaptic plasticity by strengthening or weakening synapses and/or shaping dendritic spines. While most studies of synaptic plasticity have focused on cell surface receptors and their downstream signaling partners, emerging data point to a critical new role for the very same receptors to signal from inside the cell. Intracellular receptors have been localized to the nucleus, endoplasmic reticulum, lysosome, and mitochondria. From these intracellular positions, such receptors may couple to different signaling systems, display unique desensitization patterns, and/or show distinct patterns of subcellular distribution. Intracellular GPCRs can be activated at the cell surface, endocytosed, and transported to an intracellular site or simply activated in situ by de novo ligand synthesis, diffusion of permeable ligands, or active transport of non-permeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in synaptic plasticity and learning and memory. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools. © 2018 American Chemical Society.

Author Keywords
5-HTR4;  AT1R;  AT2R;  CB1;  CB2;  FXS;  GPCR;  GPER;  mAchR;  mGlu5;  MT1;  P2Y1;  P2Y2

Document Type: Review
Source: Scopus

“Dissociation of LFP power and tuning in the frontal cortex during memory” (2018) Journal of Neuroscience

Dissociation of LFP power and tuning in the frontal cortex during memory
(2018) Journal of Neuroscience, 38 (38), pp. 8177-8186. 

Holmes, C.D.a b , Papadimitriou, C.a , Snyder, L.H.a b

a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63130, United States

Abstract
Working memory, the ability to maintain and manipulate information in the brain, is critical for cognition. During the memory period of spatial memory tasks, neurons in the prefrontal cortex code for memorized locations via persistent, spatially tuned increases in activity. Local field potentials (LFPs) are understood to reflect summed synaptic activity of local neuron populations and may offer a window into network-level processing. We recorded LFPs from areas 8A and 9/46 while two male cynomolgus macaques (Macaca fascicularis) performed a long duration (5.1–15.6 s) memory-guided saccade task. Greater than ~16 Hz, LFP power was contralaterally tuned throughout the memory period. Yet power for both contralateral and ipsilateral targets fell gradually after the first second of the memory period, dropping below baseline after a few seconds. Our results dissociate absolute LFP power from mnemonic tuning and are consistent with modeling work that suggests that decreasing synchronization within a network may improve the stability of memory coding. © 2018 the authors.

Author Keywords
Frontal eye fields;  Local field potential;  Macaque;  Prefrontal cortex;  Working memory

Document Type: Article
Source: Scopus

“Transmission disrupted: Modeling auditory synaptopathy in zebrafish” (2018) Frontiers in Cell and Developmental Biology

Transmission disrupted: Modeling auditory synaptopathy in zebrafish
(2018) Frontiers in Cell and Developmental Biology, 6 (SEP), art. no. 114, . 

Kindt, K.S.a , Sheets, L.b

a Section on Sensory Cell Development and Function, NIDCD/National Institutes of Health, Bethesda, MD, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Sensorineural hearing loss is the most common form of hearing loss in humans, and results from either dysfunction in hair cells, the sensory receptors of sound, or the neurons that innervate hair cells. A specific type of sensorineural hearing loss, referred to as auditory synaptopathy, occurs when hair cells are able to detect sound but fail to transmit sound stimuli at the hair-cell synapse. Auditory synaptopathy can originate from genetic alterations that specifically disrupt hair-cell synapse function. Additionally, environmental factors such as noise exposure can leave hair cells intact but result in loss of hair-cell synapses, and represent an acquired form of auditory synaptopathy. The zebrafish model has emerged as a valuable system for studies of hair-cell function, and specifically hair-cell synaptopathy. In this review, we describe the experimental tools that have been developed to study hair-cell synapses in zebrafish. We discuss how zebrafish genetics has helped identify and define the roles of hair-cell synaptic proteins crucial for hearing in humans, and highlight how studies in zebrafish have contributed to our understanding of hair-cell synapse formation and function. In addition, we also discuss work that has used noise exposure or pharmacological mimic of noise-induced excitotoxicity in zebrafish to define cellular mechanisms underlying noise-induced hair-cell damage and synapse loss. Lastly, we highlight how future studies in zebrafish could enhance our understanding of the pathological processes underlying synapse loss in both genetic and acquired auditory synaptopathy. This knowledge is critical in order to develop therapies that protect or repair auditory synaptic contacts. © 2018 Kindt and Sheets.

Author Keywords
Deafness/hearing loss;  Hair cells (HCs);  Ribbon synapse;  Synaptic transmission;  Zebrafish model system

Document Type: Review
Source: Scopus
Access Type: Open Access

“Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study” (2018) The Lancet Neurology

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study
(2018) The Lancet Neurology, 17 (9), pp. 782-789. Cited 1 time.

Bazarian, J.J.a , Biberthaler, P.b , Welch, R.D.c , Lewis, L.M.d , Barzo, P.e , Bogner-Flatz, V.f , Gunnar Brolinson, P.g , Büki, A.h , Chen, J.Y.i , Christenson, R.H.j , Hack, D.k , Huff, J.S.l , Johar, S.m , Jordan, J.D.n , Leidel, B.A.o , Lindner, T.o , Ludington, E.p , Okonkwo, D.O.q , Ornato, J.r , Peacock, W.F.s , Schmidt, K.k t , Tyndall, J.A.u , Vossough, A.v , Jagoda, A.S.w

a Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
b Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
c Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
d Division of Emergency Medicine, Washington University, St Louis, MO, United States
e University of Szeged, Szeged, Hungary
f Department of Trauma Surgery, Ludwig Maximilians University, Munich, Germany
g Carilion New River Valley Hospital, The Edward Via College of Osteopathic Medicine, Blacksburg, VA, United States
h Department of Neurosurgery, The MTA-PTE Clinical Neuroscience MR Research Group, János Szentágothai Research Center, Hungarian Brain Research Program, Medical School, University of Pecs, Pecs, Hungary
i Department of Radiology, VA San Diego Healthcare System/University of California, San Diego Health System, La Jolla, CA, United States
j Department of Pathology, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, MD, United States
k US Army Medical Research and Materiel Command, Fort Detrick, MD, United States
l University of Virginia, Charlottesville, VA, United States
m Neurosurgery, Orthopedics & Spine Specialist, Waterbury, CT, United States
n University of North Carolina School of Medicine, Chapel Hill, NC, United States
o Charité Universitätsmedizin Berlin, Berlin, Germany
p Agility Clinical, Carlsbad, CA, United States
q Department of Neurosurgical Science, University of Pittsburgh, Pittsburgh, PA, United States
r Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond, VA, United States
s Department of Emergency Medicine, Baylor College of Medicine, Houston, TX, United States
t US Army Medical Research and Material Command, Fort Detrick, MD, United States
u Department of Emergency Medicine, The University of Florida, Gainesville, FL, United States
v Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
w Department of Emergency Medicine, Mount Sinai Health System, New York, NY, United States

Abstract
Background: More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI. Methods: This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9–15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT. Findings: Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931–0·995) and an NPV of 0·996 (0·987–0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative. Interpretation: These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted. Funding: Banyan Biomarkers and US Army Medical Research and Materiel Command. © 2018 Elsevier Ltd

Document Type: Article
Source: Scopus

“Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study” (2018) The Lancet Psychiatry

Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study
(2018) The Lancet Psychiatry, 5 (9), pp. 717-726. Cited 1 time.

Cortese, S.a b c d , Sun, S.e , Zhang, J.f , Sharma, E.g , Chang, Z.e , Kuja-Halkola, R.e , Almqvist, C.e h , Larsson, H.e i , Faraone, S.V.j

a Center for Innovation in Mental Health, Academic Unit of Psychology, Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, United Kingdom
b Solent NHS Trust, Southampton, United Kingdom
c New York University Child Study Center, New York, NY, United States
d Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
e Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
f School of Education, Jiangsu Key Laboratory for Big Data of Psychology and Cognitive Science, Yancheng Teachers University, Yancheng, China
g Psychiatric Epidemiology, Department of Public Health, Brown School, Washington University in St Louis, St Louis, MO, United States
h Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
i School of Medical Sciences, Örebro University, Örebro, Sweden
j State University of New York Upstate Medical University, Syracuse, NY, United States

Abstract
Background: Several studies have assessed the possible association between attention deficit hyperactivity disorder (ADHD) and asthma. However, existing evidence is inconclusive as to whether this association remains after controlling for possible important confounders. To fill this knowledge gap, we did a systematic review and meta-analysis, followed by a population-based study. Methods: For the systematic review and meta-analysis, we searched PubMed, PsycINFO, Embase, Embase Classic, Ovid MEDLINE, and Web of Knowledge databases up to Oct 31, 2017, for observational studies allowing estimation of the association between asthma and ADHD. No restrictions to date, language, or article type were applied. Unpublished data were collected from authors of the identified studies. We extracted unadjusted and adjusted odds ratios (ORs) from the identified studies and calculated ORs when they were not reported. We assessed study quality using the Newcastle-Ottawa Scale and study heterogeneity using I2 statistics. A random-effects model was used to calculate pooled ORs. The systematic review is registered with PROSPERO (CRD42017073368). To address the fact that the ORs obtained in the meta-analysis were adjusted for confounders that inevitably varied across studies, we did a population-based study of individuals in multiple national registers in Sweden. We calculated an unadjusted OR and an OR that was simultaneously adjusted for all confounders identified in a directed acyclic graph based on the studies of asthma and ADHD identified in our systematic review. Findings: We identified 2649 potentially eligible citations, from which we obtained 49 datasets including a total of 210 363 participants with ADHD and 3 115 168 without. The pooled unadjusted OR was 1·66 (95% CI 1·22–2·26; I2 =99·47) and the pooled adjusted OR was 1·53 (1·41–1·65; I2 =50·76), indicating a significant association between asthma and ADHD. Possible lack of representativeness of the study population was detected with the Newcastle-Ottawa Scale in 42 of 49 datasets. In the population-based study, we included 1 575 377 individuals born between Jan 1, 1992, and Dec 31, 2006, of whom 259 253 (16·5%) had asthma and 57 957 (3·7%) had ADHD. Asthma was significantly associated with ADHD (OR 1·60, 95% CI 1·57–1·63) in the crude model adjusting for sex and year of birth, and this association remained significant after simultaneous adjustment for all covariates (1·45, 1·41–1·48). Interpretation: The combined results of the meta-analysis and the population-based study support a significant association between asthma and ADHD, which remained even after simultaneously controlling for several possible confounders in the population-based study. Awareness of this association might help to reduce delay in the diagnosis of both ADHD and asthma. Funding: Swedish Research Council and Shire International GmbH. © 2018 Elsevier Ltd

Document Type: Article
Source: Scopus

“A systematic meta-analysis of oxygen-toglucose and oxygen-to-carbohydrate ratios in the resting human brain” (2018) PLoS ONE

A systematic meta-analysis of oxygen-toglucose and oxygen-to-carbohydrate ratios in the resting human brain
(2018) PLoS ONE, 13 (9), art. no. e0204242, . 

Blazey, T.a , Snyder, A.Z.a b , Goyal, M.S.a b , Vlassenko, A.G.a , Raichle, M.E.a b c

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Glucose is the predominant fuel supporting brain function. If the brain’s entire glucose supply is consumed by oxidative phosphorylation, the molar ratio of oxygen to glucose consumption (OGI) is equal to 6. An OGI of less than 6 is evidence of non-oxidative glucose metabolism. Several studies have reported that the OGI in the resting human brain is less than 6.0, but the exact value remains uncertain. Additionally, it is not clear if lactate efflux accounts for the difference between OGI and its theoretical value of 6.0. To address these issues, we conducted a meta-analysis of OGI and oxygen-to-carbohydrate (glucose + 0.5lactate; OCI) ratios in healthy young and middle-aged adults. We identified 47 studies that measured at least one of these ratios using arterio-venous differences of glucose, lactate, and oxygen. Using a Bayesian random effects model, the population median OGI was 5.46 95% credible interval (5.25-5.66), indicating that approximately 9% of the brain’s glucose metabolism is non-oxidative. The population median OCI was 5.60 (5.36-5.84), suggesting that lactate efflux does not account for all non-oxidative glucose consumption. Significant heterogeneity across studies was observed, which implies that further work is needed to characterize how demographic and methodological factors influence measured cerebral metabolic ratios. © 2018 Blazey et al.

Document Type: Article
Source: Scopus

“Blunted Cardiac Response to Sleep Apnea a Marker of Depression after Acute Myocardial Infarction” (2018) 2018 IEEE International Conference on Consumer Electronics-Taiwan, ICCE-TW 2018

Blunted Cardiac Response to Sleep Apnea a Marker of Depression after Acute Myocardial Infarction
(2018) 2018 IEEE International Conference on Consumer Electronics-Taiwan, ICCE-TW 2018, art. no. 8448812, . 

Hayano, J.a , Yoshida, Y.a , Carbey, R.M.b , Blumenthal, J.A.c , Yuda, E.a

a Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
b Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Duke University Medical Center, Durham, NC, United States

Abstract
While depression is often overlooked in patients after acute myocardial infarction (AMI), it is an important risk of death among these patients. We examined if heart rate variability (HRV) particularly those related to sleep apnea can be a maker of depression after AMI. According to the prognosis of depression, 707 post-AMI patients were divided into 349 never, 138 remitting, 25 newly onset, and 195 persistent depression. Regardless of future prognosis, currently depressed patients had higher heart rate, lower HRV, and blunted cyclic variation of heart rate to sleep apnea during the night. © 2018 IEEE.

Document Type: Conference Paper
Source: Scopus

“Acute control of the sleep switch in drosophila reveals a role for gap junctions in regulating behavioral responsiveness” (2018) eLife

Acute control of the sleep switch in drosophila reveals a role for gap junctions in regulating behavioral responsiveness
(2018) eLife, 7, art. no. e37105, . 

Troup, M.a , Yap, M.H.W.a , Rohrscheib, C.a , Grabowska, M.J.a , Ertekin, D.a , Randeniya, R.a , Kottler, B.a b , Larkin, O.a c , Munro, K.a , Shaw, P.J.d , van Swinderen, B.a

a Queensland Brain Institute, The University of Queensland, Brisbane, Australia
b King’s College London, London, United Kingdom
c University of Cambridge, Cambridge, United Kingdom
d Washington University School of Medicine, St Louis, United States

Abstract
Sleep is a dynamic process in most animals, involving distinct stages that probably perform multiple functions for the brain. Before sleep functions can be initiated, it is likely that behavioral responsiveness to the outside world needs to be reduced, even while the animal is still awake. Recent work in Drosophila has uncovered a sleep switch in the dorsal fan-shaped body (dFB) of the fly’s central brain, but it is not known whether these sleep-promoting neurons also govern the acute need to ignore salient stimuli in the environment during sleep transitions. We found that optogenetic activation of the sleep switch suppressed behavioral responsiveness to mechanical stimuli, even in awake flies, indicating a broader role for these neurons in regulating arousal. The dFB-mediated suppression mechanism and its associated neural correlates requires innexin6 expression, suggesting that the acute need to reduce sensory perception when flies fall asleep is mediated in part by electrical synapses. We thank Leonie Kirszenblat for help and comments on the manuscript. We thank Eleni Notaras for help with behavioral experiments. We also thank Chia-Lin Wu for the INX6 antibody. This work was supported by an NIH grant RO1 NS076980-01 to PJS and BVS, and by an NHMRC grant GNT1065713 to BVS. The authors declare no conflicts of interest. © Troup et al.

Document Type: Article
Source: Scopus

“De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder” (2018) American Journal of Human Genetics

De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
(2018) American Journal of Human Genetics, 103 (2), pp. 305-316.

Gregor, A.a , Sadleir, L.G.b , Asadollahi, R.c d , Azzarello-Burri, S.c d , Battaglia, A.e , Ousager, L.B.f , Boonsawat, P.c d , Bruel, A.-L.g , Buchert, R.h , Calpena, E.i , Cogné, B.j k , Dallapiccola, B.l , Distelmaier, F.m , Elmslie, F.n , Faivre, L.g o , Haack, T.B.h , Harrison, V.p , Henderson, A.q , Hunt, D.p , Isidor, B.j , Joset, P.c d , Kumada, S.r , Lachmeijer, A.M.A.s , Lees, M.t , Lynch, S.A.u , Martinez, F.v , Matsumoto, N.w , McDougall, C.x , Mefford, H.C.y , Miyake, N.w , Myers, C.T.y , Moutton, S.g o , Nesbitt, A.z , Novelli, A.l , Orellana, C.v , Rauch, A.c d , Rosello, M.v , Saida, K.w , Santani, A.B.z aa , Sarkar, A.ab , Scheffer, I.E.ac , Shinawi, M.ad , Steindl, K.c d , Symonds, J.D.ae , Zackai, E.H.x , Reis, A.a , Sticht, H.af , Zweier, C.a , University of Washington Center for Mendelian Genomicsah , DDD Studyag  

a Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
b Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand
c Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, 8952, Switzerland
d radiz – “Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich,”, Zurich, 8032, Switzerland
e Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone, Pisa 56128, Italy
f Department of Clinical Genetics, Odense University Hospital, Odense, 5000, Denmark
g INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, 21079, France
h Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, 72076, Germany
i Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
j Department of Medical Genetics, CHU Nantes, Nantes, 44093, France
k l’Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, 44007, France
l Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
m Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, 40225, Germany
n South West Thames Regional Genetics Service, St. George’s, University of London, London, SW17 0RE, United Kingdom
o Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, 21000, France
p Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom
q Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, NE1 3BZ, United Kingdom
r Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, 183-0042, Japan
s Department of Genetics, University Medical Center Utrecht, PO Box 85090, Utrecht, AB 3508, Netherlands
t North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom
u Dept of Clinical Genetics, Temple Street Children’s Hospital Dublin 1, Dublin, D12 V004, Ireland
v Unidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, Valencia, 46026, Spain
w Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
x Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
y Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, United States
z Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
aa Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
ab Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
ac Departments of Medicine and Paediatrics, Austin Health and Royal Children’s Hospital, The University of Melbourne, Parkville, VIC 3050, Australia
ad Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
ae Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow, G51 4TF, United Kingdom
af Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
ag Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom

Abstract
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features. © 2018 American Society of Human Genetics

Author Keywords
FBXO11;  intellectual disability;  neurodevelopmental disorder

Document Type: Article
Source: Scopus

“Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator” (2018) PLoS ONE

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator
(2018) PLoS ONE, 13 (8), art. no. e0201092, . 

Joseph, A.a d , Thuy, T.T.T.b , Thanh, L.T.b , Okada, M.a c

a Department of Physiology, Kansai Medical University, Osaka, Japan
b Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Viet Nam
c Department of Medical Life Science, College of Life Science, Kurashiki University of Science and the Arts, Kurashiki, Okayama, Japan
d Division of Molecular Oncology, School of Medicine, Washington University, St Louis, MO, United States

Abstract
We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin- related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 μM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs. Copyright © 2018 Joseph et al.

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

“Use of medical care biases associations between Parkinson disease and other medical conditions” (2018) Neurology

Use of medical care biases associations between Parkinson disease and other medical conditions
(2018) Neurology, 90 (24), pp. e2146-e2154. Cited 1 time.

Gross, A.a , Racette, B.A.a b , Camacho-Soto, A.a , Dube, U.a , Nielsen, S.S.a

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa

Abstract
Objective To examine how use of medical care biases the well-established associations between Parkinson disease (PD) and smoking, smoking-related cancers, and selected positively associated comorbidities. Methods We conducted a population-based, case-control study of 89,790 incident PD cases and 118,095 randomly selected controls, all Medicare beneficiaries aged 66 to 90 years. We ascertained PD and other medical conditions using ICD-9-CM codes from comprehensive claims data for the 5 years before PD diagnosis/reference. We used logistic regression to estimate age-, sex-, and race-adjusted odds ratios (ORs) between PD and each other medical condition of interest. We then examined the effect of also adjusting for selected geographic-or individual-level indicators of use of care. Results Models without adjustment for use of care and those that adjusted for geographic-level indicators produced similar ORs. However, adjustment for individual-level indicators consistently decreased ORs: Relative to ORs without adjustment for use of care, all ORs were between 8% and 58% lower, depending on the medical condition and the individual-level indicator of use of care added to the model. ORs decreased regardless of whether the established association is known to be positive or inverse. Most notably, smoking and smoking-related cancers were positively associated with PD without adjustment for use of care, but appropriately became inversely associated with PD with adjustment for use of care. Conclusion Use of care should be considered when evaluating associations between PD and other medical conditions to ensure that positive associations are not attributable to bias and that inverse associations are not masked. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

“The Challenges of Translation” (2018) Anesthesiology

The Challenges of Translation
(2018) Anesthesiology, 128 (4), pp. 693-696. Cited 1 time.

Kharasch, E.D.a b

a Department of Anesthesiology, Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, United States
b Center for Clinical Pharmacology, St. Louis College of Pharmacy, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Review
Source: Scopus

“Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease” (2018) Neurology

Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease
(2018) Neurology, 90 (13), pp. e1134-e1144. Cited 1 time.

Fields, M.E.a , Guilliams, K.P.b c , Ragan, D.K.d , Binkley, M.M.f , Eldeniz, C.e , Chen, Y.d , Hulbert, M.L.a , McKinstry, R.C.e , Shimony, J.S.e , Vo, K.D.e , Doctor, A.c , An, H.e , Ford, A.L.d , Lee, J.-M.d e f

a Division of Pediatric Hematology/Oncology, United States
b Division of Pediatric Neurology, United States
c Division of Pediatric Critical Care Medicine, United States
d Department of Neurology, Washington University School of Medicine, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
f Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Objective To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen utilization (CMRO 2) in children with SCD. Methods Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO 2. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps. Results Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min, p < 0.001), OEF (42.7% vs 28.8%, p < 0.001), and CMRO 2 (3.7 vs 2.5 mL/100 g/min, p < 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO 2 in this region, which encompassed the CBF nadir, was low relative to all white matter (p < 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort. Conclusions Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus

“Alzheimer disease biomarkers and synucleinopathy” (2018) Neurology

Alzheimer disease biomarkers and synucleinopathy
(2018) Neurology, 90 (12), pp. 537-538. 

Bennett, D.A.a , Gordon, B.A.b

a Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
b Department of Radiology, Washington University Medical Center, St. Louis, MO, United States

Abstract
The vast majority of biomarker studies for Alzheimer disease (AD) and other neurodegenerative diseases such as Lewy body disease (LBD) are restricted to clinically diagnosed individuals, whether focused on CSF or PET. 1,2 However, data from clinical-pathologic studies find that mixed pathology, typically AD pathology plus another comorbid pathology, is the most common cause of dementia in older persons. 3 However, there are limited data examining the relation of antemortem AD biomarkers to mixed pathology because this is best accomplished by linking antemortem biomarker data with autopsies from the same persons. Such data exist for MRI 4 and PET 5 but not yet for CSF. In the current issue of Neurology®, Irwin et al. 6 examine the relation of CSF amyloid and tau to synucleinopathies with and without pathologic AD at autopsy conducted ≈5 years after CSF collection. © 2018 American Academy of Neurology.

Document Type: Review
Source: Scopus

“Personalizing acute therapies for ischemic stroke” (2018) Neurology

Personalizing acute therapies for ischemic stroke
(2018) Neurology, 90 (12), pp. 535-536. 

Lee, J.-M.a , Dziedzic, T.b

a Departments of Neurology Radiology, and Biomedical Engineering, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Jagiellonian University, Krakow, Poland

Abstract
The last 2 years has seen unprecedented advances in acute stroke care. In 2015, multiple independent clinical trials demonstrated that endovascular thrombectomy early after acute ischemic stroke (AIS) onset is highly effective for reducing long-term disability. 1-5 More recently, the DAWN trial demonstrated the efficacy of thrombectomy in select patients up to 24 hours after stroke onset. 6 Critical to the success of these trials has been the use of rapid and robust neuroimaging methods that helped select appropriate patients based on clot location or core/penumbral signatures. Neuroimaging has become the precision medicine equivalent in AIS, personalizing care based on advanced imaging measures. © 2018 American Academy of Neurology.

Document Type: Review
Source: Scopus

“Considering multiple methods for differentiating conceptually close constructs: Examples from the field of positive psychology” (2018) Social and Personality Psychology Compass

Considering multiple methods for differentiating conceptually close constructs: Examples from the field of positive psychology
(2018) Social and Personality Psychology Compass, . Article in Press. 

Hill, P.L.a , Allemand, M.b , Burrow, A.L.c

a Washington University in St. Louis, United States
b University of Zurich, Switzerland
c Cornell University, United States

Abstract
The field of positive psychology has sparked significant interest for researchers, in part given the apparent potential for individuals higher on “positive” dispositions to experience better health and well-being. However, as the field has grown, so too have the number of conceptually similar dispositions identified by researchers as important to study. As such, there is an increasing need for researchers to understand whether and how conceptually similar “positive” dispositions are actually unique, an issue that may not be unique to positive psychology but has worsened with the field’s prominence. The current manuscript provides a roadmap for one approach to differentiating conceptually close constructs in psychology, with examples couched within positive psychology. We will discuss the importance of combining quantitative and qualitative inquiries, as well as the adoption of techniques from multiple psychology disciplines, in order to better distinguish characteristics frequently studied in positive psychology. © 2018 John Wiley & Sons Ltd

Document Type: Article in Press
Source: Scopus

“Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls” (2018) Psychological Medicine

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls
(2018) Psychological Medicine, . Article in Press. 

Pettersson, E.a , Lichtenstein, P.a , Larsson, H.a b , Song, J.a , Agrawal, A.c , Børglum, A.D.d e f , Bulik, C.M.a g , Daly, M.J.h i j , Davis, L.K.k , Demontis, D.d e f , Edenberg, H.J.l m , Grove, J.d e f n , Gelernter, J.o p q , Neale, B.M.h i j , Pardiñas, A.F.r , Stahl, E.s , Walters, J.T.R.t , Walters, R.h j , Sullivan, P.F.a t , Posthuma, D.u v , Polderman, T.J.C.u

a Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
b School of Medical Sciences, Örebro University, Örebro, Sweden
c Department of Psychiatry, Washington University in Saint Louis, School of Medicine, Saint Louis, MO, United States
d Department of Biomedicine, Aarhus University, Aarhus, Denmark
e IPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
f ISEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
g University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
h Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
i Program in Medical and Population Genetics, Broad Institute of Harvard, MIT, Cambridge, MA, United States
j Stanley Center for Psychiatric Research, Broad Institute of Harvard, MIT, Cambridge, MA, United States
k Department of Medicine, Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
l Indiana University, School of Medicine, Biochemistry and Molecular Biology, Indianapolis, IN, United States
m Indiana University, School of Medicine, Medical and Molecular Genetics, Indianapolis, IN, United States
n BiRC-Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
o Yale University, School of Medicine, Genetics and Neurobiology, New Haven, CT, United States
p US Department of Veterans Affairs, Psychiatry, West Haven, CT, United States
q Yale University, School of Medicine, Psychiatry, New Haven, CT, United States
r Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
s Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
t Department of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
u Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands
v Department of Clinical Genetics, VU University Medical Center (VUMC), Amsterdam, Netherlands

Abstract
BackgroundMost studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.MethodsWe assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.ResultsHeritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.ConclusionsGiven the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research. © Cambridge University Press 2018.

Author Keywords
ADHD;  alcohol dependence;  anorexia nervosa;  autism spectrum disorders;  bipolar disorder;  genes;  heritability;  major depressive disorder;  obsessive compulsive disorder;  schizophrenia

Document Type: Article in Press
Source: Scopus

“Social Adversity and Cognitive, Language, and Motor Development of Very Preterm Children from 2 to 5 Years of Age” (2018) Journal of Pediatrics

Social Adversity and Cognitive, Language, and Motor Development of Very Preterm Children from 2 to 5 Years of Age
(2018) Journal of Pediatrics, . Article in Press. 

Lean, R.E.a , Paul, R.A.b , Smyser, T.A.a , Smyser, C.D.c d e , Rogers, C.E.a e

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To assess the extent to which social and family factors explain variability in cognitive, language, and motor development among very preterm (<30 weeks of gestation) children from 2 to 5 years of age. Study design: As part of a longitudinal study, very preterm children recruited as neonates were assessed at 2 (n = 87) and 5 (n = 83) years of age using standardized tests of cognitive, language, and motor ability alongside demographically matched full term (FT) children (n = 63). For very preterm children, developmental change scores were calculated for each domain to assess within-individual variability to 5 years of age. Multivariate regression and mixed-effect models examined social risk index, parenting stress, family functioning, and maternal intellectual ability as predictors of developmental variation among very preterm children. Results: Very preterm children demonstrated poorer cognitive, language, and motor abilities than FT children at 2 (P ≤.001) and 5 (P <.002) years of age. Social adversity was associated with cognitive (P <.001) and language (P <.001) outcomes at both ages, with parenting stress also related to cognitive outcomes (P =.03). Infant medical risk was associated with motor outcome at 5 years (P=.01). Very preterm children showed considerable within-individual variation between assessments. Among very preterm children, neonatal white matter abnormalities predicted worsening cognitive (P=.04) and motor development (P =.01). Social risk index predicted worsening language development (P =.04), but this association was subsequently explained by dysfunctional maternal affective involvement (P =.01) and lower maternal intellectual ability (P =.05). Conclusions: Both clinical and socioenvironmental factors are associated with cognitive, language, and motor developmental variation among very preterm children from infancy to early school age. © 2018 Elsevier Inc.

Author Keywords
cognition;  development;  follow-up;  language;  motor;  social adversity;  very preterm

Document Type: Article in Press
Source: Scopus

“Opioids in Adolescents’ Homes: Prevalence, Caregiver Attitudes, and Risk Reduction Opportunities” (2018) Academic Pediatrics

Opioids in Adolescents’ Homes: Prevalence, Caregiver Attitudes, and Risk Reduction Opportunities
(2018) Academic Pediatrics, . Article in Press. 

Garbutt, J.M.a b , Kulka, K.a , Dodd, S.a , Sterkel, R.a c , Plax, K.a

a Departments of Pediatrics, Washington University of St Louis, St Louis, Mo, United States
b Departments of Medicine, Washington University of St Louis, St Louis, Mo, United States
c St Louis Children’s Hospital, St Louis, Mo, United States

Abstract
Objective: The most common source of misused opioids is pain relievers prescribed for family and friends. This study was conducted to assess knowledge, attitudes, and behaviors of adolescents’ caregivers regarding prescribed opioids in the home. Methods: The self-administered survey was completed by caregivers in the waiting rooms of 12 pediatric practices in the Midwest. Eligibility required living in a home where youth age ≥10 years were frequently present. Out of 793 eligible caregivers, 700 (88.3%) completed the survey, 76.8% of whom were the parent. Results: Among the 700 caregiver respondents, 34.6% reported opioids in the home (13.6% active prescriptions, 12.7% leftover medications, 8.3% both). Of those with an active prescription, 66.0% intended to keep any leftover medications for future needs (for the patient, 60.1%; for someone else, 5.9%). Of those with leftover medications, 60.5% retained them for the same reason (for the patient, 51.0%; for someone else, 9.5%). Others kept medications unintentionally, either because they never got around to disposing of them (30.6%), they did not know how to dispose of them properly (15.7%), or it never occurred to them to dispose of the medications (7.5%). Many caregivers were unaware that adolescents commonly misuse opioids (30.0%) and use them to attempt suicide (52.3%), and that opioid use can lead to heroin addiction (38.6%). According to the surveys, 7.1% would give leftover opioid medications to an adolescent to manage pain and 5.9% might do so. Conclusions: Opioids are prevalent in homes in our community, and many parents are unaware of the risks they pose. Study findings can inform strategies to educate parents about opioid risk and encourage and facilitate timely, safe disposal of unused medications. © 2018 Academic Pediatric Association

Author Keywords
opioids;  pediatrics;  practice-based research network

Document Type: Article in Press
Source: Scopus

“American Geriatrics Society and National Institute on Aging Bench-to-Bedside Conference: Sensory Impairment and Cognitive Decline in Older Adults” (2018) Journal of the American Geriatrics Society

American Geriatrics Society and National Institute on Aging Bench-to-Bedside Conference: Sensory Impairment and Cognitive Decline in Older Adults
(2018) Journal of the American Geriatrics Society, . Article in Press. Cited 1 time.

Whitson, H.E.a b , Cronin-Golomb, A.c , Cruickshanks, K.J.d , Gilmore, G.C.e , Owsley, C.f , Peelle, J.E.g , Recanzone, G.h , Sharma, A.i , Swenor, B.j , Yaffe, K.k , Lin, F.R.j

a School of Medicine, Duke University, Durham, NC, United States
b Geriatrics Research, Education, and Clinical Center, Durham Veterans Affairs, Durham, NC, United States
c Boston University, Boston, MA, United States
d School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
e Case Western Reserve University, Cleveland, OH, United States
f University of Alabama at Birmingham, Birmingham, AL, United States
g Washington University in St. Louis, St. Louis, MO, United States
h University of California, Davis, Davis, CA, United States
i University of Colorado at Boulder, Boulder, CO, United States
j Johns Hopkins University, Baltimore, MD, United States
k University of California, San Francisco, San Francisco, CA, United States

Abstract
This article summarizes the presentations and recommendations of the tenth annual American Geriatrics Society and National Institute on Aging Bench-to-Bedside research conference, “Sensory Impairment and Cognitive Decline,” on October 2–3, 2017, in Bethesda, Maryland. The risk of impairment in hearing, vision, and other senses increases with age, and almost 15% of individuals aged 70 and older have dementia. As the number of older adults increases, sensory and cognitive impairments will affect a growing proportion of the population. To limit its scope, this conference focused on sensory impairments affecting vision and hearing. Comorbid vision, hearing, and cognitive impairments in older adults are more common than would be expected by chance alone, suggesting that some common mechanisms might affect these neurological systems. This workshop explored the mechanisms and consequences of comorbid vision, hearing, and cognitive impairment in older adults; effects of sensory loss on the aging brain; and bench-to-bedside innovations and research opportunities. Presenters and participants identified many research gaps and questions; the top priorities fell into 3 themes: mechanisms, measurement, and interventions. The workshop delineated specific research questions that provide opportunities to improve outcomes in this growing population. © 2018, Copyright the Author Journal compilation © 2018, The American Geriatrics Society

Author Keywords
cognition;  comorbidity;  dementia;  hearing;  vision

Document Type: Article in Press
Source: Scopus

“Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions” (2018) Alzheimer Disease and Associated Disorders

Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions
(2018) Alzheimer Disease and Associated Disorders, . Article in Press. 

Day, G.S.a , Musiek, E.S.b , Morris, J.C.a

a Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, Saint Louis, MO 63108, United States
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Published approaches to the evaluation and management of patients with rapidly progressive dementia (RPD) have been largely informed by experience at academic hospitals and national centers specializing in the diagnosis of Creutzfeldt-Jakob disease. Whether these approaches can be applied to patients assessed within lower-Acuity outpatient settings is unknown. Methods: A total of 96 patients with suspected RPD were assessed within the Washington University School of Medicine (Saint Louis, MO) outpatient memory clinic from February 2006 to February 2016. Consensus etiologic diagnoses were established following independent review of clinical data by 2 dementia specialists. Results: In total, 67/90 (70%) patients manifested with faster-Than-expected cognitive decline leading to dementia within 2 years of symptom onset. Female sex (42/67, 63%), median patient age (68.3 y; range, 45.4 to 89.6), and years of education (12 y; range, 6 to 14) were consistent with clinic demographics. Atypical presentations of common neurodegenerative dementing illnesses accounted for 90% (60/67) of RPD cases. Older age predicted a higher odds of amnestic Alzheimer disease dementia (OR, 2.1 per decade; 95% CI, 1.1-3.8; P=0.02). Parkinsonism (OR, 6.9; 95% CI, 1.6-30.5; P=0.01) or cortical visual dysfunction (OR, 10.8; 95% CI, 1.7-69.4; P=0.01) predicted higher odds of another neurodegenerative cause of RPD, including sporadic Creutzfeldt-Jakob disease. Conclusions and Relevance: The clinical environment influences the prevalence of RPD causes. The clinical evaluation should be adapted to promote detection of common causes of RPD, specific to the practice setting. © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Creutzfeldt-Jakob disease;  Key Words:;  memory clinic;  neurodegenerative disease;  outpatient;  rapidly progressive dementia

Document Type: Article in Press
Source: Scopus

“Reward-related regions form a preferentially coupled system at rest” (2018) Human Brain Mapping

Reward-related regions form a preferentially coupled system at rest
(2018) Human Brain Mapping, . Article in Press. 

Huckins, J.F.a , Adeyemo, B.b , Miezin, F.M.b , Power, J.D.c , Gordon, E.M.d , Laumann, T.O.b , Heatherton, T.F.a , Petersen, S.E.b , Kelley, W.M.a

a Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, United States
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Psychiatry, Weill Cornell College of Medicine, New York, NY, United States
d VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States

Abstract
Neuroimaging studies have implicated a set of striatal and orbitofrontal cortex (OFC) regions that are commonly activated during reward processing tasks. Resting-state functional connectivity (RSFC) studies have demonstrated that the human brain is organized into several functional systems that show strong temporal coherence in the absence of goal-directed tasks. Here we use seed-based and graph-theory RSFC approaches to characterize the systems-level organization of putative reward regions of at rest. Peaks of connectivity from seed-based RSFC patterns for the nucleus accumbens (NAcc) and orbitofrontal cortex (OFC) were used to identify candidate reward regions which were merged with a previously used set of regions (Power et al., 2011). Graph-theory was then used to determine system-level membership for all regions. Several regions previously implicated in reward-processing (NAcc, lateral and medial OFC, and ventromedial prefrontal cortex) comprised a distinct, preferentially coupled system. This RSFC system is stable across a range of connectivity thresholds and shares strong overlap with meta-analyses of task-based reward studies. This reward system shares between-system connectivity with systems implicated in cognitive control and self-regulation, including the fronto-parietal, cingulo-opercular, and default systems. Differences may exist in the pathways through which control systems interact with reward system components. Whereas NAcc is functionally connected to cingulo-opercular and default systems, OFC regions show stronger connectivity with the fronto-parietal system. We propose that future work may be able to interrogate group or individual differences in connectivity profiles using the regions delineated in this work to explore potential relationships to appetitive behaviors, self-regulation failure, and addiction. © 2018 Wiley Periodicals, Inc.

Author Keywords
network;  nucleus accumbens;  orbitofrontal cortex;  resting-state fMRI;  reward;  self-regulation;  system

Document Type: Article in Press
Source: Scopus

“Sculpting the skull through neurosensory epithelial–mesenchymal signaling” (2018) Developmental Dynamics

Sculpting the skull through neurosensory epithelial–mesenchymal signaling
(2018) Developmental Dynamics, . Article in Press. 

Yang, L.M., Ornitz, D.M.

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The vertebrate skull is a complex structure housing the brain and specialized sensory organs, including the eye, the inner ear, and the olfactory system. The close association between bones of the skull and the sensory organs they encase has posed interesting developmental questions about how the tissues scale with one another. Mechanisms that regulate morphogenesis of the skull are hypothesized to originate in part from the encased neurosensory organs. Conversely, the developing skull is hypothesized to regulate the growth of neurosensory organs, through mechanical forces or molecular signaling. Here, we review studies of epithelial–mesenchymal interactions during inner ear and olfactory system development that may coordinate the growth of the two sensory organs with their surrounding bone. We highlight recent progress in the field and provide evidence that mechanical forces arising from bone growth may affect olfactory epithelium development. Developmental Dynamics 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Author Keywords
craniofacial;  inner ear;  olfactory epithelium;  otic capsule;  tissue-scaling;  turbinates

Document Type: Article in Press
Source: Scopus

“Standards for Neurologic Critical Care Units: A Statement for Healthcare Professionals from The Neurocritical Care Society” (2018) Neurocritical Care

Standards for Neurologic Critical Care Units: A Statement for Healthcare Professionals from The Neurocritical Care Society
(2018) Neurocritical Care, . Article in Press. 

Moheet, A.M.a , Livesay, S.L.b , Abdelhak, T.c , Bleck, T.P.b , Human, T.d , Karanjia, N.e , Lamer-Rosen, A.a , Medow, J.f , Nyquist, P.A.g , Rosengart, A.a , Smith, W.h , Torbey, M.T.i , Chang, C.W.J.j

a Cedars-Sinai Medical Center, Los Angeles, CA, United States
b Rush University, Chicago, IL, United States
c Spectrum Health, Grand Rapids, MI, United States
d Washington University, St. Louis, MO, United States
e University of California, San Diego, San Diego, CA, United States
f School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
g Johns Hopkins, Baltimore, MD, United States
h University of California, San Francisco, San Francisco, CA, United States
i The Ohio State University, Columbus, OH, United States
j The Queen’s Medical Center, University of Hawaii, Honolulu, HI, United States

Abstract
Neurocritical care is a distinct subspecialty focusing on the optimal management of acutely ill patients with life-threatening neurologic and neurosurgical disease or with life-threatening neurologic manifestations of systemic disease. Care by expert healthcare providers to optimize neurologic recovery is necessary. Given the lack of an organizational framework and criteria for the development and maintenance of neurological critical care units (NCCUs), this document is put forth by the Neurocritical Care Society (NCS). Recommended organizational structure, personnel and processes necessary to develop a successful neurocritical care program are outlined. Methods: Under the direction of NCS Executive Leadership, a multidisciplinary writing group of NCS members was formed. After an iterative process, a framework was proposed and approved by members of the writing group. A draft was then written, which was reviewed by the NCS Quality Committee and NCS Guidelines Committee, members at large, and posted for public comment. Feedback was formally collated, reviewed and incorporated into the final document which was subsequently approved by the NCS Board of Directors. © 2018, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

Author Keywords
Consensus;  Critical care;  Critical care unit;  Intensive care;  Intensive care unit;  Neurocritical care;  Neurocritical care unit;  Performance improvement;  Quality;  Quality improvement;  Quality indicator;  Standards

Document Type: Article in Press
Source: Scopus

“Individual differences in emotion regulation goals: Does personality predict the reasons why people regulate their emotions?” (2018) Journal of Personality

Individual differences in emotion regulation goals: Does personality predict the reasons why people regulate their emotions?
(2018) Journal of Personality, . Article in Press. 

Eldesouky, L., English, T.

Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: We investigated how the Big Five traits predict individual differences in five theoretically important emotion regulation goals that are commonly pursued—pro-hedonic, contra-hedonic, performance, pro-social, and impression management. Method: We conducted two studies: (a) a large survey study consisting of undergraduates (N = 394; 18–25 years; 69% female; 56% European American) and community adults (N = 302; 19–74 years; 50% female; 75% European American) who completed a newly developed global measure of individual differences in emotion regulation goals and (b) a 9-day daily diary study with community adults (N = 272; 23–85 years; 50% female; 84% European American) who completed daily reports of emotion regulation goals. In both studies, participants completed a measure of the Big Five. Results: Across global and daily measures, pro-hedonic goals and pro-social goals were positively associated with Agreeableness, performance goals were positively associated with Openness, and impression management goals were positively associated with Neuroticism. Globally, contra-hedonic goals were also negatively associated with Agreeableness and Conscientiousness. Conclusions: The Big Five systematically predict the emotion regulation goals people typically pursue. These findings have important implications for understanding why people engage in certain forms of regulatory behavior and why personality has consequences for well-being. © 2018 Wiley Periodicals, Inc.

Author Keywords
affect;  Big Five;  emotion regulation;  goals;  motivation

Document Type: Article in Press
Source: Scopus

“Anatomic characteristics of supraorbital and supratrochlear nerves relevant to their use in corneal neurotization” (2018) Eye (Basingstoke)

Anatomic characteristics of supraorbital and supratrochlear nerves relevant to their use in corneal neurotization
(2018) Eye (Basingstoke), . Article in Press. 

Domeshek, L.F.a , Hunter, D.A.a , Santosa, K.a , Couch, S.M.b , Ali, A.c , Borschel, G.H.d , Zuker, R.M.d , Snyder-Warwick, A.K.a

a Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
d Division of Plastic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Abstract
Background: Corneal denervation can lead to opacification and blindness. A new treatment technique, surgical corneal neurotization, transfers healthy donor nerve, (most commonly contralateral supratrochlear or supraorbital) to the affected limbus to prevent corneal destruction and improve healing potential of the cornea following insult. We examine gross and histomorphometric anatomy of the supratrochlear and supraorbital nerves relevant to their use in corneal neurotization. Methods: For each of nine adult cadaver heads, bilateral supraorbital and supratrochlear nerves were dissected from the supraorbital rim to the anterior hairline. The following data were recorded for each nerve: exit from the orbit through a notch versus foramen; horizontal distance from midline at the supraorbital rim; and distance from orbital exit to first branching point. Samples of all left supraorbital and supratrochlear nerves were obtained at the level of the supraorbital rim and at points 3 cm and 6 cm distally for histomorphometric analysis. Myelinated axon counts were determined for each sample. Results: Four supraorbital foramina, 14 supraorbital notches, two supratrochlear foramina, and 15 supratrochlear notches were identified. Average supraorbital and supratrochlear distances to midline were 26.5 mm and 21 mm respectively. Average myelinated axon counts for both nerves were greater at the orbital rim (supraorbital: 6018, supratrochlear: 2533) than at 6 cm distally (supraorbital: 1621, supratrochlear: 1112). Conclusions: Anatomic dissection shows relative close approximation of the supraorbital and supratrochlear nerves, with a high proportion of both nerves exiting the orbit through foramina. The supraorbital nerve at the orbital rim contains the greatest number of myelinated axons. © 2018, The Royal College of Ophthalmologists.

Document Type: Article in Press
Source: Scopus

“Procedural Framework to Facilitate Hospital-Based Informed Consent for Dementia Research” (2018) Journal of the American Geriatrics Society

Procedural Framework to Facilitate Hospital-Based Informed Consent for Dementia Research
(2018) Journal of the American Geriatrics Society, . Article in Press. 

Holden, T.R.a b , Keller, S.a , Kim, A.a , Gehring, M.a , Schmitz, E.a , Hermann, C.a , Gilmore-Bykovskyi, A.a c , Kind, A.J.H.a d

a Geriatrics Division, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
b Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
c School of Nursing, University of Wisconsin, Madison, WI, United States
d Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, William S. Middleton Hospital, Madison, WI, United States

Abstract
Improving quality and delivery of care for people with Alzheimer disease and related dementias (ADRD) requires a comprehensive research agenda that encompasses the entire care continuum. Logistical and ethical challenges of informed consent for research participation of persons with ADRD include determination of capacity to consent, surrogate consent when capacity to consent is compromised, timely identification of the legally authorized representative (LAR) providing surrogate consent, and balancing residual autonomy with surrogate consent. Short stays; limited access to patients, caregivers, and LARs; and fluctuating influences of acute illness on capacity determination compound these challenges in the acute care setting. To address these challenges, we worked with the University of Wisconsin Health Sciences Institutional Review Board to develop a procedural framework for obtaining informed consent from hospitalized individuals with ADRD and their caregivers to participate in a minimal risk care intervention. The framework is specially designed for minimal risk situations in which rapid enrollment is a necessity and uses rapid identification of surrogates to consent for patients who lack legal capacity to make medical decisions, indicated by an activated healthcare power of attorney, and individualized formal assent procedures for patients who lack capacity to consent. These methods were proven effective in facilitating hospital-based recruitment in an ongoing randomized controlled trial and provide a basis for increasing access to acute care clinical research for persons with ADRD. Bolstering research participation through more easily used consent procedures during acute illness is critical to fostering improvements in the delivery of high-quality care to persons with ADRD. © 2018, Copyright the Author Journal compilation © 2018, The American Geriatrics Society

Author Keywords
Alzheimer’s disease;  dementia;  ethics;  informed consent;  research

Document Type: Article in Press
Source: Scopus

“Internal carotid artery dissection causing pulsatile tinnitus” (2018) American Journal of Otolaryngology – Head and Neck Medicine and Surgery

Internal carotid artery dissection causing pulsatile tinnitus
(2018) American Journal of Otolaryngology – Head and Neck Medicine and Surgery, . Article in Press. 

Chen, S.Y.a , Zipfel, G.J.b c , Wick, C.C.a

a Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Author Keywords
Carotid artery dissection;  Pulsatile tinnitus

Document Type: Article in Press
Source: Scopus

“Association between Patient Cognitive and Functional Status and Medicare Total Annual Cost of Care: Implications for Value-Based Payment” (2018) JAMA Internal Medicine

Association between Patient Cognitive and Functional Status and Medicare Total Annual Cost of Care: Implications for Value-Based Payment
(2018) JAMA Internal Medicine, . Article in Press. Cited 1 time.

Johnston, K.J.a , Wen, H.b , Hockenberry, J.M.c , Joynt Maddox, K.E.d

a Department of Health Management and Policy, Center for Outcomes Research, College for Public Health and Social Justice, St Louis University, St Louis, MO, United States
b Department of Health Management and Policy, University of Kentucky, Lexington, United States
c Department of Health Policy and Management, Rollins School of Public Health, Emory University, Atlanta, GA, United States
d Cardiovascular Division, Washington University, School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Medicare is moving toward value-based payment. The Merit-Based Incentive Payment System (MIPS) program judges outpatient clinicians’ performance on a measure of annual Medicare spending. However, this measure may disadvantage outpatient clinicians who care for vulnerable populations because the algorithm omits meaningful determinants of cost. Objectives: To determine whether factors not included in Medicare risk adjustment, including patient neuropsychological and functional status, as well as local area health resources and economic conditions, are associated with Medicare total annual cost of care (TACC), and evaluate whether accounting for these factors is associated with improved TACC performance by outpatient safety-net clinicians. Design, Setting, and Participants: In this retrospective observational study, we used the Medicare Current Beneficiary Survey (MCBS) to examine patient-reported neuropsychological and functional status and the Area Health Resources File to obtain information on local area characteristics. Included were Medicare beneficiaries with annual physician or clinic visits to outpatient safety-net (federally qualified health centers and rural health clinics) and non-safety-net clinics, contributing 76927 person-years of data to the MCBS from 2006 through 2013. We used patient-level multivariable regression models to estimate the association between each factor and annual Medicare spending, and compared outpatient safety-net performance under current risk adjustment and after adding additional adjustment for these factors. Main Outcomes and Measures: Medicare TACC, measured as the total annual reimbursed amount per patient for Medicare Part A and Part B services, in all categories. Results: Our study included 111414 unique identifiable physicians, and the final weighted sample included 213904324 patient-years (unweighted, 76927 patient-years) from 30058 unique patients, of whom 17478 (58.1%) were women. The mean (SD) patient age was 71.84 (12.48) years. The mean TACC was $9117. Those with higher than mean TACC included beneficiaries with depression ($14436), dementia ($18311), and difficulty with 3 or more activities of daily living (ADLs, $19113) or instrumental ADLs ($17443). After adjusting for comorbidities, depression and dementia were still associated with $2740 (95% CI, $2200-$2739) and $2922 (95% CI, $2399-$3445) higher TACC, respectively. Difficulty with 3 or more ADLs ($3121 higher; 95% CI, $2633-$3609) or instrumental ADLs ($895 higher; 95% CI, $452-$1337) was also associated with higher TACC. Adding these neuropsychological and functional factors, as well as local residence area factors, to risk adjustment calculations reduced outpatient safety-net clinicians’ underperformance on Medicare TACC relative to non-safety-net clinicians by 52% (from 0.098 to 0.047 difference in the observed to expected ratio). Conclusions and Relevance: Neuropsychological and functional impairment are common in Medicare beneficiaries and are associated with increased annual Medicare spending. Failure to account for these factors may inappropriately penalize outpatient clinicians who care for these vulnerable groups, such as safety-net clinicians, for factors that are arguably beyond their control. ©2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus

“Event memory uniquely predicts memory for large-scale space” (2018) Memory and Cognition

Event memory uniquely predicts memory for large-scale space
(2018) Memory and Cognition, . Article in Press. 

Sargent, J.Q.a b , Zacks, J.M.a , Hambrick, D.Z.c , Lin, N.a

a Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology, Francis Marion University, 4822 E. Palmetto St, Florence, SC 29502, United States
c Michigan State University, East Lansing, MI, United States

Abstract
When a person explores a new environment, they begin to construct a spatial representation of it. Doing so is important for navigating and remaining oriented. How does one’s ability to learn a new environment relate to one’s ability to remember experiences in that environment? Here, 208 adults experienced a first-person videotaped route, and then completed a spatial map construction task. They also took tests of general cognitive abilities (working memory, laboratory episodic memory, processing speed, general knowledge) and of memory for familiar, everyday activities (event memory). Regression analyses revealed that event memory (memory for everyday events and their temporal structure), laboratory episodic memory (memory for words and pictures) and gender were unique predictors of spatial memory. These results implicate the processing of temporal structure and organization as an important cognitive ability in large-scale spatial-memory-from-route experience. Accounting for the temporal structure of people’s experience while learning the layout of novel spaces may improve interventions for addressing navigation problems. © 2018, Psychonomic Society, Inc.

Author Keywords
Individual differences;  Memory;  Spatial cognition

Document Type: Article in Press
Source: Scopus

“The influence of everyday events on prospective timing ‘in the moment'” (2018) Psychonomic Bulletin and Review

The influence of everyday events on prospective timing “in the moment”
(2018) Psychonomic Bulletin and Review, . Article in Press. 

Bangert, A.S.a , Kurby, C.A.b , Zacks, J.M.c

a Department of Psychology, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX 79902, United States
b Department of Psychology, Grand Valley State University, Allendale, MI, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
We conducted two experiments to investigate how the eventfulness of everyday experiences influences people’s prospective timing ability. Specifically, we investigated whether events contained within movies of everyday activities serve as markers of time, as predicted by Event Segmentation Theory, or whether events pull attention away from the primary timing task, as predicted by the Attentional Gate theory. In the two experiments reported here, we asked participants to reproduce a previously learned 30-s target duration while watching a movie that contained eventful and uneventful intervals. In Experiment 2, reproduction also occurred during “blank movies” while watching a fixation. In both experiments, participants made shorter and more variable reproductions while simultaneously watching eventful as compared to uneventful movie intervals. Moreover, in Experiment 2, the longest reproductions were produced when participants had to watch the blank movies, which contained no events. These results support Event Segmentation Theory and demonstrate that the elapsing events during prospective temporal reproduction appear to serve as markers of temporal duration rather than distracting from the timing task. © 2018, Psychonomic Society, Inc.

Author Keywords
Attention;  Event cognition;  Event segmentation theory;  Time perception

Document Type: Article in Press
Source: Scopus

“Urban air quality and associations with pediatric multiple sclerosis” (2018) Annals of Clinical and Translational Neurology

Urban air quality and associations with pediatric multiple sclerosis
(2018) Annals of Clinical and Translational Neurology, . Article in Press. 

Lavery, A.M.a , Waubant, E.b , Casper, T.C.c , Roalstad, S.c , Candee, M.c , Rose, J.c , Belman, A.d , Weinstock-Guttman, B.e , Aaen, G.f , Tillema, J.-M.g , Rodriguez, M.g , Ness, J.h , Harris, Y.h , Graves, J.b , Krupp, L.i , Charvet, L.i , Benson, L.j , Gorman, M.j , Moodley, M.k , Rensel, M.k , Goyal, M.l , Mar, S.l , Chitnis, T.m , Schreiner, T.n , Lotze, T.o , Greenberg, B.p , Kahn, I.q , Rubin, J.r , Waldman, A.T.a

a Division of Child Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
b University of California San Francisco, San Francisco, United States
c University of Utah, Salt Lake City, UT, United States
d Stony Brook University, Stony Brook, NY, United States
e Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, United States
f Loma Linda University Children’s Hospital, Loma Linda, United States
g Mayo Clinic, Rochester, MN, United States
h University of Alabama, Tuscaloosa, AL, United States
i New York University Medical CenterNY, United States
j Boston Children’s Pediatric MS Center, Boston, MA, United States
k Cleveland Clinic, Cleveland, OH, United States
l Washington University in St. Louis, St. Louis, MO, United States
m Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
n Denver Children’s Hospital, Denver, CO, United States
o Texas Children’s Hospital, Houston, TX, United States
p University of Texas Southwestern Medical Center, Dallas, TX, United States
q Children’s National Medical Center, Washington, DC, United States
r Lurie Children’s Hospital, Chicago, IL, United States

Abstract
Background: We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. Methods: Pediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case–control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. Results: Fine particulate matter (PM2.5), carbon monoxide (CO), sulfur dioxide (SO2), and lead air emissions were associated with increased odds for pediatric MS (P &lt; 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls. Conclusion: Out of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO2, CO, and lead) were statistically associated with higher odds for pediatric MS. © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Document Type: Article in Press
Source: Scopus