“The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry” (2020) International Journal of Bipolar Disorders
The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry
(2020) International Journal of Bipolar Disorders, 8 (1), art. no. 13, .
McAllister-Williams, R.H.a b , Sousa, S.a b , Kumar, A.c , Greco, T.c , Bunker, M.T.c , Aaronson, S.T.d , Conway, C.R.e , Rush, A.J.f g h
a Northern Centre for Mood Disorders, Newcastle University, Newcastle upon Tyne, United Kingdom
b Regional Affective Disorders Service, Cumbria, Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
c LivaNova USA PLC, Houston, TX, United States
d Department of Clinical Research, Sheppard Pratt Health System, Baltimore, MD, United States
e Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Duke-National University of Singapore, Singapore, Singapore
g Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States
h Department of Psychiatry, Health Sciences Center, Texas Tech University Permian Basin, Midland, TX, United States
Abstract
Background: To compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone. Methods: Response was defined as ≥ 50% decrease from baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score at 3, 6, 9, or 12 months post-baseline. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan–Meier (KM) analysis and compared using log-rank test. Suicidality was assessed using the MADRS Item 10 score. Results: At baseline (entry into registry), the VNS + TAU group (N = 97) had more episodes of depression, psychiatric hospitalizations, lifetime suicide attempts and higher suicidality score, more severe symptoms (based on MADRS and other scales), and higher rate of prior electroconvulsive therapy than TAU group (N = 59). Lifetime use of medications was similar between the groups (a mean of 9) and was consistent with the severe treatment-resistant nature of their depression. Over 5 years, 63% (61/97) in VNS + TAU had an initial response compared with 39% (23/59) in TAU. The time-to-initial response was significantly quicker for VNS + TAU than for TAU (p < 0.03). Among responders in the first year after implant, the KM estimate of the median time-to-relapse from initial response was 15.2 vs 7.6 months for VNS + TAU compared with TAU (difference was not statistically significant). The mean reduction in suicidality score across the study visits was significantly greater in the VNS + TAU than in the TAU group (p < 0.001). Conclusions: The patients who received VNS + TAU included in this analysis had severe bipolar depression that had proved extremely difficult to treat. The TAU comparator group were similar though had slightly less severe illnesses on some measures and had less history of suicide attempts. Treatment with VNS + TAU was associated with a higher likelihood of attaining a response compared to TAU alone. VNS + TAU was also associated with a significantly greater mean reduction in suicidality. Limitations: In this registry study, participants were not randomized to the study treatment group, VNS Therapy stimulation parameters were not controlled, and there was a high attrition rate over 5 years. Trial registration ClinicalTrials.gov NCT00320372. Registered 3 May 2006, https://clinicaltrials.gov/ct2/show/NCT00320372 (retrospectively registered). © 2020, The Author(s).
Author Keywords
Bipolar disorder; Depression; Response; Suicidality; Treatment-resistant depression; Vagus Nerve Stimulation Therapy; VNS TRD registry
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth” (2020) Nature Communications
Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
(2020) Nature Communications, 11 (1), art. no. 2177, .
Guo, X.a , Pan, Y.a , Xiong, M.a , Sanapala, S.a , Anastasaki, C.a , Cobb, O.a , Dahiya, S.b , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting. © 2020, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Author Correction: Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone (Scientific Reports, (2020), 10, 1, (5617), 10.1038/s41598-020-62556-0)” (2020) Scientific Reports
Author Correction: Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone (Scientific Reports, (2020), 10, 1, (5617), 10.1038/s41598-020-62556-0)
(2020) Scientific Reports, 10 (1), art. no. 7680, .
Elman, I.a , Howard, M.b , Borodovsky, J.T.c , Mysels, D.d , Rott, D.e , Borsook, D.f , Albanese, M.g
a Center for Pain and the Brain, Department of Anesthesia, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States
b Rhode Island Department of Behavioral Healthcare, Cranston, RI, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Alpert Medical School of Brown University, Providence, RI, United States
e Department of Cardiology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel
f Center for Pain and the Brain, Department of Anesthesia, Critical Care and Pain Medicine, Boston Children’s Hospital, Massachusetts General Hospital and McLean Hospital, Harvard Medical School, Boston, MA, United States
g Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, United States
Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, The Author(s).
Document Type: Erratum
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Lessons learned from a pilot randomized controlled trial of dyadic interpersonal psychotherapy for perinatal depression in a low-income population” (2020) Journal of Affective Disorders
Lessons learned from a pilot randomized controlled trial of dyadic interpersonal psychotherapy for perinatal depression in a low-income population
(2020) Journal of Affective Disorders, 271, pp. 286-292.
Lenze, S.N., Potts, M.A., Rodgers, J., Luby, J.
Department of Psychiatry, Washington University School of Medicine, Campus Box 8504, 660 S Euclid, St. Louis MO 63110, United States
Abstract
Background: Perinatal depression is a public health burden impacting mothers and their offspring. This study extended brief-Interpersonal Psychotherapy delivered during pregnancy by incorporating a postpartum attachment based dyadic-component to maintain mother’s treatment gains and enhance the mother-infant relationship (called IPT-Dyad). The current report presents data from a pilot randomized controlled trial comparing IPT-Dyad to Enhanced Treatment as Usual (ETAU). Methods: Women, ages 18 and older, between 12–30 weeks gestation meeting criteria for a depressive disorder were eligible. Participants were randomized to either IPT-Dyad (n = 21) or ETAU (n = 21). Maternal and infant outcomes were assessed through one-year postpartum. Results: Participants were primarily African American (77%), single (80%), with low-incomes. Attrition was high in both groups (IPT-Dyad 30%; ETAU 40%). Depression scores improved from baseline in both groups and remained improved over the 12 month follow-up. There were no between group differences on measures of parenting stress, mother-infant interactions, and infant socioemotional functioning. Limitations: The small sample size of this study was further reduced by attrition, despite efforts to maintain engagement. Reliance on self-report outcome measures is also a limitation. Conclusions: IPT-Dyad may be a promising intervention for perinatal depression with potential benefit for mothers and babies. Treatment engagement and management of psychosocial needs were persistent challenges throughout the postpartum period. Further refinement of intervention content and schedule to better meet the needs and values of under-resourced mothers is needed. Earlier screening; better integration of care within OB settings; and delivering care in conjunction with social service resources may also improve outcomes. © 2020 Elsevier B.V.
Author Keywords
Infants; Interpersonal psychotherapy; Parenting; Perinatal depression
Document Type: Article
Publication Stage: Final
Source: Scopus
“Purpose-guided trial design in health-related behavioral intervention research” (2020) Health Psychology: Official Journal of the Division of Health Psychology, American Psychological Association
Purpose-guided trial design in health-related behavioral intervention research
(2020) Health Psychology: Official Journal of the Division of Health Psychology, American Psychological Association, 39 (6), pp. 539-548.
Freedland, K.E.
Washington University School of Medicine in St. Louis
Abstract
Purpose-guided trial design (PGTD) is a novel heuristic framework for planning randomized controlled trials of health-related behavioral interventions. Its use helps to ensure that the study design and the control or comparison group are compatible with the primary purpose of the trial. When used in conjunction with the recently developed pragmatic model for comparator selection in health-related behavioral trials (Freedland et al., 2019), the PGTD framework can help to resolve uncertainties, disagreements, and controversies about the comparators that are used in behavioral randomized controlled trials. For example, PGTD can help to answer questions about whether, when, and how to control for attention in behavioral trials. The PGTD framework can be used to evaluate published trials, but it is primarily intended for use as a behavioral trial planning tool. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
“Insufficient Evidence for ‘Autism-Specific’ Genes” (2020) American Journal of Human Genetics
Insufficient Evidence for “Autism-Specific” Genes
(2020) American Journal of Human Genetics, 106 (5), pp. 587-595.
Myers, S.M.a , Challman, T.D.a , Bernier, R.b , Bourgeron, T.c , Chung, W.K.d e , Constantino, J.N.f g , Eichler, E.E.h , Jacquemont, S.i , Miller, D.T.j , Mitchell, K.J.k l , Zoghbi, H.Y.m n o p q , Martin, C.L.a , Ledbetter, D.H.a
a Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, United States
b Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, United States
c Human Genetics and Cognitive Functions Unit, Institut Pasteur, Université de Paris, UMR 3571 CNRS, Paris, 75015, France
d Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, United States
e Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States
f Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St LouisMO 63120, United States
g Department of Pediatrics, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St LouisMO 63120, United States
h Department of Genome Sciences, University of Washington School of Medicine and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, United States
i Sainte Justine Hospital Research Center, Department of Pediatrics, University of Montreal, Montreal, Quebec , H4A3J1, Canada
j Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
k Smurfit Institute of Genetics, Trinity College Dublin, Dublin, D02PN40, Ireland
l Institute of Neuroscience, Trinity College Dublin, Dublin, D02PN40, Ireland
m Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, United States
n Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
o Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
p Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
q Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, United States
Abstract
Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively “autism-specific” genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data. © 2020 The Author(s)
Author Keywords
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Age Differences in the Effects of Speaking Rate on Auditory, Visual, and Auditory-Visual Speech Perception” (2020) Ear and Hearing
Age Differences in the Effects of Speaking Rate on Auditory, Visual, and Auditory-Visual Speech Perception
(2020) Ear and Hearing, 41 (3), pp. 549-560.
Sommers, M.S.a , Spehar, B.b , Tye-Murray, N.b , Myerson, J.a , Hale, S.a
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Central Institute for the Deaf at Washington University School of Medicine, St. Louis, MO, United States
Abstract
OBJECTIVES: This study was designed to examine how speaking rate affects auditory-only, visual-only, and auditory-visual speech perception across the adult lifespan. In addition, the study examined the extent to which unimodal (auditory-only and visual-only) performance predicts auditory-visual performance across a range of speaking rates. The authors hypothesized significant Age × Rate interactions in all three modalities and that unimodal performance would account for a majority of the variance in auditory-visual speech perception for speaking rates that are both slower and faster than normal. DESIGN: Participants (N = 145), ranging in age from 22 to 92, were tested in conditions with auditory-only, visual-only, and auditory-visual presentations using a closed-set speech perception test. Five different speaking rates were presented in each modality: an unmodified (normal rate), two rates that were slower than normal, and two rates that were faster than normal. Signal to noise ratios were set individually to produce approximately 30% correct identification in the auditory-only condition and this signal to noise ratio was used in the auditory-only and auditory-visual conditions. RESULTS: Age × Rate interactions were observed for the fastest speaking rates in both the visual-only and auditory-visual conditions. Unimodal performance accounted for at least 60% of the variance in auditory-visual performance for all five speaking rates. CONCLUSIONS: The findings demonstrate that the disproportionate difficulty that older adults have with rapid speech for auditory-only presentations can also be observed with visual-only and auditory-visual presentations. Taken together, the present analyses of age and individual differences indicate a generalized age-related decline in the ability to understand speech produced at fast speaking rates. The finding that auditory-visual speech performance was almost entirely predicted by unimodal performance across all five speaking rates has important clinical implications for auditory-visual speech perception and the ability of older adults to use visual speech information to compensate for age-related hearing loss.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Update in Soft-Tissue Filler-Associated Blindness” (2020) Dermatologic surgery : official publication for American Society for Dermatologic Surgery
Update in Soft-Tissue Filler-Associated Blindness
(2020) Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 46 (5), pp. 671-677.
Sorensen, E.P.a , Council, M.L.b
a *Both authors are affiliated with the Division of Dermatology, Washington University in St. Louis, Saint Louis, Missouri
b Both authors are affiliated with the Division of Dermatology, Washington University in St. Louis, Saint Louis, Missouri
Abstract
BACKGROUND: Soft-tissue filler administration is an increasingly popular minimally invasive cosmetic procedure. Simultaneously, there have been a greater number of adverse events reported, including the devastating complication of blindness. OBJECTIVE: To report cases of filler-related blindness published since 2015. MATERIALS AND METHODS: The Ovid MEDLINE database was searched from January 1, 2015, to August 1, 2018, using a previously described Boolean string. RESULTS: Sixty new cases of filler blindness were identified. The most common type of filler reported was hyaluronic acid (HA) (N = 42, 70.0%), followed by autologous fat (N = 7, 11.7%), and calcium hydroxyapatite (CaHA) (N = 7, 11.7%). The most common injection locations were the nose (N = 33, 55.0%), glabella (N = 21, 35.0%), and forehead (N = 11, 18.3%). Ten cases reported vision restoration (16.7%). Four of the successful cases involved hyaluronidase administration, including 1 retrobulbar hyaluronidase injection. CONCLUSION: Since 2015, there have been 60 newly reported cases of soft-tissue filler blindness. Most recent cases have occurred with HA, which is a shift from previous reports. In HA cases, hyaluronidase injection may be successful in restoring vision if administered promptly. It is imperative for providers to be familiar with strategies for managing soft-tissue filler blindness.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Brain Volume: An Important Determinant of Functional Outcome After Acute Ischemic Stroke” (2020) Mayo Clinic Proceedings
Brain Volume: An Important Determinant of Functional Outcome After Acute Ischemic Stroke
(2020) Mayo Clinic Proceedings, 95 (5), pp. 955-965.
Schirmer, M.D.a c d , Donahue, K.L.a , Nardin, M.J.a , Dalca, A.V.c e , Giese, A.-K.a , Etherton, M.R.a , Mocking, S.J.T.e , McIntosh, E.C.e , Cole, J.W.f h , Holmegaard, L.i , Jood, K.i , Jimenez-Conde, J.k , Kittner, S.J.f h , Lemmens, R.l , Meschia, J.F.m , Rosand, J.a b e , Roquer, J.k , Rundek, T.n , Sacco, R.L.n , Schmidt, R.o , Sharma, P.p , Slowik, A.q , Stanne, T.M.i , Vagal, A.r , Wasselius, J.t v , Woo, D.s , Bevan, S.w , Heitsch, L.x , Phuah, C.-L.y z , Strbian, D.aa , Tatlisumak, T.j ab , Levi, C.R.ac ad , Attia, J.ac ae , McArdle, P.F.g , Worrall, B.B.af , Wu, O.e , Jern, C.i , Lindgren, A.u ag , Maguire, J.ah , Thijs, V.ai , Rost, N.S.a , MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortiumaj
a Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts General Hospital, Boston, United States
b Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
c Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Boston, United States
d Department of Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
e Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown
f Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
g Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
h Veterans Affairs Maryland Health Care System, Baltimore, MD, United States
i Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
j Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
k Department of Neurology, Neurovascular Research Group, Institut Hospital del Mar d’Investigacions Mèdiques, Universitat Autonoma de Barcelona, Barcelona, Spain
l Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, KU Leuven–University of Leuven, Flemish Institute for Biotechnology, Vesalius Research Center, Laboratory of Neurobiology, and Department of Neurology, University Hospitals Leuven, Leuven, Belgium
m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
n Department of Neurology and Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
o Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
p Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL), Egham, UK, and St Peter’s and Ashford Hospitals Foundation Trust, Chertsey, United Kingdom
q Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
r Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
s Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
t Department of Clinical Sciences, Radiology, Lund University, Lund, Sweden
u Department of Neurology, Lund University, Lund, Sweden
v Department of Radiology, Division of Neuroradiology, Skåne University Hospital, Malmö, Sweden
w School of Life Sciences, University of Lincoln, Lincoln, United Kingdom
x Division of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
y Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
z Barnes-Jewish Hospital, St Louis, MO, United States
aa Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
ab Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
ac School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
ad Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia
ae Hunter Medical Research Institute, Newcastle, New South Wales, Australia
af Department of Neurology and Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
ag Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
ah University of Technology Sydney, Sydney, Australia
ai Stroke Division, Florey Institute of Neuroscience and Mental Health and Department of Neurology, Austin Health, Heidelberg, Australia
Abstract
Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). Patients and Methods: This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. Results: Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (β −0.3 [per 14.4 years]), male sex (β 1.0), and prior stroke (β −0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (β −0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. Conclusion: Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery. © 2020
Document Type: Conference Paper
Publication Stage: Final
Source: Scopus
“Executive function in phenylketonuria (PKU): Insights from the Behavior Rating Inventory of Executive Function (BRIEF) and a large sample of individuals with PKU” (2020) Neuropsychology
Executive function in phenylketonuria (PKU): Insights from the Behavior Rating Inventory of Executive Function (BRIEF) and a large sample of individuals with PKU
(2020) Neuropsychology, 34 (4), pp. 456-466.
Christ, S.E.a , Clocksin, H.E.a , Burton, B.K.b , Grant, M.L.c , Waisbren, S.d , Paulin, M.-C.e , Bilder, D.A.f , White, D.A.g , Saville, C.a
a Department of Psychological Sciences, University of Missouri
b Division of Genetics, Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago
c Department of Psychiatry, Drexel University College of Medicine
d Division of Genetics and Genomics, Boston Children’s Hospital
e PKU Program for New Brunswick, Dr. Georges-L.-Dumont University Hospital Centre
f Department of Psychiatry, University of Utah
g Department of Psychology, Washington University in St. Louis
Abstract
OBJECTIVE: Previous research has documented executive function (EF) impairments in individuals with early treated phenylketonuria (ETPKU). It remains unclear, however, whether some aspects of EF may be more affected than others. A number of factors, including small sample sizes and variability in EF tasks, have likely contributed to past mixed findings. The present objective was to elucidate further the EF profile associated with ETPKU, particularly as it relates to report-based assessment of EF. METHOD: Data from 286 individuals (5-48 years of age) with ETPKU on the child and adult versions of the Behavior Rating Inventory of Executive Function (BRIEF), a well-established report-based assessment tool, were analyzed. RESULTS: The Working Memory scale showed the largest effect size in both young and older ETPKU samples, with 19% of children and 29% of adults scoring in the “abnormally elevated” range. In addition, EF impairment appeared more general (i.e., affecting more domains) in the adult sample as compared to the child sample. Exploratory analyses also suggested that the presence/absence of overall impairment on the BRIEF among our ETPKU participants could be predicted based on a small subset of items. A 10-item subset showed total classification accuracy values of 90% and above for both groups. CONCLUSIONS: Working memory represents an aspect of EF that appears to be particularly affected in individuals with ETPKU. Findings also provide preliminary support of the viability for the development and/or adoption of an abbreviated screening measure for EF difficulties in children and adults with ETPKU. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
“Maternal-Fetal Circadian Communication During Pregnancy” (2020) Frontiers in Endocrinology
Maternal-Fetal Circadian Communication During Pregnancy
(2020) Frontiers in Endocrinology, 11, art. no. 198, .
Bates, K., Herzog, E.D.
Department of Biology, Washington University, St. Louis, MO, United States
Abstract
This article reviews evidence for maternal-fetal communication about the time of day. We explore the hypothesis that key maternal hormones synchronize daily rhythms in the fetus to regulate gestation duration. These findings may help to predict and prevent preterm birth. © Copyright © 2020 Bates and Herzog.
Author Keywords
daily rhythm; dopamine; glucocorticoid; melatonin; parturition
Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Development of Network Topology and Functional Connectivity of the Prefrontal Cortex” (2020) Cerebral Cortex (New York, N.Y. : 1991)
Development of Network Topology and Functional Connectivity of the Prefrontal Cortex
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (4), pp. 2489-2505.
Lopez, K.C.a , Kandala, S.b , Marek, S.b , Barch, D.M.a b c
a Department of Psychological & Brain Sciences, Washington University, St Louis, 63130 MO, USA
b Department of Psychiatry, Washington University, St Louis, 63110 MO, USA
c Department of Radiology, Washington University, St Louis, 63110 MO, USA
Abstract
The prefrontal cortex (PFC) comprises distinct regions and networks that vary in their trajectories across development. Further understanding these diverging trajectories may elucidate the neural mechanisms by which distinct PFC regions contribute to cognitive maturity. In particular, it remains unclear whether PFC regions of distinct network affiliations differ in topology and their relationship to cognition. We examined 615 individuals (8-21 years) to characterize age-related effects in participation coefficient of 28 PFC regions of distinct networks, evaluating connectivity profiles of each region to understand patterns influencing topological maturity. Findings revealed that PFC regions of attention, frontoparietal, and default mode networks (DMN) displayed varying rates of decline in participation coefficient with age, characterized by stronger connectivity with each PFC’s respective network; suggesting that PFC regions largely aid network segregation. Conversely, PFC regions of the cinguloopercular/salience network increased in participation coefficient with age, marked by stronger between-network connections, suggesting that some PFC regions feature a distinctive ability to facilitate network integration. PFC topology of the DMN, in particular, predicted improvements in global cognition, including motor speed and higher order abilities. Together, these findings elucidate systematic differences in topology across PFC regions of different network affiliation, representing important neural signatures of typical brain development. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
graph theory; hubs; large-scale networks
Document Type: Article
Publication Stage: Final
Source: Scopus
“150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression” (2020) CNS Spectrums
150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression
(2020) CNS Spectrums, 25 (2), pp. 295-296.
Dunlop, B.W.a , Parikh, S.V.b , Patel, M.c , Rothschild, A.J.d , Thase, M.E.e , DeBattista, C.f , Conway, C.R.g , Forester, B.P.h , Shelton, R.C.i , Macaluso, M.j , Li, J.c , Brown, K.k , Brown, L.c , Jablonski, M.R.c , Greden, J.F.b
a Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, United States
b University of Michigan Comprehensive Depression Center and Department of Psychiatry, National Network of Depression Centers, MI, Ann Arbor, United States
c Assurex Health, Inc., Mason, OH
d University of Massachusetts Medical School and UMass Memorial Healthcare, MA, Worcester
e Perelman School of Medicine of the University of Pennsylvania and the Corporal Michael Crescenz VAMC, Philadelphia, United States
f Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Stanford, CA
g Washington University School of Medicine, Department of Psychiatry, and the John Cochran Veteran’s Administration Hospital, St. Louis, MO
h McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, MA, Belmont
i The University of Alabama at Birmingham, Department of Psychiatry and School of Medicine, Birmingham, AL
j University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences, Wichita, United States
k Myriad Genetics, Inc., UT, Salt Lake City, United States
Abstract
BACKGROUND: The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial. METHODS: Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7). RESULTS: At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003). CONCLUSIONS: Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms. FUNDING ACKNOWLEDGEMENTS: Assurex Health, Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“160 Lurasidone and Metabolic Syndrome: Results from Short- and Long-Term Clinical Studies in Patients with Bipolar Depression” (2020) CNS Spectrums
160 Lurasidone and Metabolic Syndrome: Results from Short- and Long-Term Clinical Studies in Patients with Bipolar Depression
(2020) CNS Spectrums, 25 (2), pp. 302-303.
Tocco, M.a , Newcomer, J.W.b , Mao, Y.a , Pikalov, A.a
a Sunovion Pharmaceuticals Inc., MA, Fort Lee, United States
b Thriving Mind South Florida, Miami, FL and Washington University School of Medicine, St. Louis, MO
Abstract
BACKGROUND: Among patients with depressive disorders, the prevalence of metabolic syndrome (MetS) is estimated to range from 35-40% and has been associated with increased mortality rates. The aim of this post-hoc analysis was to assess the effect of treatment with lurasidone on the prevalence of MetS in patients with bipolar depression. METHOD: Lurasidone data (dose range, 20-120 mg/d) used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (total N=1,192), consisting of 1 monotherapy, and 2 adjunctive therapy trials with lithium or valproate. Patients who completed the short-term trials continued into a 6-month open-label (OL) extension study, with 6-month (LOCF-endpoint) data available on 274 patients treated with lurasidone monotherapy, and 436 patients treated with lurasidone adjunctive therapy. Also analyzed was a recurrence prevention study in stabilized bipolar patients who completed up to 20 weeks of OL adjunctive treatment with lurasidone, and then were randomized to 28 weeks of DB adjunctive therapy with lurasidone or placebo (N=497). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: In the short-term monotherapy and adjunctive therapy studies, the proportion of patients at baseline meeting NCEP III criteria for MetS were 27.6% and 23.6%, respectively, for lurasidone, and 23.8% and 25.1%, respectively, for placebo; and at week 6 (LOCF) the proportion with MetS was 27.5% and 26.6%, respectively, for lurasidone and 29.9% and 20.2%, respectively, for placebo. The proportion of patients who did not meet MetS criteria at baseline but developed MetS at week 6 (LOCF) was similar for lurasidone vs. placebo in the monotherapy study (9.9% vs. 11.6%); and in the two adjunctive therapy studies (10.3% vs. 8.3%). During the 6-month OL extension study, the proportion of patients treated with lurasidone monotherapy and adjunctive therapy who did not meet MetS criteria at OL baseline but developed MetS at month 6 (LOCF) was 11.7% and 11.9%, respectively. Conversely, the proportion of patients who met MetS criteria at OL baseline, but no longer met criteria at month 6 (LOCF) was 9.5% and 7.7%, respectively. In the 20-week, OL phase of the recurrence prevention study, the proportion of patients treated with adjunctive lurasidone who did not meet MetS criteria at OL baseline but developed MetS at endpoint was 11.5% (LOCF). After up to 28 weeks of DB treatment, the proportion of patients who did not meet MetS criteria at DB baseline but developed MetS at endpoint was 9.0% in the adjunctive lurasidone group, and 10.5% in the adjunctive placebo group (LOCF). CONCLUSION: This post-hoc analysis found that short- and long-term treatment with lurasidone was associated with a relatively low risk for the development of metabolic syndrome in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia. FUNDING ACKNOWLEDGEMENTS: Supported by funding from Sunovion Pharmaceuticals Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Mechanisms of action of autophagy modulators dissected by quantitative systems pharmacology analysis” (2020) International Journal of Molecular Sciences
Mechanisms of action of autophagy modulators dissected by quantitative systems pharmacology analysis
(2020) International Journal of Molecular Sciences, 21 (8), art. no. 2855, .
Shi, Q.a b , Pei, F.a , Silverman, G.A.c , Pak, S.C.c , Perlmutter, D.H.c , Liu, B.a , Bahar, I.a
a Department of Computational and Systems Biology, School of Medicine, University of PittsburghPA 15213, United States
b School of Medicine, Tsinghua University, Beijing, 100084, China
c Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63130, United States
Abstract
Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1- antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-kB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Autophagy; Drug-target interactions; Machine learning; Mechanism of action; Mtor; Pi3k; Pka; Quantitative systems pharmacology; Signal transduction
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Beyond the Lost Smile – Exploring Individual-Specific Facets of Facial Paralysis” (2020) JAMA Otolaryngology – Head and Neck Surgery
Beyond the Lost Smile – Exploring Individual-Specific Facets of Facial Paralysis
(2020) JAMA Otolaryngology – Head and Neck Surgery, 146 (4), pp. 337-338.
Wamkpah, N.S.a , Chi, J.J.b
a Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis, St Louis, MO, United States
b Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis, St. Louis, MO, United States
Document Type: Note
Publication Stage: Final
Source: Scopus
“Association Between Preoperative Obstructive Sleep Apnea and Preoperative Positive Airway Pressure With Postoperative Intensive Care Unit Delirium” (2020) JAMA Network Open
Association Between Preoperative Obstructive Sleep Apnea and Preoperative Positive Airway Pressure With Postoperative Intensive Care Unit Delirium
(2020) JAMA Network Open, 3 (4), p. e203125.
King, C.R.a , Fritz, B.A.a , Escallier, K.b , Ju, Y.-E.S.c , Lin, N.d , McKinnon, S.a , Avidan, M.S.a , Palanca, B.J.a
a Department of Anesthesiology, Washington University in St Louis, St Louis, MO, United States
b Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Department of Mathematics and Statistics, Washington University in St Louis, St Louis, MO, United States
Abstract
Importance: Obstructive sleep apnea has been associated with postoperative delirium, which predisposes patients to major adverse outcomes. Positive airway pressure may be an effective intervention to reduce delirium in this population. Objectives: To determine if preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit and if preoperative positive airway pressure adherence modifies the association. Design, Setting, and Participants: A retrospective single-center cohort study was conducted at a US tertiary hospital from November 1, 2012, to August 31, 2016, among 7792 patients admitted to an intensive care unit who underwent routine Confusion Assessment Method for the intensive care unit after major surgery. Patients were adults who had undergone a complete preoperative anesthesia assessment, received general anesthesia, underwent at least 1 delirium assessment, were not delirious preoperatively, and had a preoperative intensive care unit stay of less than 6 days. Statistical analysis was conducted from August 20, 2019, to January 11, 2020. Exposures: Self-reported obstructive sleep apnea, billing diagnosis of obstructive sleep apnea, or STOP-BANG (Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender) questionnaire score greater than 4, as well as self-reported use of preoperative positive airway pressure. Main Outcomes and Measures: Delirium within 7 days of surgery. Results: A total of 7792 patients (4562 men; mean [SD] age, 59.2 [15.3] years) met inclusion criteria. Diagnosed or likely obstructive sleep apnea occurred in 2044 patients (26%), and delirium occurred in 3637 patients (47%). The proportion of patients with incident delirium was lower among those with obstructive sleep apnea than those without (897 of 2044 [44%] vs 2740 of 5748 [48%]; unadjusted risk difference, -0.04; 99% credible interval [CrI], -0.07 to -0.00). Positive airway pressure adherence had minimal association with delirium (risk difference, -0.00; 99% CrI, -0.09 to 0.09). Doubly robust confounder adjustment eliminated the association between obstructive sleep apnea and delirium (risk difference, -0.01; 99% CrI, -0.04 to 0.03) and did not change that of preoperative positive airway pressure adherence (risk difference, -0.00, 99% CrI, -0.07 to 0.07). The results were consistent across multiple sensitivity analyses. Conclusions and Relevance: After risk adjustment, this study found no association between obstructive sleep apnea and postoperative delirium in the context of usual care in the intensive care unit, with 99% CrIs excluding clinically meaningful associations. With limited precision, no association was found between positive airway pressure adherence and delirium. Selection bias and measurement error limit the validity and generalizability of these observational associations; however, they suggest that interventions targeting sleep apnea and positive airway pressure are unlikely to have a meaningful association with postoperative intensive care unit delirium.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Pharmacokinetics and safety of VALTOCO (NRL-1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: A phase 1, open-label study” (2020) Epilepsia
Hogan, R.E.a , Tarquinio, D.b , Sperling, M.R.c , Klein, P.d , Miller, I.e , Segal, E.B.f , Rabinowicz, A.L.g , Carrazana, E.h
a Washington University in St Louis, St Louis, MO, United States
b Center for Rare Neurological Diseases, Atlanta, GA, United States
c Thomas Jefferson University, Philadelphia, PA, United States
d Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, United States
e Nicklaus Children’s Hospital, Miami, FL, United States
f Hackensack University Medical Center, Hackensack Meridian School of Medicine and Northeast Regional Epilepsy Group, Hackensack, NJ, United States
g Neurelis, San Diego, CA, United States
h Consultant for Neurelis, San Diego, CA, United States
Abstract
Objective: To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. Methods: A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. Results: Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%) had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain. Significance: The epileptic conditions (ictal/peri-ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics in patients with epilepsy. Therefore, diazepam nasal spray can be administered ictally and interictally. Diazepam nasal spray safety was consistent with the profile of diazepam. © 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
Author Keywords
diazepam; ictal; intranasal; pharmacokinetics; VALTOCO
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Comparison of automated and expert human grading of diabetic retinopathy using smartphone-based retinal photography” (2020) Eye (Basingstoke)
Comparison of automated and expert human grading of diabetic retinopathy using smartphone-based retinal photography
(2020) Eye (Basingstoke), .
Kim, T.N.a b , Aaberg, M.T.a , Li, P.a , Davila, J.R.a , Bhaskaranand, M.c , Bhat, S.c , Ramachandra, C.c , Solanki, K.c , Myers, F.d , Reber, C.d , Jalalizadeh, R.a , Margolis, T.P.e , Fletcher, D.d , Paulus, Y.M.a f
a Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States
b Department of Ophthalmology, University of California San Francisco, San Francisco, CA, United States
c Eyenuk Inc, Woodland Hills, CA, United States
d Department of Bioengineering, University of California Berkeley, Berkeley, CA, United States
e Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
Abstract
Purpose: The aim of this study is to investigate the efficacy of a mobile platform that combines smartphone-based retinal imaging with automated grading for determining the presence of referral-warranted diabetic retinopathy (RWDR). Methods: A smartphone-based camera (RetinaScope) was used by non-ophthalmic personnel to image the retina of patients with diabetes. Images were analyzed with the Eyenuk EyeArt® system, which generated referral recommendations based on presence of diabetic retinopathy (DR) and/or markers for clinically significant macular oedema. Images were independently evaluated by two masked readers and categorized as refer/no refer. The accuracies of the graders and automated interpretation were determined by comparing results to gold standard clinical diagnoses. Results: A total of 119 eyes from 69 patients were included. RWDR was present in 88 eyes (73.9%) and in 54 patients (78.3%). At the patient-level, automated interpretation had a sensitivity of 87.0% and specificity of 78.6%; grader 1 had a sensitivity of 96.3% and specificity of 42.9%; grader 2 had a sensitivity of 92.5% and specificity of 50.0%. At the eye-level, automated interpretation had a sensitivity of 77.8% and specificity of 71.5%; grader 1 had a sensitivity of 94.0% and specificity of 52.2%; grader 2 had a sensitivity of 89.5% and specificity of 66.9%. Discussion: Retinal photography with RetinaScope combined with automated interpretation by EyeArt achieved a lower sensitivity but higher specificity than trained expert graders. Feasibility testing was performed using non-ophthalmic personnel in a retina clinic with high disease burden. Additional studies are needed to assess efficacy of screening diabetic patients from general population. © 2020, The Author(s), under exclusive licence to The Royal College of Ophthalmologists.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Effects of Electrode Location on Estimates of Neural Health in Humans with Cochlear Implants” (2020) JARO – Journal of the Association for Research in Otolaryngology
Effects of Electrode Location on Estimates of Neural Health in Humans with Cochlear Implants
(2020) JARO – Journal of the Association for Research in Otolaryngology, .
Schvartz-Leyzac, K.C.a b c , Holden, T.A.d , Zwolan, T.A.b , Arts, H.A.b , Firszt, J.B.c , Buswinka, C.J.a , Pfingst, B.E.a
a Kresge Hearing Research Institute, Department of Otolaryngology, Michigan Medicine, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5616, United States
b Hearing Rehabilitation Center, Department of Otolaryngology, Michigan Medicine, 475 W. Market Place, Building 1, Suite A, Ann Arbor, MI 48108, United States
c Department of Otolaryngology, Medical University of South Carolina, 135 Rutledge Ave, MSC 550, Charleston, SC 29425, United States
d Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
There are a number of psychophysical and electrophysiological measures that are correlated with SGN density in animal models, and these same measures can be performed in humans with cochlear implants (CIs). Thus, these measures are potentially applicable in humans for estimating the condition of the neural population (so called “neural health” or “cochlear health”) at individual sites along the electrode array and possibly adjusting the stimulation strategy in the CI sound processor accordingly. Some measures used to estimate neural health in animals have included the electrically evoked compound potential (ECAP), psychophysical detection thresholds, and multipulse integration (MPI). With regard to ECAP measures, it has been shown that the change in the ECAP response as a function of increasing the stimulus interphase gap (“IPG Effect”) also reflects neural density in implanted animals. These animal studies have typically been conducted using preparations in which the electrode was in a fixed position with respect to the neural population, whereas in human cochlear implant users, the position of individual electrodes varies widely within an electrode array and also across subjects. The current study evaluated the effects of electrode location in the implanted cochlea (specifically medial-lateral location) on various electrophysiological and psychophysical measures in eleven human subjects. The results demonstrated that some measures of interest, specifically ECAP thresholds, psychophysical detection thresholds, and ECAP amplitude-growth function (AGF) linear slope, were significantly related to the distances between the electrode and mid-modiolar axis (MMA). These same measures were less strongly related or not significantly related to the electrode to medial wall (MW) distance. In contrast, neither the IPG Effect for the ECAP AGF slope or threshold, nor the MPI slopes were significantly related to MMA or MW distance from the electrodes. These results suggest that “within-channel” estimates of neural health such as the IPG Effect and MPI slope might be more suitable for estimating nerve condition in humans for clinical application since they appear to be relatively independent of electrode position. © 2020, Association for Research in Otolaryngology.
Author Keywords
cochlear implant; electrode placement; neural health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Cerebral vascular malformations and their imaging modalities” (2020) Neurological Sciences
Cerebral vascular malformations and their imaging modalities
(2020) Neurological Sciences, .
Zafar, A.a , Fiani, B.b , Hadi, H.b , Arshad, M.b , Cathel, A.b , Naeem, M.c , Parsons, M.S.c , Farooqui, M.a , Bucklin, A.A.d , Leone, M.J.d , Baig, A.e , Quadri, S.A.d
a Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
b Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, CA, United States
c Division of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
d Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
e Liaquat National Hospital and Medical College, Karachi, Pakistan
Abstract
Cerebrovascular malformations are uncommon diverse group of dysmorphic vascular communications that may occur sporadically or as part of genetic syndromes. These include non-neoplastic lesions such as arteriovenous malformations (AVM), cavernous malformations (CM), developmental venous anomalies (DVA), and telangiectasias as well as others like arteriovenous fistulas (AVF), vein of Galen malformations (VOGM), and mixed or unclassified angiomas. These lesions often carry a high degree of morbidity and mortality often requiring surgical or endovascular interventions. The field of cerebrovascular anomalies has seen considerable advancement in the last few years. Treatment and management options of various types of brain anomalies have evolved in neurological, neurosurgical, and neuro-interventional radiology arena. The use of radiological imaging studies is a critical element for treatment of such neurosurgical cases. As imaging modalities continue to evolve at a rapid pace, it is imperative for neurological surgeons to be familiar with current imaging modalities essential for a precise diagnosis. Better understanding of these cerebrovascular lesions along with their associated imaging findings assists in determining the appropriate treatment options. In the current review, authors highlight various cerebrovascular malformations and their current imaging modalities. © 2020, Fondazione Società Italiana di Neurologia.
Author Keywords
Arteriovenous; Cavernous; Cerebrovascular; Fistula; Malformations; Telangiectasia; Vein of Galen malformation; Venous anomaly
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline” (2020) Nature
APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline
(2020) Nature, .
Montagne, A.a , Nation, D.A.a b c d , Sagare, A.P.a , Barisano, G.a , Sweeney, M.D.a , Chakhoyan, A.a , Pachicano, M.a , Joe, E.b e , Nelson, A.R.a , D’Orazio, L.M.b e , Buennagel, D.P.f , Harrington, M.G.f , Benzinger, T.L.S.g h , Fagan, A.M.h i j , Ringman, J.M.b e , Schneider, L.S.b e k , Morris, J.C.i j , Reiman, E.M.l , Caselli, R.J.m , Chui, H.C.b e , Tcw, J.n o , Chen, Y.a , Pa, J.b p , Conti, P.S.q , Law, M.b r s , Toga, A.W.b p , Zlokovic, B.V.a b
a Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
b Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
c Department of Psychological Science, University of California, Irvine, Irvine, CA, United States
d Institute for Memory Disorders and Neurological Impairments, University of California, Irvine, Irvine, CA, United States
e Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
f Huntington Medical Research Institutes, Pasadena, CA, United States
g Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
h The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, United States
i Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
j The Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
k Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, United States
l Banner Alzheimer Institute, Phoenix, AZ, United States
m Department of Neurology, Mayo Clinic, Scottsdale, AZ, United States
n Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
o Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
p Laboratory of Neuroimaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
q Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
r Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
s Department of Neuroscience and Radiology, Monash University, Alfred Health, Melbourne, VIC, Australia
Abstract
Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized1–6. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer’s disease5,8–10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease11–14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15–19, which maintain BBB integrity20–22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“A curved port delivery system for laser interstitial thermal therapy of brain tumors” (2019) Frontiers in Biomedical Devices, BIOMED – 2019 Design of Medical Devices Conference, DMD 2019
A curved port delivery system for laser interstitial thermal therapy of brain tumors
(2019) Frontiers in Biomedical Devices, BIOMED – 2019 Design of Medical Devices Conference, DMD 2019, .
Agwu, N.a , Deprow, K.a , Williams, J.E.a , Gorlewicz, J.L.a , Leuthardt, E.C.b
a St. Louis University, St. Louis, MO, United States
b Washington University in St. Louis, St. Louis, MO, United States
Abstract
Laser interstitial thermal therapy (LITT) is a neurosurgical procedure that involves using heat treatment to ablate glioblastomas in the brain. Current methods for placing probes in LITT involve straight trajectory pathways. This limitation often requires surgeons to make multiple trajectories or leave undesired margins. There has been extensive work in steerable needles, concentric tube cannulas, and flexible surgical tools. In this work, we present an approach which focuses on providing steerability to tools that aren’t inherently steerable. To do this, we developed a curved port delivery system that leverages an active cannula for the deployment of a plastic, flexible port that delivers existing surgical tools. We present an initial prototype coupled with feasibility results illustrating that the port can be placed to steer probes to a desired location. Copyright © 2019 ASME
Author Keywords
Active cannula; Laser ablation; Steerable devices
Conference name: 2019 Design of Medical Devices Conference, DMD 2019
Conference date: 15 April 2019 through 18 April 2019
Conference code: 149721
Document Type: Conference Paper
Publication Stage: Final
Source: Scopus
Access Type: Open Access