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WashU weekly Neuroscience publications

“Diffusion Tensor Model links to Neurite Orientation Dispersion and Density Imaging at high b-value in Cerebral Cortical Gray Matter” (2019) Scientific Reports

Diffusion Tensor Model links to Neurite Orientation Dispersion and Density Imaging at high b-value in Cerebral Cortical Gray Matter
(2019) Scientific Reports, 9 (1), art. no. 12246, . 

Fukutomi, H.a b , Glasser, M.F.c d , Murata, K.e , Akasaka, T.b , Fujimoto, K.b , Yamamoto, T.b , Autio, J.A.a , Okada, T.b , Togashi, K.b , Zhang, H.f , Van Essen, D.C.c , Hayashi, T.a g

a Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
b Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kawaramachi 54, Shogoin, Sakyo-ku, Kyoto city, 606-8507, Japan
c Department of Neuroscience, Washington University School of Medicine, Campus Box 8108, 660 South Euclid Avenue, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
e Siemens Healthcare K.K., Gate City Osaki West Tower, 1-11-1, Osaki, Shinagawa-ku, Tokyo, 141-8644, Japan
f Centre for Medical Image Computing and Department of Computer Science, University College London, The Front Engineering Building, Floor 3, Malet Place, London, WC1E 7JE, United Kingdom
g RIKEN Compass to Healthy Life Research Complex Program, Integrated Innovation Building (IIB), 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, Japan

Abstract
Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are widely used models to infer microstructural features in the brain from diffusion-weighted MRI. Several studies have recently applied both models to increase sensitivity to biological changes, however, it remains uncertain how these measures are associated. Here we show that cortical distributions of DTI and NODDI are associated depending on the choice of b-value, a factor reflecting strength of diffusion weighting gradient. We analyzed a combination of high, intermediate and low b-value data of multi-shell diffusion-weighted MRI (dMRI) in healthy 456 subjects of the Human Connectome Project using NODDI, DTI and a mathematical conversion from DTI to NODDI. Cortical distributions of DTI and DTI-derived NODDI metrics were remarkably associated with those in NODDI, particularly when applied highly diffusion-weighted data (b-value = 3000 sec/mm2). This was supported by simulation analysis, which revealed that DTI-derived parameters with lower b-value datasets suffered from errors due to heterogeneity of cerebrospinal fluid fraction and partial volume. These findings suggest that high b-value DTI redundantly parallels with NODDI-based cortical neurite measures, but the conventional low b-value DTI is hard to reasonably characterize cortical microarchitecture. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Personality disorders and physical comorbidities: a complex relationship” (2019) Current Opinion in Psychiatry

Personality disorders and physical comorbidities: a complex relationship
(2019) Current Opinion in Psychiatry, 32 (5), pp. 435-441. 

Dokucu, M.E.a , Cloninger, C.R.b

a Department of Psychiatry & Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
b Departments of Psychiatry, Psychological and Brain Sciences, Genetics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
PURPOSE OF REVIEW: It is not uncommon for clinicians to label patients’ complaints as ‘psychogenic’ when they present with symptoms that are difficult to understand. This article reviews recent reports about the comorbidity of personality disorders and nonpsychiatric medical problems, which call into question the adequacy of the mind-body dichotomy in medicine. RECENT FINDINGS: The strong association of any personality disorders with poor health in cross-sectional and community-based studies is now confirmed by personality disorder predicting future deterioration in longitudinal studies. Borderline personality disorder has been studied most frequently, but recent data suggest that severity of any personality disorder is associated with poor and worsening health. SUMMARY: Personality disorder is associated with the full range of physical, mental, and social disorders. Greater attention to the common features of personality disorders, which are crucial for the self-regulation of behavior, would facilitate more effective health promotion and disease prevention across all medical specialties, thereby helping to relieve the burdens of chronic common diseases.

Document Type: Article
Publication Stage: Final
Source: Scopus

“TSPO PET Using (18F)PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat” (2019) Toxicological Sciences : an Official Journal of the Society of Toxicology

TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat
(2019) Toxicological Sciences : an Official Journal of the Society of Toxicology, 170 (2), pp. 330-344. 

Hobson, B.A.a , Rowland, D.J.b , Sisó, S.c , Guignet, M.A.d , Harmany, Z.T.b , Bandara, S.B.d , Saito, N.e , Harvey, D.J.e , Bruun, D.A.d , Garbow, J.R.f , Chaudhari, A.J.a b , Lein, P.J.d

a Department of Radiology, University of California Davis School of Medicine, Sacramento, CA 95817, United States
b Center for Molecular and Genomic Imaging, Department of Biomedical Engineering, University of California Davis College of Engineering, Davis, CA 95616, United States
c Department of Pathology, Microbiology and Immunology, Argentina
d Department of Molecular Biosciences, University of California Davis School of Veterinary Medicine, Davis, CA 95616, United States
e Department of Public Health Sciences, University of California Davis School of Medicine, Davis, CA 95616, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
in vivo imaging;  diisopropylfluorophosphate;  GFAP;  IBA1;  neuroinflammation;  organophosphate;  positron emission tomography;  TSPO

Document Type: Article
Publication Stage: Final
Source: Scopus

“The role of economic analyses in promoting adoption of behavioral and psychosocial interventions in clinical settings” (2019) Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association

The role of economic analyses in promoting adoption of behavioral and psychosocial interventions in clinical settings
(2019) Health Psychology : Official Journal of the Division of Health Psychology, American Psychological Association, 38 (8), pp. 680-688. 

Jacobsen, P.B.a , Prasad, R.b , Villani, J.c , Lee, C.-M.d , Rochlin, D.d , Scheuter, C.d , Kaplan, R.M.d , Freedland, K.E.e , Manber, R.f , Kanaan, J.g , Wilson, D.K.h

a Division of Cancer Control and Population Sciences, National Cancer Institute, Egypt
b Department of Anesthesiology and Pain Medicine, School of Medicine, University of California, Davis, United States
c Office of Disease Prevention, National Institutes of Health, Japan
d Stanford School of Medicine Clinical Excellence Research Center
e Department of Psychiatry, Washington University School of Medicine, United States
f Stanford Neurosciences Institute, Stanford University, Australia
g Economic and Regulatory Services
h Department of Psychology, Luxembourg

Abstract
In this report, we offer three examples of how economic data could promote greater adoption of behavioral and psychosocial interventions in clinical settings where primary or specialty medical care is delivered to patients. The examples are collaborative care for depression, chronic pain management, and cognitive-behavioral therapy for insomnia. These interventions illustrate differences in the availability of cost and cost-effectiveness data and in the extent of intervention adoption and integration into routine delivery of medical care. Collaborative care has been widely studied from an economic perspective, with most studies demonstrating its relative cost-effectiveness per quality-adjusted life year (QALY) and some studies demonstrating its potential for cost neutrality or cost savings. The success of collaborative care for depression can be viewed as a model for how to promote greater adoption of other interventions, such as psychological therapies for chronic pain and insomnia. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Factors Associated With Receipt of Cognitive-Behavioral Therapy or Prolonged Exposure Therapy Among Individuals With PTSD” (2019) Psychiatric Services (Washington, D.C.)

Factors Associated With Receipt of Cognitive-Behavioral Therapy or Prolonged Exposure Therapy Among Individuals With PTSD
(2019) Psychiatric Services (Washington, D.C.), 70 (8), pp. 703-713. 

van den Berk Clark, C., Moore, R., Secrest, S., Tuerk, P., Norman, S., Myers, U., Lustman, P.J., Schneider, F.D., Barnes, J., Gallamore, R., Ovais, M., Plurad, J.A., Scherrer, J.F.

Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis (Clark, Moore, Secrest, Barnes, Gallamore, Ovais, Plurad, Scherrer); Research and Development Program, Veterans Affairs St. Louis Health Care System, St. Louis (Clark); Research Service, Harry S. Truman Veteran’s Hospital, Columbia, Missouri (Scherrer); Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston and PTSD Clinical Team, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (Tuerk); PTSD Consultation Program, National Center of PTSD, White River Junction, Vermont, and Department of Psychiatry, University of California, San Diego (Norman); U.S. Department of Veterans Affairs, Washington, D.C. (Myers); Department of Psychiatry, Washington University School of Medicine, St. Louis (Lustman); Department of Family and Community Medicine, University of Texas Southwestern, Dallas (Schneider)

Abstract
OBJECTIVE: The aim of this study was to systematically review variables associated with initiation of trauma-centered cognitive-behavioral therapy (TC-CBT) among individuals with posttraumatic stress disorder (PTSD). METHODS: PubMed, PsycINFO, Web of Science, Published International Literature on Traumatic Stress (PILOTS), and Scopus were searched in a systematic manner up to 2018, and 26 relevant studies were recovered and analyzed. RESULTS: The average weighted initiation rate was 6% in larger hospital systems with a high rate of trauma and 28% in outpatient mental health settings (range 4%-83%). Older age (odds ratio [OR]=1.56, 95% confidence interval [CI]=0.51-1.61), female gender (OR=1.18, 95% CI=1.08-1.27), black or other racial-ethnic minority group (OR=1.16, 95% CI=1.03-1.28), Veterans Affairs PTSD service connection status (OR=2.30, 95% CI=2.18-2.42), mental health referral (OR=2.28, 95% CI=1.05-3.50), greater staff exposure to TC-CBT (OR=2.30, 95% CI=2.09-2.52), adaptability of TC-CBT to staff workflow (OR=4.66, 95% CI=1.60-7.72), greater PTSD severity (OR=1.46, 95% CI=1.13-1.78), and comorbid depression (OR=1.21, 95% CI=1.14-1.29) increased the likelihood of TC-CBT initiation, whereas delayed treatment reduced the likelihood of TC-CBT initiation (OR=0.93, 95% CI=0.92-0.95). Qualitative studies showed that mental health beliefs (stigma and lack of readiness), provider organizational factors (low availability, privacy issues), and patient lack of time (logistics) were perceived as barriers to initiation by patients and providers. CONCLUSIONS: TC-CBT initiation increased among patients who were older and female. Initiation was also higher among providers who had more exposure to TC-CBT in their work environment and when TC-CBT fit into their existing workflow.

Author Keywords
behavioral health services utilization;  Cognitive behavioral therapy;  Posttraumatic stress disorder (PTSD;  Prolonged Exposure Therapy;  Treatment Initiation

Document Type: Article
Publication Stage: Final
Source: Scopus

“Mapping brain function during naturalistic viewing using high-density diffuse optical tomography” (2019) Scientific reports

Mapping brain function during naturalistic viewing using high-density diffuse optical tomography
(2019) Scientific reports, 9 (1), p. 11115. 

Fishell, A.K.a b , Burns-Yocum, T.M.c , Bergonzi, K.M.d e , Eggebrecht, A.T.b , Culver, J.P.b f g

a Washington University School of Medicine, Division of Biology and Biomedical Sciences, St. Louis, United States
b Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, United States
c Indiana University, Department of Psychological and Brain Sciences, Bloomington, United States
d University of Pennsylvania, Department of Anesthesia and Critical Care, Philadelphia, United States
e University of Pennsylvania, Department of Physics, Philadelphia, United States
f Washington University, Department of Physics, St. Louis, United States
g Washington University, Department of Biomedical Engineering, St. Louis, United States

Abstract
Naturalistic stimuli, such as movies, more closely recapitulate “real life” sensory processing and behavioral demands relative to paradigms that rely on highly distilled and repetitive stimulus presentations. The rich complexity inherent in naturalistic stimuli demands an imaging system capable of measuring spatially distributed brain responses, and analysis tools optimized for unmixing responses to concurrently presented features. In this work, the combination of passive movie viewing with high-density diffuse optical tomography (HD-DOT) is developed as a platform for naturalistic brain mapping. We imaged healthy young adults during free viewing of a feature film using HD-DOT and observed reproducible, synchronized cortical responses across a majority of the field-of-view, most prominently in hierarchical cortical areas related to visual and auditory processing, both within and between individuals. In order to more precisely interpret broad patterns of cortical synchronization, we extracted visual and auditory features from the movie stimulus and mapped the cortical responses to the features. The results demonstrate the sensitivity of HD-DOT to evoked responses during naturalistic viewing, and that feature-based decomposition strategies enable functional mapping of naturalistic stimulus processing, including human-generated speech.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Cannabinoids, cannabis, and cannabis-based medicine for pain management: A protocol for an overview of systematic reviews and a systematic review of randomised controlled trials” (2019) Pain Reports

Cannabinoids, cannabis, and cannabis-based medicine for pain management: A protocol for an overview of systematic reviews and a systematic review of randomised controlled trials
(2019) Pain Reports, 4 (3), art. no. e741, . 

Fisher, E.a b , Eccleston, C.a b c , Degenhardt, L.d , Finn, D.P.e , Finnerup, N.B.f , Gilron, I.g h i j , Haroutounian, S.k , Krane, E.l , Rice, A.S.C.m , Rowbotham, M.n o , Wallace, M.p , Andrew Moore, R.q

a Centre for Pain Research, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom
b Cochrane Pain, Palliative, and Supportive Care Review Groups, Oxford University Hospitals, Oxford, United Kingdom
c Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium
d National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia
e Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, Centre for Pain Research, NCBES, National University of Ireland Galway, Galway, Ireland
f Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
g Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
h Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital, Queen’s University, Kingston, ON, Canada
i Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
j School of Policy Studies, Queen’s University, Kingston, ON, Canada
k Division of Clinical and Translational Research, Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
l Department of Anesthesiology, Perioperative, and Pain Medicine, and Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
m Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
n Department of Anesthesia, University of California, San Francisco, CA, United States
o Sutter Health, CPMC Research Institute, California Pacific Medical Center Research Institute, San Francisco, CA, United States
p Division of Pain Medicine, Department of Anesthesiology, University of California San Diego, San Diego, CA, United States
q Pain Research, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Abstract
Pain is an experience that affects many people worldwide and is associated with higher mortality and lower quality of life. Cannabinoid, cannabis, and cannabis-based medicines (CBMs) are thought to reduce pain, but a proliferation of different products has led to variability in trials, creating a challenge when determining the assessment of efficacy in systematic reviews. We will conduct 2 systematic reviews commissioned by the International Association for the Study of Pain Task Force on the use of cannabinoids, cannabis, and CBMs for pain management: first, an overview review of systematic reviews to summarise the evidence base and second, a systematic review of randomised controlled trials of cannabinoids, cannabis, and CBMs. In these reviews we will determine the harm and benefit of CBM from the current literature and will interpret the findings in light of the quality of evidence and reviews included. We will search online databases and registries in any language for systematic reviews and randomised controlled trials. We will include studies that evaluate any cannabinoid or CBM vs any control for people with acute and chronic pain. Our primary outcomes for both reviews are the number of participants achieving (1) a 30% and (2) 50% reduction in pain intensity, (3) moderate improvement, and (4) substantial improvement. A number of secondary outcome measures will also be included. We will assess risk of bias and quality of evidence. We will analyse data using fixed and random effect models, with separate comparators for cannabis and CBMs. Prospero ID (CRD42019124710; CRD42019124714). © 2019 The Author(s).

Author Keywords
Cannabinoids;  Cannabis;  Meta-analysis;  Overview;  Pain;  Protocol;  Systematic review

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: Protocol for an overview of systematic reviews” (2019) Pain Reports

Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: Protocol for an overview of systematic reviews
(2019) Pain Reports, 4 (3), art. no. e742, . Cited 1 time

Gilron, I.a b c , Blyth, F.M.d , Degenhardt, L.e , Di Forti, M.f g h , Eccleston, C.i , Haroutounian, S.j , Moore, A.k , Rice, A.S.C.l , Wallace, M.m

a Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital, Queen’s University, 76 Stuart Street, Kingston, ON K7L2V7, Canada
b Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
c School of Policy Studies, Queen’s University, Kingston, ON, Canada
d University of Sydney, Centre for Education and Research on Ageing, Concord Repatriation General Hospital, Concord, NSW, Australia
e National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, NSW, Australia
f Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom
g National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom
h South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom
i Centre for Pain Research, University of Bath, Bath, United Kingdom
j Division of Clinical and Translational Research, Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
k Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research, the Churchill, Oxford, United Kingdom
l Pain Research Group, Department Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
m Department of Anesthesiology, University of California San Diego, San Diego, CA, United States

Abstract
Introduction:With the increasing availability of cannabis and cannabinoids and their potential utility for pain treatment, there is a growing need to evaluate the risk-benefit considerations of cannabinoids for the management of pain. As part of the IASP Cannabis and Cannabinoids Task Force, this protocol describes a planned overview of systematic reviews summarizing the risks of harm with cannabinoids that are relevant to patients receiving pain treatment.Methods:This overview will involve literature searches of several databases and a defined search strategy that will target systematic reviews or meta-analyses of cannabinoids where harms are the primary focus. Data extraction will include various features of the cannabinoid(s) and the harm(s) being studied as well as other methodological features of each included systematic review. Methodological quality of each included review will be assessed using AMSTAR-2 as well as compliance with the PRISMA harms checklist. Prospero registration pending.Discussion:The broad overview of reviews defined by this protocol is expected to synthesize available good quality evidence of harms that will help inform risk-benefit considerations about the use of cannabinoids for pain management. © 2019 The Author(s).

Author Keywords
Adverse effects;  Adverse events;  Cannabinoids;  Cannabis;  Clinical trials;  Harms;  Pain management

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“ACMT Position Statement: Remove the Waiver Requirement for Prescribing Buprenorphine for Opioid Use Disorder” (2019) Journal of Medical Toxicology

ACMT Position Statement: Remove the Waiver Requirement for Prescribing Buprenorphine for Opioid Use Disorder
(2019) Journal of Medical Toxicology, . 

Marino, R.a , Perrone, J.b , Nelson, L.S.c , Wiegand, T.J.d , Schwarz, E.S.e , Wax, P.M.f , Stolbach, A.I.g

a Case Western Reserve University School of Medicine, Cleveland, OH, United States
b University of Pennsylvania, Philadelphia, PA, United States
c Rutgers New Jersey Medical School, Newark, NJ, United States
d University of Rochester Medical Center, Rochester, NY, United States
e Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
f University of Texas Southwestern, Dallas, TX, United States
g Johns Hopkins University School of Medicine, Baltimore, MD, United States

Author Keywords
Buprenorphine;  Opioid agonist therapy;  Opioid use disorder;  Waiver;  X-waiver

Document Type: Note
Publication Stage: Article in Press
Source: Scopus

“Association between Clinically Meaningful Posttraumatic Stress Disorder Improvement and Risk of Type 2 Diabetes” (2019) JAMA Psychiatry

Association between Clinically Meaningful Posttraumatic Stress Disorder Improvement and Risk of Type 2 Diabetes
(2019) JAMA Psychiatry, . 

Scherrer, J.F.a b , Salas, J.a b , Norman, S.B.c , Schnurr, P.P.d , Chard, K.M.e f , Tuerk, P.g , Schneider, F.D.h , Van Den Berk-Clark, C.a , Cohen, B.E.i j , Friedman, M.J.d , Lustman, P.J.k l

a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 N Grand Blvd, St Louis, MO 63104, United States
b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
c National Center for PTSD, Veterans Affairs (VA) Center of Excellence for Stress and Mental Health, Department of Psychiatry, University of California, San Diego, United States
d National Center for PTSD, Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
e Trauma Recovery Center, Cincinnati Veterans Affairs Medical Center (VAMC), Cincinnati, OH, United States
f Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States
g Sheila C. Johnson Center for Clinical Services, Department of Human Services, University of Virginia, Charlottesville, United States
h Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, United States
i School of Medicine, Department of Medicine, University of California, San Francisco, United States
j San Francisco VAMC, San Francisco, CA, United States
k Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
l Bell Street Clinic Opioid Treatment Program, Mental Health Service, VA St Louis Health Care System, St Louis, MO, United States

Abstract
Importance: Posttraumatic stress disorder (PTSD) is associated with increased risk of type 2 diabetes (T2D). Improvement in PTSD has been associated with improved self-reported physical health and hypertension; however, there is no literature, to our knowledge, on whether PTSD improvement is associated with T2D risk. Objective: To examine whether clinically meaningful PTSD symptom reduction is associated with lower risk of T2D. Design, Setting, and Participants: This retrospective cohort study examined Veterans Health Affairs medical record data from 5916 patients who received PTSD specialty care between fiscal years 2008 and 2012 and were followed up through fiscal year 2015. Eligible patients had 1 or more PTSD Checklist (PCL) scores of 50 or higher between fiscal years 2008 and 2012 and a second PCL score within the following 12 months and at least 8 weeks after the first PCL score of 50 or higher. The index date was 12 months after the first PCL score. Patients were free of T2D diagnosis or an antidiabetic medication use for 12 months before the index date and had at least 1 visit after the index date. Data analyses were completed during January 2019. Exposures: Reduction in PCL scores during a 12-month period was used to define patients as those with a clinically meaningful improvement (≥20-point PCL score decrease) and patients with less or no improvement (<20-point PCL score decrease). Main Outcomes and Measures: Incident T2D diagnosed during a 2-to 6-year follow-up. Results: Medical records from a total of 1598 patients (mean [SD] age, 42.1 [13.4] years; 1347 [84.3%] male; 1060 [66.3%] white) were studied. The age-adjusted cumulative incidence of T2D was 2.6% among patients with a clinically meaningful PCL score decrease and 5.9% among patients without a clinically meaningful PCL score decrease (P =.003). After control for confounding, patients with a clinically meaningful PCL score decrease were significantly less likely to develop T2DM compared with those without a clinically meaningful decrease (hazard ratio, 0.51; 95% CI, 0.26-0.98). Conclusions and Relevance: The findings suggest that clinically meaningful reductions in PTSD symptoms are associated with a lower risk of T2D. A decrease in PCL score, whether through treatment or spontaneous improvement, may help mitigate the greater risk of T2D in patients with PTSD. © 2019 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Linking openness to cognitive ability in older adulthood: The role of activity diversity” (2019) Aging and Mental Health

Linking openness to cognitive ability in older adulthood: The role of activity diversity
(2019) Aging and Mental Health, . 

Jackson, J.J.a , Hill, P.L.a , Payne, B.R.b , Parisi, J.M.c , Stine-Morrow, E.A.L.d

a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology, University of Utah, Salt Lake City, UT, United States
c Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
d Department of Educational Psychology and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Champaign, IL, United States

Abstract
Relatively few studies have examined the reasons older individuals participate in activities that may benefit cognition with aging. Personality traits, particularly, openness to experience, are likely to influence how activities are selected. Openness to experience has also reliably shown to relate to cognitive and intellectual capacities. The current study tested whether diversity in activity helped to explain the overlap between openness to experience and cognitive functioning in an older adult sample (n = 476, mean age: 72.5 years). Results suggest that openness is a better predictor of activity diversity than of time spent engaged in activities or time spent in cognitively challenging activities. Further, activity diversity explained significant variance in the relationship between openness and cognitive ability for most constructs examined. This relationship did not vary with age, but differed as a function of education level, such that participating in a more diverse array of activities was most beneficial for those with less formal education. These results suggest that engagement with a diverse behavioral repertoire in late life may compensate for lack of early life resources. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
activity;  cognitive ability;  education;  openness;  Personality

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“30-Day Emergency Department Revisit Rates among Older Adults with Documented Dementia” (2019) Journal of the American Geriatrics Society

30-Day Emergency Department Revisit Rates among Older Adults with Documented Dementia
(2019) Journal of the American Geriatrics Society, . 

Kent, T.a , Lesser, A.a , Israni, J.a , Hwang, U.b , Carpenter, C.c , Ko, K.J.a

a The Gary and Mary West Health Institute, La Jolla, CA, United States
b Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
c Washington University Division of Emergency Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
OBJECTIVES: Published literature on national emergency department (ED) revisit rates among older adults with dementia is sparse, despite anecdotal evidence of higher ED utilization. Thus we evaluated the odds ratio (OR) of 30-day ED revisits among older adults with dementia using a nationally representative sample. DESIGN: We assessed the frequency of claims associated with a 30-day ED revisit among Medicare beneficiaries with and without a dementia diagnosis before or at index ED visit. We used a logistic regression model controlling for dementia, age, sex, race, region, Medicaid status, transfer to a skilled nursing facility after ED, primary care physician use 12 months before index, and comorbidity. SETTING: A nationally representative sample of claims data for Medicare beneficiaries aged 65 and older who maintained continuous fee-for-service enrollment during 2015 and 2016. Only outpatient claims associated with an ED visit between January 2016 and November 2016 were included as a qualifying index encounter. PARTICIPANTS: We identified 240 249 patients without dementia and 54 622 patients for whom a dementia code was recorded in the year before the index encounter in 2016. RESULTS: Our results indicate a significant difference in unadjusted 30-day ED revisit rates among those with an ED dementia diagnoses (22.0%) compared with those without (13.9%). Our adjusted results indicated that dementia is a significant predictor of 30-day ED revisits (P <.0001). Those with a dementia diagnosis at or before the index ED visit were more likely to have experienced an ED revisit within 30 days (OR = 1.27; 95% confidence interval = 1.24-1.31). CONCLUSION: Dementia diagnoses were a significant predictor of 30-day ED revisits. Further research should assess potential reasons why dementia is associated with markedly higher revisit rates, as well as opportunities to manage and transition dementia patients from the ED back to the community more effectively. © 2019 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.

Author Keywords
dementia;  emergency;  geriatric;  revisits

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Maternal and family factors differentiate profiles of psychiatric impairments in very preterm children at age 5-years” (2019) Journal of Child Psychology and Psychiatry and Allied Disciplines

Maternal and family factors differentiate profiles of psychiatric impairments in very preterm children at age 5-years
(2019) Journal of Child Psychology and Psychiatry and Allied Disciplines, . 

Lean, R.E.a , Lessov-Shlaggar, C.N.a , Gerstein, E.D.b , Smyser, T.A.a , Paul, R.A.c , Smyser, C.D.d e f , Rogers, C.E.a f

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

Abstract
Background: Very preterm (VPT; <30 weeks gestation) children are a heterogeneous group, yet the co-occurrence of psychiatric and neurodevelopmental impairments remains unclear. Moreover, the clinical and socio-environmental factors that promote resilient developmental outcomes among VPT children are poorly understood. Methods: One hundred and twenty five children (85 VPT and 40 full-term) underwent neurodevelopmental evaluation at age 5-years. Parents and teachers completed measures of internalizing, externalizing, attention-deficit/hyperactivity (ADHD), and autism symptoms. Psychiatric and neurodevelopmental measures were analyzed using Latent Profile Analysis. Multinomial regression examined the extent that infant, sociodemographic, and family factors, collected prospectively from birth to follow-up, independently differentiated resilient and impaired children. Results: Four latent profiles were identified, including a Typically Developing Group which represented 27.1% of the VPT group and 65.0% of the full-term group, an At-Risk Group with mild psychiatric and neurodevelopmental problems (VPT 44.7%, full-term 22.5%), a Psychiatric Group with moderate-to-severe psychiatric ratings (VPT 12.9%, full-term 10.0%), and a school-based Inattentive/Hyperactive Group (VPT 15.3%, full-term 2.5%). Clinical diagnoses were highest among the Psychiatric Group (80%). Factors that differentiated resilient and impaired subgroups of VPT children included prolonged exposure to maternal psychosocial distress (p ≤.04), current family dysfunction (p ≤.05), and maternal ADHD symptoms (p ≤.02), whereas social risk index scores differentiated resilient and impaired full-term children (p <.03). Conclusions: Lower levels of maternal distress, family dysfunction, and maternal ADHD symptoms were associated with resilience among VPT children. Maternal distress and family dysfunction are modifiable factors to be targeted as part of psychiatric interventions embedded in the long-term care of VPT children. © 2019 Association for Child and Adolescent Mental Health

Author Keywords
latent profile analysis;  neurodevelopment;  Prematurity;  psychiatric impairments

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion among Patients with Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials” (2019) JAMA Neurology

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion among Patients with Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials
(2019) JAMA Neurology, . Cited 1 time.

Gladstone, D.J.a b , Aviv, R.I.b c , Demchuk, A.M.d , Hill, M.D.d e , Thorpe, K.E.f g , Khoury, J.C.h i , Sucharew, H.J.h i , Al-Ajlan, F.j , Butcher, K.k , Dowlatshahi, D.l , Gubitz, G.m , De Masi, S.g , Hall, J.g , Gregg, D.n , Mamdani, M.g , Shamy, M.o , Swartz, R.H.a b , Del Campo, C.M.a , Cucchiara, B.p , Panagos, P.q , Goldstein, J.N.r , Carrozzella, J.s , Jauch, E.C.t , Broderick, J.P.u , Flaherty, M.L.u

a Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
b Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
c Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
d Department of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
e Department of Community Health Sciences and Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
f Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
g Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, ON, Canada
h Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
i Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
j Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
k University of New South Wales, Prince of Wales Clinical School, Sydney, NSW, Australia
l Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
m Division of Neurology, Department of Medicine, Dalhousie University, Halifax, NS, Canada
n Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, United States
o University of Ottawa, Ottawa, ON, Canada
p Department of Neurology, University of Pennsylvania, Philadelphia, United States
q Department of Emergency Medicine, Washington University in St Louis, St Louis, MO, United States
r Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States
s Department of Radiology, University of Cincinnati Academic Health Center, Cincinnati, OH, United States
t Mission Research Institute, Mission Health System, Asheville, NC, United States
u Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, United States

Abstract
Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion – the computed tomography (CT) angiography spot sign – may identify a subgroup that could benefit from hemostatic therapy. Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH. Design, Setting, and Participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada (“Spot Sign” Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017. Interventions: Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset. Main Outcomes and Measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial. Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P =.60). Conclusions and Relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888. © 2019 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Elevated maternal and child mortality among women with multiple DUI convictions compared with socio-demographically matched controls” (2019) Addiction

Elevated maternal and child mortality among women with multiple DUI convictions compared with socio-demographically matched controls
(2019) Addiction, . 

McCutcheon, V.V., Bucholz, K.K., Houston-Ludlam, A.N., Heath, A.C.

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Aims: To assess whether having multiple convictions for driving while under the influence of alcohol (MDUI) in women is a risk factor for maternal, infant and child mortality. Design: Retrospective cohort design using record linkage, comparing women with MDUI convictions with propensity-matched women without alcohol-related driving offences ascertained through state records, on rates of maternal, infant and child mortality. Setting: Missouri, United States. Participants: MDUI women (n = 1658) and women with no alcohol-related driving convictions (control, n = 184 252) who gave birth from 2000 to 2004. Measurements: Data were obtained from state administrative records and US Census data. The outcomes were maternal, infant and child mortality. The input variable was presence or absence of MDUI convictions. Propensity-matching variables were maternal (smoking during pregnancy, delayed prenatal care, previous child deaths, age at birth, mother Missouri-born, education, pre-pregnancy obesity, marital status), reproductive partner (un-named partner, race/ethnicity, education, DUI status) and census tract (socio-economic advantage, urbanicity) characteristics. Findings: Women with MDUI convictions had higher odds of maternal, infant and child mortality than propensity-matched controls [odds ratio (OR) = 2.65, 95% confidence interval (CI) = 2.07–3.40 and OR = 1.75, 95% CI = 1.17–2.61, respectively]. Conclusions: Having multiple convictions for driving under the influence of alcohol in women appears to be a risk factor for increased maternal, infant and child mortality. © 2019 Society for the Study of Addiction

Author Keywords
Child mortality;  drunk driving;  DUI;  maternal alcohol use;  maternal mortality;  parental alcohol use

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Impact of Cognitive Impairment Across Specialties: Summary of a Report From the U13 Conference Series” (2019) Journal of the American Geriatrics Society

Impact of Cognitive Impairment Across Specialties: Summary of a Report From the U13 Conference Series
(2019) Journal of the American Geriatrics Society, . 

Carpenter, C.R.a , McFarland, F.b , Avidan, M.c , Berger, M.d , Inouye, S.K.e , Karlawish, J.f , Lin, F.R.g , Marcantonio, E.h , Morris, J.C.i , Reuben, D.B.j , Shah, R.C.k , Whitson, H.E.l m , Asthana, S.n , Verghese, J.o

a Division of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
b Science Writer, Independent Consultant, Annapolis, MD, United States
c Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
d Anesthesiology Department, Duke University Medical Center, Durham, NC, United States
e Marcus Institute for Aging Research, Aging Brain Center, Harvard Medical School and Hebrew SeniorLife, Boston, MA, United States
f University of Pennsylvania, Philadelphia, PA, United States
g Department of Otolaryngology, The Johns Hopkins University, Baltimore, MD, United States
h Divisions of General Medicine and Gerontology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, United States
i Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
j Department of Medicine, Division of Geriatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
k Family Medicine and Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
l Department of Medicine, Division of Geriatrics, Duke University School of Medicine, Durham, NC, United States
m Geriatrics Research Education and Clinical Center, Durham VA Health Care System, Durham, NC, United States
n Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, Bronx, NY, United States
o Departments of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, United States

Abstract
Although declines in cognitive capacity are assumed to be a characteristic of aging, increasing evidence shows that it is age-related disease, rather than age itself, that causes cognitive impairment. Even so, older age is a primary risk factor for cognitive decline, and with individuals living longer as a result of medical advances, cognitive impairment and dementia are increasing in prevalence. On March 26 to 27, 2018, the American Geriatrics Society convened a conference in Bethesda, MD, to explore cognitive impairment across the subspecialties. Bringing together representatives from several subspecialties, this was the third of three conferences, supported by a U13 grant from the National Institute on Aging, to aid recipients of Grants for Early Medical/Surgical Specialists’ Transition to Aging Research (GEMSSTAR) in integrating geriatrics into their subspecialties. Scientific sessions focused on the impact of cognitive impairment, sensory contributors, comorbidities, links between delirium and dementia, and issues of informed consent in cognitively impaired populations. Discussions highlighted the complexity not only of cognitive health itself, but also of the bidirectional relationship between cognitive health and the health of other organ systems. Thus, conference participants noted the importance of multidisciplinary team science in future aging research. This article summarizes the full conference report, “The Impact of Cognitive Impairment Across Specialties,” and notes areas where GEMSSTAR scholars can contribute to progress as they embark on their careers in aging research. © 2019 The American Geriatrics Society

Author Keywords
Aging;  delirium;  dementia;  interdisciplinary research;  research ethics

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Pretreatment Volume of MRI-Determined White Matter Injury Predicts Neurocognitive Decline After Hippocampal Avoidant Whole-Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology Radiation Therapy Oncology Group 0933” (2019) Advances in Radiation Oncology

Pretreatment Volume of MRI-Determined White Matter Injury Predicts Neurocognitive Decline After Hippocampal Avoidant Whole-Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology Radiation Therapy Oncology Group 0933
(2019) Advances in Radiation Oncology, . 

Bovi, J.A.a , Pugh, S.L.b , Sabsevitz, D.c , Robinson, C.G.d , Paulson, E.a , Mehta, M.P.e , Gondi, V.f , Kundapur, V.g , Shahin, M.S.h , Chao, S.T.i , Machtay, M.j , DeNittis, A.S.k , Laack, N.N.l , Greenspoon, J.N.m , Moore, K.N.n , Huang, J.d , Dominello, M.M.o , Kachnic, L.A.p

a Department of Radiation Oncology, Froedtert and the Medical College of Wisconsin, Milwaukee, WI, United States
b NRG Oncology Statistics and Data Management Center, Philadelphia, PA, United States
c Department of Psychiatry and Psychology, Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, United States
d Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, United States
e Department of Radiation Oncology, Baptist Hospital of Miami, Miami, FL, United States
f Department of Radiation Oncology, Northwestern Medicine Cancer Center Warrenville and Northwestern University Feinberg School of Medicine, Chicago, IL, United States
g Department of Radiation Oncology, Cross Cancer Institute, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
h Thomas Jefferson University Hospital, Abington Memorial Hospital, Gynecologic Oncology, Abington, PA, United States
i Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
j Department of Radiation Oncology, University Hospitals of Cleveland, Case Western Reserve, Cleveland, OH, United States
k Department of Radiation Oncology, Main Line CCOP Lankenau Medical Center, Philadelphia, PA, United States
l Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States
m Division of Radiation Oncology, Department of Oncology, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton Ontario, Canada
n University of Oklahoma Health Sciences Center, Section of Gynecologic Oncology, Oklahoma City, OK, United States
o Division of Radiation Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
p Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, United States

Abstract
Purpose: NRG Oncology’s RTOG 0933 demonstrated benefits to memory preservation after hippocampal avoidant whole-brain radiation therapy (HA-WBRT), the avoidance of radiation dose to the hippocampus (using intensity modulated radiation planning and delivery techniques) during WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity play a role. White matter injury (WMI) has been implicated in radiation therapy–induced neurocognitive decline. This secondary analysis explored the relationship between pretreatment WMI and memory after HA-WBRT. Methods and Materials: Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pretreatment magnetic resonance image. Correlational analyses were performed examining the relationship between pretreatment WMI and Hopkins Verbal Learning Test-Revised (HVLT-R) outcomes at baseline and 4 months after HA-WBRT. Results: In the study, 113 patients received HA-WBRT. Of 113 patients, 33 underwent pretreatment and 4-month posttreatment HVLT testing and pretreatment postcontrast volumetric T1 and axial T2/fluid-attenuated inversion recovery magnetic resonance imaging. Correlation was found between larger volumes of pretreatment WMI and decline in HVLT-R recognition (r = 0.54, P < .05), and a correlational trend was observed between larger volume of pretreatment WMI and decline in HVLT-R delayed recall (r = 0.31, P = .08). Patients with higher pretreatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-R recall and delayed recall after HA-WBRT (r = –0.36 and r = –0.36, P < .05), compared to the magnitude of stability or positive shift in those with lesser disease burden. Conclusions: In patients receiving HA-WBRT for brain metastases, extent of pretreatment WMI predicts posttreatment memory decline, suggesting a mechanism for radiation therapy–induced neurocognitive toxicity independent of hippocampal stem cell radiosensitivity. Stability or improvement in HVLT after HA-WBRT for patients with higher pretreatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on neurocognition. © 2019

Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

“Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study” (2019) PLoS ONE

Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study
(2019) PLoS ONE, 14 (8), art. no. e0219596, . 

Matthews, L.G.a , Smyser, C.D.b c d , Cherkerzian, S.e , Alexopoulos, D.c , Kenley, J.b , Tuuli, M.G.f , Michael Nelson, D.f , Inder, T.E.a

a Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
b Department of Pediatrics, Washington University, Saint Louis, MO, United States
c Department of Neurology, Washington University, Saint Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO, United States
e Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
f Department of Obstetrics and Gynecology, Washington University, Saint Louis, MO, United States

Abstract
Polyphenol-rich pomegranate juice has been shown to have benefit as a neuroprotectant in animal models of neonatal hypoxic-ischemia. No published studies have investigated maternal polyphenol administration as a potential neuroprotectant in at-risk newborns, such as those with intrauterine growth restriction (IUGR). This was a randomized, placebo-controlled, double-blind pilot study to investigate the impact of maternal pomegranate juice intake in pregnancies with IUGR, on newborn brain structure and function at term-equivalent age (TEA). Mothers with IUGR at 24–34 weeks’ gestation were recruited from Barnes-Jewish Hospital obstetrical clinic. Consented mothers were randomized to treatment (8 oz. pomegranate juice) or placebo (8 oz. polyphenol-free juice) and continued to take juice daily from enrollment until delivery (mean 20.1 and 27.1 days, respectively). Infants underwent brain MRI at TEA (36–41 weeks’ gestation). Brain measures were compared between groups including: brain injury score, brain metrics, brain volumes, diffusion tensor imaging and resting state functional connectivity. Statistical analyses were undertaken as modified intention-to-treat (including randomized participants who received their allocated intervention and whose infants received brain MRI) and per-protocol (including participants who strictly adhered to the protocol, based on metabolite status). Seventy-seven mothers were randomized to treatment (n = 40) or placebo (n = 37). Of these, 28 and 27 infants, respectively, underwent term-equivalent MRI. There were no group differences in brain injury, metrics or volumes. However, treatment subjects displayed reduced diffusivity within the anterior and posterior limbs of the internal capsule compared with placebo. Resting state functional connectivity demonstrated increased correlation and covariance within several networks in treatment subjects, with alterations most apparent in the visual network in per-protocol analyses. Direct effects on health were not found. In conclusion, maternal pomegranate juice intake in pregnancies with known IUGR was associated with altered white matter organization and functional connectivity in the infant brain, suggesting differences in brain structure and function following in utero pomegranate juice exposure, warranting continued investigation. © 2019 Matthews et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes” (2019) European Journal of Medical Genetics

Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes
(2019) European Journal of Medical Genetics, art. no. 103736, . 

Zhang, S.Q.a , Fleischer, J.b d , Al-Kateb, H.c e , Mito, Y.c f , Amarillo, I.c , Shinawi, M.b

a Saint Louis University School of Medicine, St. Louis, MO, United States
b Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Southern Illinois University, Springfield, IL, United States
e Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
f Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract
Deletions and duplications involving the CNTN4 gene, which encodes for the contactin 4 protein, have been reported in children with autism spectrum disorder (ASD) and other neurodevelopmental phenotypes. In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this gene were mostly inherited from unaffected fathers, raising questions regarding reduced penetrance and potential parent-of-origin effect. Our findings are compared with previously reported patients and patients in the DECIPHER database. The speech impairment in the three probands suggests a role for CNTN4 in language development. We discuss potential factors contributing to phenotypic heterogeneity and reduced penetrance and attempt to find possible genotype-phenotype correlation. Larger cohorts are needed for comprehensive and unbiased phenotyping and molecular characterization that may lead to better understanding of the underlying mechanisms of reduced penetrance, variable expressivity, and potential parent-of-origin effect of copy number variants encompassing CNTN4. © 2019

Author Keywords
Autism;  BIG-2;  CNTN4;  Contactins;  Speech apraxia

Document Type: Article
Publication Stage: Article in Press
Source: Scopus