Scopus list of publications for October 17, 2022
Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination
(2022) Genome Medicine, 14 (1), art. no. 108, .
Rosen, S.F.a b , Soung, A.L.a b , Yang, W.c , Ai, S.a b , Kanmogne, M.a b , Davé, V.A.a b , Artyomov, M.d , Magee, J.A.b c d e , Klein, R.S.a b d f
a Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. Methods: Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. Results: Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 not only is required for the maintenance of WNV-specific CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. Conclusions: We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 in mice during recovery may reduce CNS CD8+ TRM cells. © 2022, The Author(s).
Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHR012052632, R01NS104471, R01NS116788, T32AI007172
Document Type: Article
Publication Stage: Final
Source: Scopus
Multi-modulated frequency domain high density diffuse optical tomography
(2022) Biomedical Optics Express, 13 (10), pp. 5275-5294.
Perkins, G.A.a b , Eggebrecht, A.T.c , Dehghani, H.b
a University of Birmingham, Sci-Phy-4-Health Centre for Doctoral Training, College of Engineering and Physical Sciences, Birmingham, B15 2TT, United Kingdom
b University of Birmingham, School of Computer Science, College of Engineering and Physical Sciences, Birmingham, B15 2TT, United Kingdom
c Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St Louis, MO 63110, United States
Abstract
Frequency domain (FD) high density diffuse optical tomography (HD-DOT) utilising varying or combined modulation frequencies (mFD) has shown to theoretically improve the imaging accuracy as compared to conventional continuous wave (CW) measurements. Using intensity and phase data from a solid inhomogeneous phantom (NEUROPT) with three insertable rods containing different contrast anomalies, at modulation frequencies of 78 MHz, 141 MHz and 203 MHz, HD-DOT is applied and quantitatively evaluated, showing that mFD outperforms FD and CW for both absolute (iterative) and temporal (linear) tomographic imaging. The localization error (LOCA), full width half maximum (FWHM) and effective resolution (ERES) were evaluated. Across all rods, the LOCA of mFD was 61.3% better than FD and 106.1% better than CW. For FWHM, CW was 6.0% better than FD and mFD and for ERES, mFD was 1.20% better than FD and 9.83% better than CW. Using mFD data is shown to minimize the effect of inherently noisier FD phase data whilst maximising its strengths through improved contrast. © 2022 OSA – The Optical Society. All rights reserved.
Funding details
Engineering and Physical Sciences Research CouncilEPSRCEP/L016346/1
Politecnico di Milano
Document Type: Article
Publication Stage: Final
Source: Scopus
Amygdalar functional connectivity during resting and evoked pain in youth with functional abdominal pain disorders
(2022) Pain, 163 (10), pp. 2031-2043.
Cunningham, N.R.a , Nahman-Averbuch, H.b c d , Lee, G.R.e f , King, C.D.b c g , Coghill, R.C.b c g
a Department of Family Medicine, Michigan State University, Grand RapidsMI, United States
b Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
c Pediatric Pain Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
d Department of Anesthesiology, Washington University Pain Center and Division of Clinical and Translational Research, Washington University in St Louis School of Medicine, St Louis, MO, United States
e Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
f Department of Radiology, University of Cincinnati, Cincinnati, OH, United States
g Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Abstract
ABSTRACT: Pediatric functional abdominal pain disorders (FAPD) are highly prevalent, difficult to diagnose, and challenging to treat. The brain systems supporting FAPD remain poorly understood. This investigation examined the neuromechanisms of FAPD during a well-tolerated visceral pain induction task, the water load symptom provocation task (WL-SPT). Youth between the ages of 11 and 17 years participated. Functional connectivity (FC) was examined through the blood oxygenation level-dependent effect using the left and right amygdala (AMY) as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. Arterial spin labeling was used to assess regional brain activation by examining cerebral blood flow. Increased FC between the left AMY with regions associated with nociceptive processing (eg, thalamus) and right AMY FC changes with areas associated with cognitive functioning (dorsolateral prefrontal cortex) and the default mode network (DMN; parietal lobe) were observed in youth with FAPD after the WL-SPT. These changes were related to changes in pain unpleasantness. Amygdala FC changes post-WL-SPT were also related to changes in pain intensity. Amygdala FC with the DMN in youth with FAPD also differed from healthy controls. Global cerebral blood flow changes were also noted between FAPD and healthy controls, but no significant differences in grey matter were detected either between groups or during the WL-SPT in youth with FAPD. Findings confirm youth with FAPD undergo changes in brain systems that could support the development of biomarkers to enhance understanding of the mechanisms of pain and treatment response. Copyright © 2022 International Association for the Study of Pain.
Document Type: Article
Publication Stage: Final
Source: Scopus
Teaching NeuroImage: Needle-like Occipital Spikes in Children With Visual Impairment
(2022) Neurology, 99 (12), pp. 537-538.
Nascimento, F.A., McLaren, J.R., Musolino, P.L., Thiele, E.A.
From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston and the Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Posttraumatic Growth in Youth, Young Adults, and Caregivers Who Experienced Solid Organ Transplant
(2022) Journal of Pediatric Psychology, 47 (9), pp. 965-977.
Triplett, K.N.a b , Mayersohn, G.S.c d , Masood, S.S.a b , Pickwith, K.a , Mbroh, H.e f , Killian, M.g
a Department of Solid Organ Transplant, Children’s Medical Center Dallas, Dallas, TX, United States
b Department of Psychiatry, University of Texas Southwestern, Dallas, TX, United States
c Department of Psychology, St. Louis Children’s Hospital, St. Louis, MO, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, Children’s Hospital Los Angeles, Los Angeles, CA, United States
f Department of Psychiatry, University of Southern California, Los Angeles, CA, United States
g College of Social Work, Florida State University, Tallahassee, FL, United States
Abstract
OBJECTIVE: To explore posttraumatic growth (PTG) in pediatric patients who have undergone solid organ transplant (SOT) and their caregivers, and to examine potential correlates of PTG. METHOD: Youth and young adults with a history of SOT (heart, kidney, liver) at least 1 month prior to participation and caregivers completed measures of PTG, demographic, and medical factors. In total, 59 youth (M = 12.68 years, SD = 1.91), 21 young adults (M = 19.37, SD = 0.82), and 95 caregivers (M = 37.95 years, SD = 9.37) participated. RESULTS: Overall, 67% of youth, 76% of young adults, and 89% of caregivers reported PTG within the medium to very high range. Appreciation of Life was the highest PTG subscale across all groups. Youth and caregiver PTG scores were significantly positively correlated. Religious affiliation and religious coping were positively associated with PTG for caregivers, and the relationship yielded large effect sizes for young adults. Caregivers of children with kidney transplants endorsed lower PTG than other organ types and caregivers of children who had an acute medical condition endorsed greater PTG than caregivers of children who had chronic illness. CONCLUSION: Findings suggest the pediatric SOT experience can yield positive changes such as a greater appreciation of life. Although small sample sizes may have led to reduced power for detecting significant findings for some analyses, results suggest religious, medical, and parent-child relationship factors are likely related to PTG in pediatric SOT and warrant future investigation. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
parent psychosocial functioning; psychosocial functioning; resilience; transplant services
Document Type: Article
Publication Stage: Final
Source: Scopus
Aqp4 stop codon readthrough facilitates amyloid-β clearance from the brain
(2022) Brain: A Journal of Neurology, 145 (9), pp. 2982-2990.
Sapkota, D.a b c , Florian, C.a b , Doherty, B.M.d , White, K.M.a b , Reardon, K.M.d , Ge, X.e f , Garbow, J.R.e f g , Yuede, C.M.a , Cirrito, J.R.d , Dougherty, J.D.a b
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
g Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Alzheimer’s disease is initiated by the toxic aggregation of amyloid-β. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer’s disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer’s disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance. Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-β clearance in vivo, which depends on AQP4X. This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Alzheimer’s disease; amyloid beta; Aqp4; glymphatic; readthrough
Document Type: Article
Publication Stage: Final
Source: Scopus
Tissue Rotation of the Xenopus Anterior–Posterior Neural Axis Reveals Profound but Transient Plasticity at the Mid-Gastrula Stage
(2022) Journal of Developmental Biology, 10 (3), art. no. 38, .
Bolkhovitinov, L.a , Weselman, B.T.b , Shaw, G.A.c , Dong, C.d , Giribhattanavar, J.e , Saha, M.S.f
a Department of Molecular Biology, Massachusetts General Hospital, Harvard University, Boston, MA 02114, United States
b School of Medicine, Georgetown University, Washington, DC 20007, United States
c Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Baystate Medical Center, Springfield, MA 01199, United States
f Department of Biology, College of William and Mary, Williamsburg, VA 23185, United States
Abstract
The establishment of anterior–posterior (AP) regional identity is an essential step in the appropriate development of the vertebrate central nervous system. An important aspect of AP neural axis formation is the inherent plasticity that allows developing cells to respond to and recover from the various perturbations that embryos continually face during the course of development. While the mechanisms governing the regionalization of the nervous system have been extensively studied, relatively less is known about the nature and limits of early neural plasticity of the anterior–posterior neural axis. This study aims to characterize the degree of neural axis plasticity in Xenopus laevis by investigating the response of embryos to a 180-degree rotation of their AP neural axis during gastrula stages by assessing the expression of regional marker genes using in situ hybridization. Our results reveal the presence of a narrow window of time between the mid- and late gastrula stage, during which embryos are able undergo significant recovery following a 180-degree rotation of their neural axis and eventually express appropriate regional marker genes including Otx, Engrailed, and Krox. By the late gastrula stage, embryos show misregulation of regional marker genes following neural axis rotation, suggesting that this profound axial plasticity is a transient phenomenon that is lost by late gastrula stages. © 2022 by the authors.
Author Keywords
anterior–posterior; axis formation; embryo; gastrula; neural; plasticity; Xenopus
Funding details
National Institutes of HealthNIH1R15HD077624-01, 1R15HD096415-01
Document Type: Article
Publication Stage: Final
Source: Scopus
Ehrlich Tumor Induces TRPV1-Dependent Evoked and Non-Evoked Pain-like Behavior in Mice
(2022) Brain Sciences, 12 (9), art. no. 1247, .
Bertozzi, M.M.a , Saraiva-Santos, T.a , Zaninelli, T.H.a , Pinho-Ribeiro, F.A.a b , Fattori, V.a , Staurengo-Ferrari, L.a , Ferraz, C.R.a , Domiciano, T.P.a , Calixto-Campos, C.a , Borghi, S.M.a c , Zarpelon, A.C.a , Cunha, T.M.d , Casagrande, R.e , Verri, W.A.a
a Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, PR, Londrina, 86057-970, Brazil
b Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Center for Research in Health Sciences, University of Northern Londrina, PR, Londrina, 86041-120, Brazil
d Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, SP, Ribeirão Preto, 14049-900, Brazil
e Department of Pharmaceutical Sciences, Center of Health Science, Londrina State University, PR, Londrina, 86038-440, Brazil
Abstract
We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals (p < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice (p < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia (p < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain. © 2022 by the authors.
Author Keywords
AMG9810; calcium imaging; cancer pain; dorsal root ganglia; Ehrlich tumor; mechanical hyperalgesia; nociception; pain; thermal hyperalgesia; TRPV1
Funding details
405027/2021-4, 427946/2018-2
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCAPES
Ministério da Ciência, Tecnologia e InovaçãoMCTI
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq
Secretário de Ciência, Tecnologia e Ensino Superior, Governo do Estado de ParanaSETI
Fundação Araucária
Fundação Nacional de Desenvolvimento do Ensino Superior ParticularFUNADESP
Document Type: Article
Publication Stage: Final
Source: Scopus
Statistical Validation of Risk Alleles in Genetic Addiction Risk Severity (GARS) Test: Early Identification of Risk for Alcohol Use Disorder (AUD) in 74,566 Case–Control Subjects
(2022) Journal of Personalized Medicine, 12 (9), art. no. 1385, .
Blum, K.a b c d e f , Han, D.g , Gupta, A.h , Baron, D.a , Braverman, E.R.c , Dennen, C.A.i , Kazmi, S.a , Llanos-Gomez, L.c , Badgaiyan, R.D.j , Elman, I.k l , Thanos, P.K.m n , Downs, B.W.f , Bagchi, D.f o , Gondre-Lewis, M.C.p , Gold, M.S.q , Bowirrat, A.r
a Graduate College, Western University Health Sciences, Pomona, CA 91766, United States
b Institute of Psychology, ELTE Eötvös Loránd University, Egyetem tér 1-3, Budapest, 1053, Hungary
c The Kenneth Blum Institute on Behavior & Neurogenetics, LLC, Austin, TX 78701, United States
d Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT 05405, United States
e Dayton VA Medical Centre, Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH 45324, United States
f Division of Precision Nutrition, Victory Nutrition International, LLC, Lederoch, PA 19438, United States
g Department of Management Science and Statistics, University of Texas at San Antonio, San Antonio, TX 78249, United States
h Future Biologics, Lawrenceville, GA 30043, United States
i Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA 19114, United States
j Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX 78229, United States
k Center for Pain and the Brain (P.A.I.N Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
l Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, United States
m Behavioral Neuropharmacology and Neuroimaging Laboratory, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Clinical Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, United States
n Department of Psychology, University at Buffalo, Buffalo, NY 14260, United States
o Department of Pharmaceutical Science, College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, United States
p Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC 20059, United States
q Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
r Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel
Abstract
Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least Alcohol Use Disorder (AUD), Blum’s group developed the Genetic Addiction Risk Severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions published from 1990 until 2021. This analysis calculated the Hardy–Weinberg Equilibrium of each polymorphism in cases and controls. If available, the Pearson’s χ2 test or Fisher’s exact test was applied to comparisons of the gender, genotype, and allele distribution. The statistical analyses found the OR, 95% CI for OR, and a post-risk for 8% estimation of the population’s alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings. © 2022 by the authors.
Author Keywords
dopamine; Genetic Addiction Risk Severity (GARS); neurotransmitters; odds ratios; opioids; Reward Deficiency Syndrome (RDS); statistical validation of GARS
Funding details
U.S. Department of Veterans AffairsVA
Document Type: Article
Publication Stage: Final
Source: Scopus
Late-Life Depression is Associated With Increased Levels of GDF-15, a Pro-Aging Mitokine
(2022) American Journal of Geriatric Psychiatry, .
Mastrobattista, E.a , Lenze, E.J.b , Reynolds, C.F.c , Mulsant, B.H.d , Wetherell, J.e , Wu, G.F.f , Blumberger, D.M.d , Karp, J.F.g , Butters, M.A.c , Mendes-Silva, A.P.d , Vieira, E.L.d , Tseng, G.h , Diniz, B.S.a i
a UConn Center on Aging (EM, BSD), University of Connecticut, Farmington, CT, United States
b Department of Psychiatry (EJL), Washington University School of Medicine, St Louis, MO, United States
c Department of Psychiatry (CFR, MAB), University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
d Department of Psychiatry (BHM, DMB, APMS, ELV), Temerty Faculty of Medicine, University of Toronto, Centre for Addiction and Mental Health, Toronto, ON, Canada
e VA San Diego Healthcare System (JW), Mental Health Impact Unit 3, University of California, San Diego Department of Psychiatry, United States
f Department of Neurology (GFW), Washington University, St Louis, MO, United States
g Department of Psychiatry (JFK), The University of Arizona College of Medicine, Tucson, AZ, United States
h Department of Biostatistics (GT), University of Pittsburgh School of Public HealthPA, United States
i Department of Psychiatry (BSD), UConn School of Medicine, Farmington, CT, United States
Abstract
Objective: In older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance. Design: This study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals. Results: After adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression. Conclusion: Our results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging. © 2022 American Association for Geriatric Psychiatry
Author Keywords
Aging; biological markers; GDF-15; Geroscience; Late life depression
Funding details
R01 MH083660, R01AG049369, R01MH118311
National Institutes of HealthNIH
U.S. Department of JusticeDOJ
Novartis
Roche
Patient-Centered Outcomes Research InstitutePCORI
Fondation Brain Canada
Centre for Addiction and Mental HealthCAMH
Centre for Addiction and Mental Health FoundationCAMH
BrainsWay
Canadian Institutes of Health ResearchIRSC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance
(2022) Alzheimer’s and Dementia, .
Pichet Binette, A.a , Janelidze, S.a , Cullen, N.a , Dage, J.L.b , Bateman, R.J.c , Zetterberg, H.d e f g h , Blennow, K.d e , Stomrud, E.a i , Mattsson-Carlgren, N.a j k , Hansson, O.a i
a Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
b Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
d Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
e Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
f Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
g UK Dementia Research Institute at UCL, London, United Kingdom
h Hong Kong Center for Neurodegenerative Diseases, Hong Kong
i Memory Clinic, Skåne University Hospital, Malmö, Sweden
j Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
k Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
Abstract
Introduction: Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer’s disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. Methods: Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n = 748, BioFINDER-2: n = 421). We measured beta-amyloid (Aβ42, Aβ40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Results: In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. Discussion: Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. Highlights: Creatinine and body mass index (BMI) are related to certain plasma biomarker levels. Adjusting for creatinine and BMI has minor influence on plasma-cerebrospinal fluid (CSF) associations. Adjusting for creatinine and BMI has minor influence on prediction of dementia using plasma biomarkers. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; cerebrospinal fluid; dementia; glial fibrillary acidic protein; neurofilament light; p-tau
Funding details
715986
JPND2019‐466‐236
1280/20
2020‐0314
2019‐0228
720931
2018‐Projekt0279
National Institutes of HealthNIH1R01AG068398‐01
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
BrightFocus FoundationBFFA2021013F
Familjen Erling-Perssons Stiftelse
Stiftelsen för Gamla Tjänarinnor2019‐00845
EU Joint Programme – Neurodegenerative Disease ResearchJPND2019‐03401
Fonds de Recherche du Québec – SantéFRQS298314
European Research CouncilERC681712
Lunds Universitet
HjärnfondenFO2019‐0029, FO2019‐0326
Knut och Alice Wallenbergs Stiftelse2017‐0383
VetenskapsrådetVR2016‐00906
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse2018‐02532
Horizon 2020860197
AlzheimerfondenAF‐745911, AF‐930655
Region Skåne
Marcus och Amalia Wallenbergs minnesfondMAW2015.0125
UK Dementia Research InstituteUK DRI2017‐00915, 2017‐0243, 201809‐2016615, 742881
University Hospital FoundationUHF2020‐O000028
Olav Thon Stiftelsen
Stiftelsen Bundy Academy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Modulation of the mammalian GABAA receptor by type I and type II positive allosteric modulators of the α7 nicotinic acetylcholine receptor
(2022) British Journal of Pharmacology, .
Arias, H.R.a , Germann, A.L.b , Pierce, S.R.b , Sakamoto, S.c , Ortells, M.O.d , Hamachi, I.c , Akk, G.b e
a Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
d Facultad de Medicina, Universidad de Morón and CONICET, Morón, Argentina
e The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background and Purpose: Positive allosteric modulators of the α7 nicotinic acetylcholine (nACh) receptor (α7-PAMs) possess promnesic and procognitive properties and have potential in the treatment of cognitive and psychiatric disorders including Alzheimer’s disease and schizophrenia. Behavioural studies in rodents have indicated that α7-PAMs can also produce antinociceptive and anxiolytic effects that may be associated with positive modulation of the GABAA receptor. The overall goal of this study was to investigate the modulatory actions of selected α7-PAMs on the GABAA receptor. Experimental Approach: We employed a combination of cell fluorescence imaging, electrophysiology, functional competition and site-directed mutagenesis to investigate the functional and structural mechanisms of modulation of the GABAA receptor by three representative α7-PAMs. Key Results: We show that the α7-PAMs at micromolar concentrations enhance the apparent affinity of the GABAA receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi-effective at binary αβ and ternary αβγ GABAA receptors. Functional competition and site-directed mutagenesis indicate that the α7-PAMs bind to the classic anaesthetic binding sites in the transmembrane region in the intersubunit interfaces, which results in stabilization of the active state of the receptor. Conclusion and Implications: We conclude that the tested α7-PAMs are micromolar-affinity, intermediate- to low-efficacy allosteric potentiators of the mammalian αβγ GABAA receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABAA receptors to α7-PAMs, we propose that doses used to produce nACh receptor-mediated behavioural effects in vivo are likely to modulate GABAA receptor function. © 2022 British Pharmacological Society.
Author Keywords
activation; GABAA receptor; modulation; α7-PAM
Funding details
National Institutes of HealthNIH
National Institute of General Medical SciencesNIGMSR01GM108580, R35GM140947
University of Oklahoma Health Sciences CenterOUHSC
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
An Amplitude-Integrated EEG Evaluation of Neonatal Opioid Withdrawal Syndrome
(2022) American Journal of Perinatology, .
Lust, C.a , Vesoulis, Z.b , Zempel, J.c , Gu, H.d , Lee, S.b , Rao, R.b , Mathur, A.M.e
a Department of Neonatology, Children’s Minnesota NICU, St. Louis, MO, United States
b Division of Newborn Medicine, Department of Pediatrics, Washington University in St Louis, School of Medicine, St Louis, MO, United States
c Department of Neurology, Washington University in St Louis, School of Medicine, St Louis, MO, United States
d Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
e Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Saint Louis University, St. Louis, MO, United States
Abstract
Objective Infants with neonatal opioid withdrawal syndrome (NOWS) have disrupted neurobehavior that requires hospitalization and treatment. This article aimed to evaluate electroencephalography (EEG) abnormalities using amplitude-integrated EEG (aEEG) in NOWS. Study Design Eighteen term born infants with NOWS were recruited prospectively for an observational pilot study. aEEG monitoring was started within 24 hours of recruitment and twice weekly through discharge. aEEG data were analyzed for background and seizures. Severity of withdrawal was monitored using the modified Finnegan scoring (MFS) system. Results Fifteen neonates had complete datasets. Thirteen (87%) had continuous aEEG background in all recordings. None had sleep-wake cyclicity (SWC) at initial recording. Brief seizures were noted in 9 of 15 (60%) infants. Lack of SWC was associated with higher MFS scores. At discharge, 8 of 15 (53%) had absent or emerging SWC. Conclusion aEEG abnormalities (absent SWC) are frequent and persist despite treatment at the time of discharge in the majority of patients with NOWS. Brief electrographic seizures are common. Neonates with persistent aEEG abnormalities at discharge warrant close follow-up. Key Points EEG abnormalities are common and persist after clinical signs resolve in patients with NOWS. Short subclinical seizures may be seen. aEEG may identify neonates who need follow-up. © 2022 Thieme Medical Publishers, Inc.. All rights reserved.
Author Keywords
amplitude-integrated EEG; modified Finnegan score; neonatal opioid withdrawal syndrome; neonatal seizures; neonatal sleep-wake cyclicity
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
To Calibrate or not to Calibrate? A Methodological Dilemma in Experimental Pain Research
(2022) Journal of Pain, .
Adamczyk, W.M.a b , Szikszay, T.M.b , Nahman-Averbuch, H.d , Skalski, J.a , Nastaj, J.a , Gouverneur, P.e , Luedtke, K.b c
a Laboratory of Pain Research, Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
b Institute of Health Sciences, Department of Physiotherapy, Pain & Exercise Research Luebeck (P.E.R.L.), University of Lübeck, Lübeck, Germany
c Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
d Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
e Institute of Medical Informatics, University of Lübeck, Lübeck, Germany
Abstract
To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the nociceptive system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of “noxiousness” by the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the optimal approach for experimental pain studies and provides recommendations for different study designs. © 2022 The Authors
Author Keywords
Calibration; Experimental Pain; Fixed Stimulus; Individualized Intensity; offset analgesia; Scaling
Funding details
Narodowe Centrum NaukiNCN2020/37/B/HS6/04196
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Survival After Resection of Newly-Diagnosed Intracranial Grade II Ependymomas: An Initial Multicenter Analysis and the Logistics of Intraoperative Magnetic Resonance Imaging
(2022) World Neurosurgery, .
Yahanda, A.T.a , Rich, K.M.a , Dacey, R.G., Jr.a , Zipfel, G.J.a , Dunn, G.P.a , Dowling, J.L.a , Smyth, M.D.a , Leuthardt, E.C.a , Limbrick, D.D., Jr.a , Honeycutt, J.b , Sutherland, G.R.c , Jensen, R.L.d , Evans, J.a , Chicoine, M.R.a
a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Neurological Surgery, Cook Children’s Medical Center, Fort Worth, TX, United States
c Department of Neurological Surgery, University of Calgary School of Medicine, Calgary, AB, Canada
d Department of Neurological Surgery, University of Utah School of Medicine, Salt Lake City, UT, United States
Abstract
Objective: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions. Methods: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined. Results: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan–Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72). Conclusions: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI. © 2022 Elsevier Inc.
Author Keywords
Ependymoma; Extent of resection; Grade II glioma; Intraoperative MRI; Overall survival; Progression-free survival
Funding details
UL1 TR000448
National Cancer InstituteNCIP30 CA091842
Alvin J. Siteman Cancer Center
Head for the Cure FoundationHFTC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Long-term neurologic outcomes of COVID-19
(2022) Nature Medicine, .
Xu, E.a , Xie, Y.a b c , Al-Aly, Z.a b d e f
a Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO, United States
b Veterans Research and Education Foundation of St. Louis, St. Louis, MO, United States
c Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
d Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Nephrology Section, Medicine Service, VA St. Louis Health Care System, St. Louis, MO, United States
f Institute for Public Health, Washington University in St. Louis, St. Louis, MO, United States
Abstract
The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19. © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Funding details
U.S. Department of Veterans AffairsVA
American Society of NephrologyASN
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Predicting at-risk opioid use three months after ed visit for trauma: Results from the AURORA study
(2022) PloS One, 17 (9), p. e0273378.
Punches, B.E.a b , Stolz, U.c , Freiermuth, C.E.c d , Ancona, R.M.e , McLean, S.A.f g , House, S.L.e , Beaudoin, F.L.h , An, X.f , Stevens, J.S.i , Zeng, D.j , Neylan, T.C.k , Clifford, G.D.l m , Jovanovic, T.n , Linnstaedt, S.D.f , Germine, L.T.o p q , Bollen, K.A.r , Rauch, S.L.o q s , Haran, J.P.t , Storrow, A.B.u , Lewandowski, C.v , Musey, P.I., Jrw , Hendry, P.L.x , Sheikh, S.x , Jones, C.W.y , Kurz, M.C.z aa ab , Gentile, N.T.ac , McGrath, M.E.ad , Hudak, L.A.ae , Pascual, J.L.af ag , Seamon, M.J.ag ah , Harris, E.ai aj , Chang, A.M.ak , Pearson, C.al , Peak, D.A.am , Merchant, R.C.an , Domeier, R.M.ao , Rathlev, N.K.ap , O’Neil, B.J.al , Sanchez, L.D.aq ar , Bruce, S.E.as , Pietrzak, R.H.at au , Joormann, J.av , Barch, D.M.aw , Pizzagalli, D.A.q ax , Smoller, J.W.ay az , Luna, B.ba , Harte, S.E.bb bc , Elliott, J.M.bd be bf , Kessler, R.C.bg , Ressler, K.J.q ax , Koenen, K.C.bh , Lyons, M.S.c d
a College of Nursing, Ohio State University, Columbus, OH, United States
b Department of Emergency Medicine College of Medicine, Ohio State University, Columbus, OH, United States
c Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, United States
d Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, United States
e Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
f Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel HillNC, United States
g Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel HillNC, United States
h Department of Emergency Medicine & Department of Health Services, Policy, Practice, Alpert Medical School of Brown University, Rhode Island Hospital and The Miriam Hospital, Providence, RI, United States
i Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
j Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel HillNC, United States
k Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
l Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
m Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
n Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MA, United States
o Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
p Many Brains Project, Belmont, MA, United States
q Department of Psychiatry, Harvard Medical School, Boston, MA, United States
r Department of Psychology and Neuroscience & Department of Sociology, University of North Carolina at Chapel Hill, Chapel HillNC, United States
s Department of Psychiatry, McLean Hospital, Belmont, MA, United States
t Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, United States
u Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
v Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
w Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
x Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, United States
y Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
z Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, AL, United States
aa Department of Surgery, Division of Acute Care Surgery, University of Alabama School of Medicine, Birmingham, AL, United States
ab Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States
ac Department of Emergency Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
ad Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
ae Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
af Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Pennsylvania, PA, United States of America
ag Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, United States of America
ah Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Pennsylvania, PA, United States of America
ai Department of Emergency Medicine, Einstein Healthcare Network, Pennsylvania, PA, United States of America
aj Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Pennsylvania, PA, United States of America
ak Department of Emergency Medicine, Jefferson University Hospitals, Pennsylvania, PA, United States of America
al Department of Emergency Medicine, Wayne State University, Detroit, MA, United States
am Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
an Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ao Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
ap Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
aq Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
ar Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
as Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO, United States
at National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, United States
au Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
av Department of Psychology, Yale School of Medicine, New Haven, CT, United States
aw Department of Psychological & Brain Sciences, Washington University in St. LouisMO, United States
ax McLean Hospital, Belmont, MA, United States
ay Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
az Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
ba Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
bb Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
bc Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
bd Kolling Institute, University of Sydney, St Leonards, NSW, Australia
be Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health DistrictNSW, Australia
bf Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
bg Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
bh Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
Abstract
OBJECTIVE: Whether short-term, low-potency opioid prescriptions for acute pain lead to future at-risk opioid use remains controversial and inadequately characterized. Our objective was to measure the association between emergency department (ED) opioid analgesic exposure after a physical, trauma-related event and subsequent opioid use. We hypothesized ED opioid analgesic exposure is associated with subsequent at-risk opioid use. METHODS: Participants were enrolled in AURORA, a prospective cohort study of adult patients in 29 U.S., urban EDs receiving care for a traumatic event. Exclusion criteria were hospital admission, persons reporting any non-medical opioid use (e.g., opioids without prescription or taking more than prescribed for euphoria) in the 30 days before enrollment, and missing or incomplete data regarding opioid exposure or pain. We used multivariable logistic regression to assess the relationship between ED opioid exposure and at-risk opioid use, defined as any self-reported non-medical opioid use after initial ED encounter or prescription opioid use at 3-months. RESULTS: Of 1441 subjects completing 3-month follow-up, 872 participants were included for analysis. At-risk opioid use occurred within 3 months in 33/620 (5.3%, CI: 3.7,7.4) participants without ED opioid analgesic exposure; 4/16 (25.0%, CI: 8.3, 52.6) with ED opioid prescription only; 17/146 (11.6%, CI: 7.1, 18.3) with ED opioid administration only; 12/90 (13.3%, CI: 7.4, 22.5) with both. Controlling for clinical factors, adjusted odds ratios (aORs) for at-risk opioid use after ED opioid exposure were: ED prescription only: 4.9 (95% CI 1.4, 17.4); ED administration for analgesia only: 2.0 (CI 1.0, 3.8); both: 2.8 (CI 1.2, 6.5). CONCLUSIONS: ED opioids were associated with subsequent at-risk opioid use within three months in a geographically diverse cohort of adult trauma patients. This supports need for prospective studies focused on the long-term consequences of ED opioid analgesic exposure to estimate individual risk and guide therapeutic decision-making.
Document Type: Article
Publication Stage: Final
Source: Scopus