"Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage" (2021) Brain Research
Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage
(2021) Brain Research, 1750, art. no. 147169, .
Athiraman, U.a , Liu, M.a , Jayaraman, K.b , Yuan, J.a , Mehla, J.b , Zipfel, G.J.c
a Department of Anesthesiology, Washington University, St. Louis, MO 63110, United States
b Department of Neurological Surgery, Washington University, St. Louis, MO 63110, United States
c Departments of Neurological Surgery and Neurology, Washington University, St. Louis, MO 63110, United States
Abstract
Delayed cerebral ischemia (DCI) is identified as one of the significant contributors to poor patient outcome after aneurysmal subarachnoid hemorrhage (SAH). We previously reported that a supratherapeutic dose of isoflurane conditioning (2%) provided robust protection against SAH-induced DCI. The aim of our current study is to compare the efficacy of the supratherapeutic dose of isoflurane to that typically used to establish general anesthesia or sedation. After IRB approval for animal studies, ten to fourteen-week-old wild-type male mice (C57BL/6) were divided into five groups – sham, SAH alone, or SAH with isoflurane conditioning (0.5%, 1%, and 2%). Conditioning was performed with one-hour of isoflurane initiated one-hour after induction of SAH via endovascular perforation technique. Vasospasm measurement in the middle cerebral artery was assessed 72 h after SAH. Neurological assessment was performed at baseline and for next three days after SAH. It was identified that all tested doses of isoflurane conditioning (0.5%, 1%, and 2%) significantly attenuated large artery vasospasm and markedly improved neurological deficits following SAH. No significant differences in neurovascular outcome were noted between the three doses of isoflurane conditioning. Our data show that isoflurane dosing typically used for general anesthesia (1%) or sedation (0.5%) provide similar levels of DCI protection in SAH as that provided by a supratherapeutic dose (2%). This result has important implications for future translational studies. Additional studies examining the therapeutic potential of anesthetic conditioning for SAH are therefore warranted. © 2020 Elsevier B.V.
Author Keywords
Aneurysmal subarachnoid hemorrhage; DCI; Isoflurane concentration; Neurologic outcome
Document Type: Article
Publication Stage: Final
Source: Scopus
"Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits" (2020) Nature Communications
Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits
(2020) Nature Communications, 11 (1), art. no. 5562, .
Quach, B.C.a , Bray, M.J.b , Gaddis, N.C.a , Liu, M.c , Palviainen, T.d , Minica, C.C.e , Zellers, S.c , Sherva, R.f , Aliev, F.g h , Nothnagel, M.i j , Young, K.A.k , Marks, J.A.a , Young, H.c , Carnes, M.U.a , Guo, Y.a l , Waldrop, A.a , Sey, N.Y.A.m , Landi, M.T.n , McNeil, D.W.o p , Drichel, D.i j , Farrer, L.A.f q r s t , Markunas, C.A.a , Vink, J.M.u , Hottenga, J.-J.e , Iacono, W.G.c , Kranzler, H.R.v w , Saccone, N.L.x y , Neale, M.C.z aa , Madden, P.b , Rietschel, M.ab , Marazita, M.L.ac , McGue, M.c , Won, H.m , Winterer, G.ad , Grucza, R.ae , Dick, D.M.g af ag , Gelernter, J.ah ai aj ak , Caporaso, N.E.al , Baker, T.B.am , Boomsma, D.I.e , Kaprio, J.d an , Hokanson, J.E.k , Vrieze, S.c , Bierut, L.J.b , Johnson, E.O.a ao , Hancock, D.B.a
a GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC 27709, United States
b Department of Psychiatry, Washington University, St. Louis, MO 63130, United States
c Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN 55455, United States
d Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00290, Finland
e Department of Biological Psychology, Vrije Universiteit, Amsterdam, 1081 BT, Netherlands
f Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, United States
g Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284, United States
h Faculty of Business, Karabuk University, Kılavuzlar/Karabük Merkez/Karabük, 78050, Turkey
i Cologne Center for Genomics, University of Cologne, Köln, 50931, Germany
j University Hospital Cologne, Köln, 50931, Germany
k Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
l GeneCentric Therapeutics, Research Triangle Park, NC 27709, United States
m Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
n Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD 20892, United States
o Department of Psychology, West Virginia University, Morgantown, WV 26505, United States
p Department of Dental Practice and Rural Health, West Virginia University, Morgantown, WV 26505, United States
q Department of Neurology, Boston University School of Medicine, Boston, MA 02118, United States
r Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, United States
s Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, United States
t Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, United States
u Behavioural Science Institute, Radboud University, Nijmegen, 6500 HE, Netherlands
v Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States
w VISN 4 MIRECC, Crescenz VA Medical Center, Philadelphia, PA 19104, United States
x Department of Genetics, Washington University, St. Louis, MO 63130, United States
y Division of Biostatistics, Washington University, St. Louis, MO 63130, United States
z Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, United States
aa Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23284, United States
ab Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, 68159, Germany
ac Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States
ad Experimental & Clinical Research Center, Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, Berlin, 10117, Germany
ae Departments of Family and Community Medicine and Health and Clinical Outcomes Research, Saint Louis University, St. Louis, MO 63130, United States
af College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA 23284, United States
ag Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23284, United States
ah Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, United States
ai Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, United States
aj Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, United States
ak Department of Psychiatry, VA CT Healthcare Center, West Haven, CT 06511, United States
al Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD 20892, United States
am Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, United States
an Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
ao Fellow Program, RTI International, Research Triangle Park, NC 27709, United States
Abstract
Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking. © 2020, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina" (2020) NPJ Aging and Mechanisms of Disease
Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
(2020) NPJ Aging and Mechanisms of Disease, 6 (1), art. no. 12, .
Mandala, A.a , Armstrong, A.a , Girresch, B.b , Zhu, J.b , Chilakala, A.a , Chavalmane, S.c , Chaudhary, K.d , Biswas, P.c , Ogilvie, J.b , Gnana-Prakasam, J.P.a e
a Department of Ophthalmology, Saint Louis University, St. Louis, MO, United States
b Department of Biology, Saint Louis University, St. Louis, MO, United States
c Department of Energy, Environmental and Chemical Engineering, Washington University, St. Louis, MO, United States
d Department of Medicine, Washington University, St. Louis, MO, United States
e Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, United States
Abstract
Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin–angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin–angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases. © 2020, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Voltage-based automated detection of postictal generalized electroencephalographic suppression: Algorithm development and validation" (2020) Clinical Neurophysiology
Voltage-based automated detection of postictal generalized electroencephalographic suppression: Algorithm development and validation
(2020) Clinical Neurophysiology, 131 (12), pp. 2817-2825.
Brian Hickman, L.a b , Edward Hogan, R.c , Labonte, A.K.b , Kafashan, M.b , Chan, C.W.b , Huels, E.R.d e , Ching, S.f g , Lenze, E.J.h , Maccotta, L.c , Eisenman, L.N.c , Keith Day, B.c , Farber, N.B.h , Avidan, M.S.b h , Palanca, B.J.A.b g i
a Department of Internal Medicine, University of California, Irvine School of Medicine, Orange, CA, United States
b Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
e Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States
f Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
g Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
h Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
i Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objective: Postictal generalized electroencephalographic suppression (PGES) is a pattern of low-voltage scalp electroencephalographic (EEG) activity following termination of generalized seizures. PGES has been associated with both sudden unexplained death in patients with epilepsy and therapeutic efficacy of electroconvulsive therapy (ECT). Automated detection of PGES epochs may aid in reliable quantification of this phenomenon. Methods: We developed a voltage-based algorithm for detecting PGES. This algorithm applies existing criteria to simulate expert epileptologist readings. Validation relied on postictal EEG recording from patients undergoing ECT (NCT02761330), assessing concordance among the algorithm and four clinical epileptologists. Results: We observed low-to-moderate concordance among epileptologist ratings of PGES. Despite this, the algorithm displayed high discriminability in comparison to individual epileptologists (C-statistic range: 0.86–0.92). The algorithm displayed high discrimination (C-statistic: 0.91) and substantial peak agreement (Cohen’s Kappa: 0.65) in comparison to a consensus of clinical ratings. Interrater agreement between the algorithm and individual epileptologists was on par with that among expert epileptologists. Conclusions: An automated voltage-based algorithm can be used to detect PGES following ECT, with discriminability nearing that of experts. Significance: Algorithmic detection may support clinical readings of PGES and improve precision when correlating this marker with clinical outcomes following generalized seizures. © 2020
Author Keywords
Algorithms; Electroconvulsive Therapy (ECT); Major depressive disorder; Postictal generalized EEG suppression; Seizure; Sudden unexplained death in epilepsy
Document Type: Article
Publication Stage: Final
Source: Scopus
"Is cochlear synapse loss an origin of low-frequency hearing loss associated with endolymphatic hydrops?" (2020) Hearing Research
Is cochlear synapse loss an origin of low-frequency hearing loss associated with endolymphatic hydrops?
(2020) Hearing Research, 398, art. no. 108099, .
Valenzuela, C.V.a , Lee, C.b , Mispagel, A.c , Bhattacharyya, A.d , Lefler, S.M.a , Payne, S.a , Goodman, S.S.e , Ortmann, A.J.a b , Buchman, C.A.a , Rutherford, M.A.a , Lichtenhan, J.T.a c
a Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine in St. Louis, 660 South Euclid Avenue, Saint Louis, MO 63110, United States
b Department of Otolaryngology, University of Rochester, Rochester, NY, United States
c Program in Audiology and Communication Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Washington University in St. Louis, St. Louis, MO, United States
e Communication Sciences and Disorders, University of Iowa, Iowa City, IA, United States
Abstract
There is a strong association between endolymphatic hydrops and low-frequency hearing loss, but the origin of the hearing loss remains unknown. A reduction in the number of cochlear afferent synapses between inner hair cells and auditory nerve fibres may be the origin of the low-frequency hearing loss, but this hypothesis has not been directly tested in humans or animals. In humans, measurements of hearing loss and postmortem temporal-bone based measurements of endolymphatic hydrops are generally separated by large amounts of time. In animals, there has not been a good objective, physiologic, and minimally invasive measurement of low-frequency hearing. We overcame this obstacle with the combined use of a reliable surgical approach to ablate the endolymphatic sac in guinea pigs and create endolymphatic hydrops, the Auditory Nerve Overlapped Waveform to measure low-frequency hearing loss (≤ 1 kHz), and immunohistofluorescence-based confocal microscopy to count cochlear synapses. Results showed low- and mid-(1–4 kHz) frequency hearing loss at all postoperative days, 1, 4, and 30. There was no statistically significant loss of cochlear synapses, and there was no correlation between synapse loss and hearing function. We conclude that cochlear afferent synaptic loss is not the origin of the low-frequency hearing loss in the early days following endolymphatic sac ablation. Understanding what is, and is not, the origin of a hearing loss can help guide preventative and therapeutic development. © 2020
Author Keywords
Auditory Nerve Overlapped Waveform; Endolymphatic hydrops; Low-frequency hearing loss; Ménière’s disease; Ribbon synapse
Document Type: Article
Publication Stage: Final
Source: Scopus
"Cognitive behavioral intervention for trauma in adolescent girls in child welfare: A randomized controlled trial" (2020) Children and Youth Services Review
Cognitive behavioral intervention for trauma in adolescent girls in child welfare: A randomized controlled trial
(2020) Children and Youth Services Review, 119, art. no. 105602, .
Auslander, W., Edmond, T., Foster, A., Smith, P., McGinnis, H., Gerke, D., Tlapek, S., Threlfall, J., Voth Schrag, R., Dunn, J., Jonson-Reid, M.
Washington University in St. Louis, United States
Abstract
Objective: This study tested the effectiveness of Cognitive Behavioral Intervention for Trauma in Schools (CBITS) in adolescent girls involved in the child welfare system. Three outcomes were evaluated: symptoms of posttraumatic stress disorder (PTSD), depression, and social problem-solving skills. Method: A randomized controlled trial was utilized to compare the effects of an adapted version of CBITS with usual care (UC) services. Participants were ages 12 to 19 (N = 249), the majority of whom (69.5%) were African American. Participants’ symptoms of PTSD, depression, and social problem-solving skills were evaluated at pre, post (3 months), and follow-up (6 months) assessments. Linear mixed models were used to compare condition by time interactions using all available data. Control variables were demographics, service use, and number of types of traumas. Treatment fidelity, participant acceptability, and satisfaction with the intervention were also examined. Results: Analyses indicated that participants in the CBITS condition showed significantly greater increases in social problem-solving than the UC condition. For both PTSD and depression symptoms, there were no significant differences between the two conditions. Both the CBITS and UC participants showed significant reductions in symptoms. Results also indicated that this intervention is an acceptable model for this population. Conclusions: Despite the growth of trauma-focused, evidence-supported interventions for reducing PTSD and depression, knowledge of effective interventions in child welfare youth lags behind. Because CBITS is more effective than UC in increasing social problem-solving skills, this intervention may be an important treatment option for this population. © 2020 The Author(s)
Author Keywords
Child welfare; Depression; PTSD; Social problem-solving; Trauma
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Spontaneously emerging patterns in human visual cortex and their functional connectivity are linked to the patterns evoked by visual stimuli" (2020) Journal of Neurophysiology
Spontaneously emerging patterns in human visual cortex and their functional connectivity are linked to the patterns evoked by visual stimuli
(2020) Journal of Neurophysiology, 124 (5), pp. 1343-1363.
Kim, D.a , Livne, T.b c , Metcalf, N.V.c , Corbetta, M.c d e f g h , Shulman, G.L.c d
a Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MS, United States
b Department of Neurobiology, Weizmann Institution of Science, Rehovot, Israel
c Department of Neurology, Washington University School of Medicine, St. Louis, MS, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MS, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MS, United States
f Department of Neuroscience, University of Padova, Padova, Italy
g Padova Neuroscience Center (PNC), University of Padova, Padova, Italy
h Venetian Institute of Molecular Medicine (VIMM), Padova, Italy
Abstract
The function of spontaneous brain activity is an important issue in neuroscience. Here we test the hypothesis that patterns of spontaneous activity code representational patterns evoked by stimuli. We compared in human visual cortex multivertex patterns of spontaneous activity to patterns evoked by ecological visual stimuli (faces, bodies, scenes) and low-level visual features (e.g., phase-scrambled faces). Specifically, we identified regions that preferred particular stimulus categories during localizer scans (e.g., extrastriate body area for bodies), measured multivertex patterns for each category during event-related task scans, and then correlated over vertices these stimulus-evoked patterns to the pattern measured on each frame of resting-state scans. The mean correlation coefficient was essentially zero for all regions/stimulus categories, indicating that resting multivertex patterns were not biased toward particular stimulus-evoked patterns. However, the spread of correlation coefficients between stimulus-evoked and resting patterns, positive and negative, was significantly greater for the preferred stimulus category of an ROI. The relationship between spontaneous and stimulus-evoked multivertex patterns also governed the temporal correlation or functional connectivity of patterns of spontaneous activity between individual regions (pattern-based functional connectivity). Resting multivertex patterns related to an object category fluctuated preferentially between ROIs preferring the same category, and fluctuations of the pattern for a category (e.g., body) within its preferred ROIs were largely uncorrelated with fluctuations of the pattern for a disparate category (e.g., scene) within its preferred ROIs. These results support the proposal that spontaneous multivertex activity patterns are linked to stimulus-evoked patterns, consistent with a representational function for spontaneous activity. NEW & NOTEWORTHY Spontaneous brain activity was once thought to reflect only noise, but evidence of strong spatiotemporal regularities has motivated a search for functional explanations. Here we show that the spatial pattern of spontaneous activity in human high-level and early visual cortex is related to the spatial patterns evoked by stimuli. Moreover, these patterns partly govern spontaneous spatiotemporal interactions between regions, so-called functional connectivity. These results support the hypothesis that spontaneous activity serves a representational function. © 2020 American Physiological Society. All rights reserved.
Author Keywords
Bold fMRI; Functional connectivity; Multivariate pattern analysis (MVPA); Resting state; Spontaneous activity
Document Type: Article
Publication Stage: Final
Source: Scopus
"Stability of motor cortex network states during learning-associated neural reorganizations" (2020) Journal of Neurophysiology
Stability of motor cortex network states during learning-associated neural reorganizations
(2020) Journal of Neurophysiology, 124 (5), pp. 1327-1342.
Ma, Z.a , Liu, H.b , Komiyama, T.b , Wessel, R.a
a Department of Physics, Washington University in St. Louis, Saint Louis, Missouri
b Neurobiology Section and Department of Neuroscience, University of California San Diego, La JollaCA
Abstract
A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.
Author Keywords
brain state; criticality; motor learning; neuronal avalanches; two-photon calcium imaging
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Natural History of Hemodynamics in Vertebrobasilar Disease: Temporal Changes in the VERiTAS Study Cohort" (2020) Stroke
Natural History of Hemodynamics in Vertebrobasilar Disease: Temporal Changes in the VERiTAS Study Cohort
(2020) Stroke, 51 (11), pp. 3295-3301.
Amin-Hanjani, S.a , See, A.P.a , Du, X.a , Rose-Finnell, L.a , Pandey, D.K.b , Chen, Y.-F.c , Elkind, M.S.V.d , Zipfel, G.J.e , Liebeskind, D.S.f , Silver, F.L.g , Kasner, S.E.h , Gorelick, P.B.i , Charbel, F.T.a , Derdeyn, C.P.j , VERiTAS Study Groupk
a Department of Neurosurgery (S.A.-H., A.P.S., F.T.C.), University of Illinois at Chicago
b Department of Neurology and Rehabilitation (D.K.P.), University of Illinois at Chicago
c Center for Clinical and Translational Science (Y.-F.C.), University of Illinois at Chicago
d Departments of Neurology and Epidemiology, Columbia University
e Departments of Neurosurgery and Neurology, Washington University in St Louis
f Department of Neurology
g Division of Neurology, Department of Medicine, University of Toronto, ON
h Department of Neurology, University of Pennsylvania
i Department of Translational Neuroscience, Michigan State University College of Human Medicine
j Department of Radiology, University of Iowa Hospitals and Clinics
Abstract
BACKGROUND AND PURPOSE: The role of regional hypoperfusion as a contributor to stroke risk in atherosclerotic vertebrobasilar disease has recently been confirmed by the observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) Study. We examined the stability of hemodynamic status over time and its relationship to stroke risk in patients from this prospective cohort. METHODS: VERiTAS enrolled patients with recently symptomatic ≥50% atherosclerotic stenosis/occlusion of vertebral and/or basilar arteries. Large vessel flow in the vertebrobasilar territory was assessed using quantitative magnetic resonance angiography, and patients were designated as low or normal flow based on distal territory regional flow, incorporating collateral capacity. Patients underwent standard medical management and follow-up for primary outcome event of vertebrobasilar territory stroke. Quantitative magnetic resonance angiography imaging was repeated at 6, 12, and 24 months. Flow status over time was examined relative to baseline and relative to subsequent stroke risk using a cause-specific proportional hazard model, with flow status treated as a time-varying covariate. Mean blood pressure was examined to assess for association with changes in flow status. RESULTS: Over 19±8 months of follow-up, 132 follow-up quantitative magnetic resonance angiography studies were performed in 58 of the 72 enrolled patients. Of the 13 patients with serial imaging who had low flow at baseline, 7 (54%) had improvement to normal flow at the last follow-up. Of the 45 patients who had normal flow at baseline, 3 (7%) converted to low flow at the last follow-up. The mean blood pressure did not differ in patients with or without changes in flow status. The time-varying flow status remained a strong predictor of subsequent stroke (hazard ratio, 10.3 [95% CI, 2.2-48.7]). CONCLUSIONS: There is potential both for improvement and worsening of hemodynamics in patients with atherosclerotic vertebrobasilar disease. Flow status, both at baseline and over time, is a risk factor for subsequent stroke, thus serving as an important prognostic marker. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00590980.
Author Keywords
atherosclerosis; blood pressure; hemodynamics; ischemic attack, transient; magnetic resonance angiography; stroke; vertebrobasilar insufficiency
Document Type: Article
Publication Stage: Final
Source: Scopus
"The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach" (2020) International Journal of Environmental Research and Public Health
The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach
(2020) International Journal of Environmental Research and Public Health, 17 (21), art. no. 7921, pp. 1-14.
Ekblad, M.O.a , Marceau, K.b , Rolan, E.c , Palmer, R.H.C.d , Todorov, A.e , Heath, A.C.e , Knopik, V.S.b
a Department of General Practice, Institute of Medicine, Turku University and Turku University Hospital, Turku, 20014, Finland
b Department of Human Development and Family Studies, Purdue University, West Lafayette, IN 47906, United States
c Department of Psychology, Michigan State University, East Lansing, MI 48824, United States
d Department of Psychology, Behavioral Genetics of Addiction Laboratory, Emory University, Atlanta, GA 30322, United States
e Department of Psychiatry, Midwest Alcoholism Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
Abstract
The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07, p = 0.04) was observed in the sibling comparison model. The positive directionality score indicates that SDP is associated with differentiation of symptoms towards externalizing rather than internalizing symptoms after controlling for familial confounds with a sibling comparison model. This supports a potentially causal relationship between SDP and externalizing behavior. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Genetically-informed designs; Health consequences; Prenatal exposure; Sibling comparison; Tobacco
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Rapid transfer of knowledge for multiple sclerosis clinical care during COVID-19: ECHO MS" (2020) Multiple Sclerosis and Related Disorders
Rapid transfer of knowledge for multiple sclerosis clinical care during COVID-19: ECHO MS
(2020) Multiple Sclerosis and Related Disorders, 46, art. no. 102600, .
Alschuler, K.N.a b , von Geldern, G.a b , Ball, D.c , Costello, K.c , Skeen, M.d , Chahin, S.e , Wundes, A.a b
a Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA, United States
b Department of Neurology, University of Washington School of Medicine, Seattle, WA, United States
c National Multiple Sclerosis Society, New York, NY, United States
d Department of Neurology, Duke University School of Medicine, Durham, NC, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Healthcare providers caring for people with multiple sclerosis (MS) have had significant concerns about the intersection of MS and COVID-19. As a result, there has been an urgency to understand and share information about how to best provide MS clinical care during COVID-19. The Project ECHO model is well-suited for this challenge, as it provides a uniquely efficient and effective approach to sharing information in real-time using real cases. We report on the translation of the Project ECHO model for the rapid sharing of knowledge among MS clinical providers during COVID-19. Methods: The ECHO MS COVID-19 Response Clinic was a videoconference-based education and case consultation program offered to providers in the U.S. who care for individuals with MS. The Response Clinic was offered as four sessions, each delivered by three regional hubs. Data were collected on participation and the self-reported impact of the program. Results: A total of 132 unique providers participated in the Response Clinic, which consisted of 11 didactic modules and 43 case consultations. Participant providers overwhelmingly indicated that the program improved their knowledge, attitude, and skills for providing healthcare for people with MS during the COVID-19 pandemic. Discussion: The Project ECHO model was successfully adapted to serve the needs of the MS community during COVID-19, suggesting the program could be continued or could be expanded to other disease areas for a similar purpose. More research is needed to objectively measure the impact of the program on patient outcomes. © 2020
Author Keywords
CME; COVID-19; Methods of education; Multiple sclerosis
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Relations between sensory responsiveness and features of autism in children" (2020) Brain Sciences
Relations between sensory responsiveness and features of autism in children
(2020) Brain Sciences, 10 (11), art. no. 775, pp. 1-15.
Feldman, J.I.a , Cassidy, M.b c , Liu, Y.b d , Kirby, A.V.e , Wallace, M.T.a f g h i j k , Woynaroski, T.G.a f g h
a Department of Hearing & Speech Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States
b Neuroscience Undergraduate Program, Vanderbilt University, Nashville, TN 37232, United States
c National Institutes of Health, BethesdaMD 20814, United States
d Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
e Department of Occupational and Recreational Therapies, University of Utah, Salt Lake City, UT 84112, United States
f Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States
g Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, United States
h Frist Center for Autism & Innovation, Vanderbilt University, Nashville, TN 37232, United States
i Department of Psychology, Vanderbilt University, Nashville, TN 37232, United States
j Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States
k Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States
Abstract
Autism is a neurodevelopmental condition defined by differences in social communication and by the presence of restricted and repetitive patterns of behavior, interests, and activities (RRBs). Individuals with autism also commonly present with atypical patterns of sensory responsiveness (i.e., hyporesponsiveness, hyperresponsiveness, and sensory seeking), which are theorized to produce cascading effects across other domains of development. The purpose of this study was to examine differences in sensory responsiveness in children with and without autism (ages 8–18 years), as well as relations between patterns of sensory responsiveness and core and related features of autism. Participants were 50 children with autism and 50 non-autistic peers matched on age and sex. A comprehensive clinical battery included multiple measures of sensory responsiveness, core features of autism, adaptive behavior, internalizing behaviors, cognitive ability, and language ability. Groups significantly differed on all three patterns of sensory responsiveness. Some indices of core and related autism features were robustly associated with all three patterns of sensory responsiveness (e.g., RRBs), while others were more strongly associated with discrete patterns of sensory responsiveness (i.e., internalizing problem behaviors and hyperresponsiveness, language and sensory seeking). This study extends prior work to show that differences in sensory responsiveness that are linked with core and related features of autism persist in older children and adolescents on the spectrum. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Autism; Hyperresponsiveness; Hyporesponsiveness; Language; Sensory responsiveness; Sensory seeking
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing loss in mice" (2020) Journal of Neuroscience
Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing loss in mice
(2020) Journal of Neuroscience, 40 (44), pp. 8556-8572.
Perkins, G.a , Lee, J.H.b , Park, S.b , Kang, M.b , Perez-Flores, M.C.b , Ju, S.a , Phillips, G.c , Lysakowski, A.d , Gratton, M.A.c , Yamoah, E.N.b
a National Center for Microscopy and Imaging Research, University of California, San Diego, San Diego, CA 92093, United States
b University of Nevada, Reno, NV 89557, United States
c Washington University, School of Medicine, St. Louis, MO 63110, United States
d Departments of Anatomy and Cell Biology and Otolaryngology, University of Illinois at Chicago, Chicago, IL 60612, United States
Abstract
Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular Ca21 flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing loss, the objective of this study was to investigate whether the structural and functional coupling of mitochondria with subsurface cisternae (SSC) was affected by aging. We applied functional and structural probes to equal numbers of male and female mice with a hearing phenotype akin to human aging. We discovered the polarization of cristae and crista junctions in mitochondria tethered to the SSC in OHCs. Aging was associated with SSC stress and decoupling of mitochondria with the SSC, mitochondrial fission/ fusion imbalance, a remarkable reduction in mitochondrial and cytoplasmic Ca21 levels, reduced K1-induced Ca21 uptake, and marked plasticity of cristae membranes. A model of structure-based ATP production predicts profound energy stress in older OHCs. This report provides data suggesting that altered membrane organelle connectomics may result in progressive hearing loss. © 2020 the authors
Author Keywords
Calcium homeostasis; Deafness; Hearing loss; Inner ear; Mitochondria; Outer hair cells
Document Type: Article
Publication Stage: Final
Source: Scopus
"SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration" (2020) eLife
SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration
(2020) eLife, 9, .
Sasaki, Y.a , Kakita, H.a b , Kubota, S.c , Sene, A.c , Lee, T.J.c , Ban, N.c , Dong, Z.c , Lin, J.B.c , Boye, S.L.d , DiAntonio, A.e f , Boye, S.E.g , Apte, R.S.c e h , Milbrandt, J.a f
a Department of Genetics, Washington University School of Medicine, St. Louis, United States
b Department of Perinatal and Neonatal Medicine, Aichi Medical UniversityAichi, Japan
c Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, United States
d Department of Pediatrics, Powell Gene Therapy Center, Gainesville, United States
e Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States
f Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, United States
g Department of Pediatrics, Division of Cellular and Molecular Therapy, Gainesville, United States
h Department of Medicine, Washington University School of Medicine, St. Louis, United States
Abstract
Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies. © 2020, Sasaki et al.
Author Keywords
axonal degeneration; LCA9; mouse; NAD+; neuroscience; NMNAT1; retinal degenerations; SARM1
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants" (2020) JAMA Network Open
Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants
(2020) JAMA Network Open, 3 (10), p. e2022847.
Staffaroni, A.M.a , Goh, S.-Y.M.a , Cobigo, Y.a , Ong, E.a , Lee, S.E.a , Casaletto, K.B.a , Wolf, A.a , Forsberg, L.K.b , Ghoshal, N.c d , Graff-Radford, N.R.e , Grossman, M.f , Heuer, H.W.a , Hsiung, G.-Y.R.g , Kantarci, K.h , Knopman, D.S.b , Kremers, W.K.i , Mackenzie, I.R.j , Miller, B.L.a , Pedraza, O.k , Rascovsky, K.f , Tartaglia, M.C.l , Wszolek, Z.K.e , Kramer, J.H.a , Kornak, J.m , Boeve, B.F.b , Boxer, A.L.a , Rosen, H.J.a , ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortiumn
a Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, Mexico
b Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN
c Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
e Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
f Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
g Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
h Department of Radiology, College of Medicine, Mayo Clinic, Rochester, MN
i Department of Health Sciences Research, Mayo Clinic, Rochester, MN
j Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
k Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, United States
l Division of Neurology, Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
m Department of Epidemiology and Biostatistics, Memory and Aging Center, University of California, San Francisco, Mexico
Abstract
Importance: Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect. Objective: To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia. Design, Setting, and Participants: This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between January 2009 and September 2018. Participants with f-FTLD (n = 100) with a known pathogenic variant (MAPT [n = 28], GRN [n = 33], or C9orf72 [n = 39]) were grouped according to disease stage (ie, Clinical Dementia Rating [CDR] plus National Alzheimer’s Coordinating Center [NACC] FTLD module). Included were participants with at least 2 structural magnetic resonance images at presymptomatic (CDR + NACC FTLD = 0 [n = 57]), mild or questionable (CDR + NACC FTLD = 0.5 [n = 15]), or symptomatic (CDR + NACC FTLD = ≥1 [n = 28]) disease stages. The control group included family members of known pathogenic variant carriers who did not carry the pathogenic variant (n = 60). Main Outcomes and Measures: This study fitted bayesian linear mixed-effects models in each voxel of the brain to quantify the rate of atrophy in each of the 3 genes, at each of the 3 disease stages, compared with controls. The study also analyzed rates of clinical decline in each of these groups, as measured by the CDR + NACC FTLD box score. Results: The sample included 100 participants with f-FTLD with a known pathogenic variant (mean [SD] age, 50.48 [13.78] years; 53 [53%] female) and 60 family members of known pathogenic variant carriers who did not carry the pathogenic variant (mean [SD] age, 47.51 [12.43] years; 36 [60%] female). MAPT and GRN pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In MAPT pathogenic variant carriers, statistically significant regions of accelerated volume loss compared with controls were identified in temporal regions bilaterally in the presymptomatic stage, with global spread in the symptomatic stage. For example, mean [SD] rates of atrophy in the left temporal were -231 [47] mm3 per year during the presymptomatic stage, -381 [208] mm3 per year during the mild stage, and -1485 [1025] mm3 per year during the symptomatic stage (P < .05). GRN pathogenic variant carriers generally had minimal increases in atrophy rates between the presymptomatic and mild stages, with rapid increases in atrophy rates in the symptomatic stages. For example, in the right frontal lobes, annualized volume loss was -267 [81] mm3 per year in the presymptomatic stage and -182 [90] mm3 per year in the mild stage, but -1169 [555] mm3 per year in the symptomatic stage. Compared with the other groups, C9orf72 expansion carriers showed minimal increases in rate of volume loss with disease progression. For example, the mean (SD) annualized rates of atrophy in the right frontal lobe in C9orf72 expansion carriers was -272 (118) mm3 per year in presymptomatic stages, -310 (189) mm3 per year in mildly symptomatic stages, and -251 (145) mm3 per year in symptomatic stages. Conclusions and Relevance: These findings are relevant to clinical trial planning and suggest that the mechanism by which C9orf72 pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia" (2020) Brain: A Journal of Neurology
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
(2020) Brain: A Journal of Neurology, 143 (10), pp. 2929-2944.
Ebrahimi-Fakhari, D.a , Teinert, J.a b , Behne, R.a c , Wimmer, M.a , D’Amore, A.a d , Eberhardt, K.a , Brechmann, B.a , Ziegler, M.a , Jensen, D.M.e , Nagabhyrava, P.a f , Geisel, G.a f , Carmody, E.a f , Shamshad, U.a f , Dies, K.A.a f , Yuskaitis, C.J.a , Salussolia, C.L.a , Ebrahimi-Fakhari, D.g h , Pearson, T.S.i , Saffari, A.b , Ziegler, A.b , Kölker, S.b , Volkmann, J.c , Wiesener, A.j , Bearden, D.R.k , Lakhani, S.l , Segal, D.l m , Udwadia-Hegde, A.n , Martinuzzi, A.o , Hirst, J.p , Perlman, S.q , Takiyama, Y.r , Xiromerisiou, G.s , Vill, K.t , Walker, W.O.u , Shukla, A.v , Dubey Gupta, R.w , Dahl, N.x , Aksoy, A.y , Verhelst, H.z , Delgado, M.R.aa , Kremlikova Pourova, R.ab , Sadek, A.A.ac , Elkhateeb, N.M.ad , Blumkin, L.ae , Brea-Fernández, A.J.af , Dacruz-Álvarez, D.ag , Smol, T.ah , Ghoumid, J.ah , Miguel, D.ai , Heine, C.aj , Schlump, J.-U.ak , Langen, H.al , Baets, J.am , Bulk, S.an , Darvish, H.ao , Bakhtiari, S.ap , Kruer, M.C.ap , Lim-Melia, E.aq , Aydinli, N.ar , Alanay, Y.as , El-Rashidy, O.at , Nampoothiri, S.au , Patel, C.av , Beetz, C.aw , Bauer, P.aw , Yoon, G.ax , Guillot, M.ay , Miller, S.P.ay , Bourinaris, T.az , Houlden, H.az , Robelin, L.ba , Anheim, M.ba , Alamri, A.S.bb , Mahmoud, A.A.H.bc , Inaloo, S.bd , Habibzadeh, P.be , Faghihi, M.A.be bf , Jansen, A.C.bg , Brock, S.bg , Roubertie, A.bh , Darras, B.T.a , Agrawal, P.B.bi , Santorelli, F.M.d , Gleeson, J.bj , Zaki, M.S.bk , Sheikh, S.I.bl , Bennett, J.T.e , Sahin, M.a f
a Department of Neurology, Boston Children’s Hospital, Harvard Medical School, MA, Boston, United States
b Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
c Department of Neurology, University Hospital Würzburg, Würzburg, Germany
d Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy
e Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
f Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, MA, Boston, United States
g Pediatric Neurology, Saarland University Medical Center, Homburg/Saar, Germany
h Department of General Pediatrics, University Children’s Hospital Muenster, Muenster, Germany
i Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
j Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
k Child Neurology, University of Rochester School of Medicine, Rochester, NY, USA
l Center for Neurogenetics, Weill Cornell Medical College, NY, NY, United States
m Division of Child Neurology, Weill Cornell Medicine, New York City, NY, USA
n Department of Pediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India
o Scientific Institute, IRCCS E. Medea, Treviso, Italy
p Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
q Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, IA, Iowa City, United States
r Department of Neurology, University of YamanashiYamanashi, Japan
s Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece
t Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
u Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, USA
v Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
w Pediatric Neurology, Medanta Hospital, Indore, India
x Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala UniversityUppsala, Sweden
y Pediatric Neurology, Dr. Sami Ulus HospitalAnkara, Turkey
z Pediatric Neurology, Ghent University Hospital, Ghent, Belgium
aa Department of Neurology, University of Texas Southwestern Medical Center, TX, Dallas, United States
ab Department of Biology and Medical Genetics, Second Medical Faculty, Charles University and UH Motol, Prague, Czech Republic
ac Pediatric Neurology, Faculty of Medicine, Sohag UniversitySohag, Egypt
ad Pediatric Neurology, Cairo UniversityCairo, Egypt
ae Movement Disorders Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Holon, Israel
af Grupo de Medicina Xenómica, CIBERER, Santiago de Compostela, Spain
ag Neurología Pediátrica, Complexo Hospitalario Universitario, Santiago de Compostela, Spain
ah Institut de Génétique Médicale, RADEME, CHU Lille, Lille, France
ai Serviço de Genética Médica, Universidade Federal da Bahia, Salvador, Brazil
aj Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany
ak Pediatrics, Evangelisches Krankenhaus Oberhausen, Oberhausen, Germany
al Hannover, Germany
am Neurogenetics Group and Neuromuscular Reference Center, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
an Medical Genetics, Centre Hospitalier Universitaire de Liège, Liège, Belgium
ao Cancer Research Center and Department of Medical Genetics, Semnan University of Medical SciencesSemnan, Iran
ap Barrow Neurological Institute, Phoenix Children’s Hospital, AZ, Phoenix, United States
aq Pediatric Medical Genetics, Maria Fareri Children’s Hospital, Valhalla, NY, USA
ar Pediatric Genetics, Department of Pediatrics, Acibadem Mehmet Ali Aydinlar UniversityIstanbul, Turkey
as Pediatric Neurology, Istanbul Medical FacultyIstanbul, Turkey
at Pediatrics, Ain Shams UniversityCairo, Egypt
au Amrita Institute of Medical Sciences and Research Centre, Cochin, India
av Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia
aw Centogene AG, Rostock, Germany
ax Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
ay Department of Paediatrics, Hospital for Sick Children and The University of Toronto, Toronto, Canada
az Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
ba Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
bb Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
bc Pediatrics, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
bd Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
be Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran
bf Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, FL, Miami, United States
bg Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium
bh Pediatric Neurology, CHU Montpellier, Montpellier, France
bi Divisions of Newborn Medicine and Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, MA, Boston, United States
bj Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital, San Diego, CA, USA
bk Clinical Genetics, Human Genetics and Genome Research Division, National Research CentreCairo, Egypt
bl Translational Neuroscience, Celgene, MA, Cambridge, United States
Abstract
Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Author Keywords
neurodegeneration; SPG47; SPG50; SPG51; SPG52
Document Type: Article
Publication Stage: Final
Source: Scopus
"Optimizing treatment strategies in paediatric, adult and late-onset multiple sclerosis" (2020) Brain: A Journal of Neurology
Optimizing treatment strategies in paediatric, adult and late-onset multiple sclerosis
(2020) Brain: A Journal of Neurology, 143 (10), pp. 2866-2868.
Gaudioso, C., Naismith, R.T.
Department of Neurology, Washington University, St. Louis, MO, USA
Document Type: Article
Publication Stage: Final
Source: Scopus
"Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus" (2020) PLoS ONE
Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus
(2020) PLoS ONE, 15 (10 October), art. no. e0235877, .
Koenig, M.R.a b , Razo, E.c , Mitzey, A.b , Newman, C.M.a , Dudley, D.M.a , Breitbach, M.E.a , Semler, M.R.a , Stewart, L.M.a , Weiler, A.M.d , Rybarczyk, S.d , Bach, K.M.e , Mohns, M.S.a , Simmons, H.A.d , Mejia, A.d , Fritsch, M.a , Dennis, M.f , Teixeira, L.B.C.g , Schotzko, M.L.d , Michael Nork, T.h , Rasmussen, C.A.h , Katz, A.h , Nair, V.i , Hou, J.i , Hartman, A.j , Hoeve, J.V.h , Kim, C.h , Schneider, M.L.e , Ausderau, K.e , Kohn, S.i , Jaeger, A.S.k , Aliota, M.T.k , Hayes, J.M.d , Schultz-Darken, N.d , Eickhoff, J.l , Antony, K.M.m , Noguchi, K.n , Zeng, X.o , Permar, S.f , Prabhakaran, V.i , Capuano, S., IIId , Friedrich, T.C.d g , Golos, T.G.b d m , O’Connor, D.H.a d , Mohr, E.L.c
a Department of Pathology and Laboratory Medicine, UW-Madison, Madison, WI, United States
b Department of Comparative Biosciences, UW-Madison, Madison, WI, United States
c Department of Pediatrics, UW-Madison, Madison, WI, United States
d Wisconsin National Primate Research Center, UW-Madison, Madison, WI, United States
e Department of Kinesiology, UW-Madison, Madison, WI, United States
f Department of Pediatrics, Duke University, Durham, NC, United States
g Department of Pathobiological Sciences, UW-Madison, Madison, WI, United States
h Department of Ophthalmology and Visual Sciences, UW-Madison, Madison, WI, United States
i Department of Radiology, UW-Madison, Madison, WI, United States
j Department of Communication Sciences and Disorders, UW-Madison, Madison, WI, United States
k Department of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, MN, United States
l Biostatistics and Medical Informatics, UW-Madison, Madison, WI, United States
m Department of Obstetrics and Gynecology, UW-Madison, Madison, WI, United States
n Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
o United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
Abstract
Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design. © 2020 Public Library of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process" (2020) British Journal of Anaesthesia
Perioperative Pain and Addiction Interdisciplinary Network (PAIN): consensus recommendations for perioperative management of cannabis and cannabinoid-based medicine users by a modified Delphi process
(2020) British Journal of Anaesthesia, .
Ladha, K.S.b , McLaren-Blades, A.a , Goel, A.ad , Buys, M.J.c , Farquhar-Smith, P.d , Haroutounian, S.e , Kotteeswaran, Y.f , Kwofie, K.g , Le Foll, B.h i j k l m n , Lightfoot, N.J.o , Loiselle, J.p , Mace, H.q r , Nicholls, J.s , Regev, A.t , Rosseland, L.A.u v , Shanthanna, H.w , Sinha, A.x , Sutherland, A.y , Tanguay, R.z ae af , Yafai, S.aa ab , Glenny, M.a , Choi, P.a , Ladak, S.S.J.a , Leroux, T.S.ac , Kawpeng, I.a , Samman, B.a , Singh, R.a , Clarke, H.a ag
a Department of Anesthesia and Pain Management, Toronto General Hospital and University of Toronto, Toronto, ON, Canada
b Department of Anesthesia and Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, ON, Canada
c Department of Anesthesiology, University of Utah, Salt Lake City, UT, United States
d Department of Anaesthetics, The Royal Marsden NHS Foundation Trust, London, United Kingdom
e Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
f Department of Anesthesia, Northern Ontario School of Medicine, Sudbury, Thunder Bay, ON, Canada
g Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
h Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
i Acute Care Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
j Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
k Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
l Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
m Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada
n Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
o Department of Anaesthesia and Pain Medicine, Counties Manukau Health, Auckland, New Zealand
p Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
q Department of Anaesthesia, Pain and Perioperative Medicine, Fiona Stanley Fremantle Hospital Group, Melville, Australia
r University of Western Australia, Perth, Australia
s Department of Anaesthesia, Intensive Care and Pain, Cayman Islands Health Services Authority, George Town, Cayman Islands
t PureForm Global, Los Angeles, CA, United States
u Department of Research and Development, Division of Emergencies and Critical Care, University of Oslo, Oslo, Norway
v Institute of Clinical Medicine, University of Oslo, Oslo, Norway
w Department of Anesthesia, McMaster University, Hamilton, ON, Canada
x Department of Anesthesia, McGill University, Montreal, QC, Canada
y Department of Anesthesiology, St Paul’s Hospital, Vancouver, BC, Canada
z Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
aa Releaf Institute, Santa Monica, CA, United States
ab John Wayne Cancer Institute, Santa Monica, CA, United States
ac The Arthritis Program, University Health Network, Toronto, ON, Canada
ad Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University, Stanford, CA, United States
ae Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Canada
af Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Canada
ag Centre for Cannabinoid Therapeutics, Toronto, ON, Canada
Abstract
In many countries, liberalisation of the legislation regulating the use of cannabis has outpaced rigorous scientific studies, and a growing number of patients presenting for surgery consume cannabis regularly. Research to date suggests that cannabis can impact perioperative outcomes. We present recommendations obtained using a modified Delphi method for the perioperative care of cannabis-using patients. A steering committee was formed and a review of medical literature with respect to perioperative cannabis use was conducted. This was followed by the recruitment of a panel of 17 experts on the care of cannabis-consuming patients. Panellists were blinded to each other’s participation and were provided with rater forms exploring the appropriateness of specific perioperative care elements. The completed rater forms were analysed for consensus. The expert panel was then unblinded and met to discuss the rater form analyses. Draft recommendations were then created and returned to the expert panel for further comment. The draft recommendations were also sent to four independent reviewers (a surgeon, a nurse practitioner, and two patients). The collected feedback was used to finalise the recommendations. The major recommendations obtained included emphasising the importance of eliciting a history of cannabis use, quantifying it, and ensuring contact with a cannabis authoriser (if one exists). Recommendations also included the consideration of perioperative cannabis weaning, additional postoperative nausea and vomiting prophylaxis, and additional attention to monitoring and maintaining anaesthetic depth. Postoperative recommendations included anticipating increased postoperative analgesic requirements and maintaining vigilance for cannabis withdrawal syndrome. © 2020 British Journal of Anaesthesia
Author Keywords
anaesthesiology; cannabinoids; cannabis; pain; perioperative care; postoperative nausea and vomiting
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Effects of Procedural Discomfort and Expectation of Benefit on Therapy Continuation in Chronic Migraine Patients Treated With OnabotulinumtoxinA" (2020) Headache
Effects of Procedural Discomfort and Expectation of Benefit on Therapy Continuation in Chronic Migraine Patients Treated With OnabotulinumtoxinA
(2020) Headache, .
Anderson, C.C., Ray, C.A., Butler, M.R., Darken, R.S.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: OnabotulinumtoxinA (BTX) has become a mainstream treatment for chronic migraine (CM). Patients often have varied expectations for treatment success but little is known about how these initial impressions influence continuation of therapy. Objective: To record expectations of benefit and procedural discomfort (PD) from initial BTX treatment and to investigate their association with treatment success, defined as continuation of treatment for >3 sessions within a 2-year period. Methods: A retrospective chart review of CM patients receiving initial treatment with BTX was performed. Patients were questioned about their expectations of benefit and PD as rated on a 0-10 scale. Responses were then compared with continuation of therapy beyond 3 sessions to identify the presence of significant association. Results: Responses from patients (N = 297) were analyzed. About 173 subjects continued with BTX therapy for more than 3 sessions (173/297, 58.3%). Unadjusted odds ratios (OR) for expectation of benefit (EOB) (OR 1.11, 95% CI 0.99-1.24, P =.087) and PD (OR 1.02, 95% CI 0.90-1.16, P =.780) were not significantly predictive of continuing treatment. After considering sex, age, year of treatment, and previous headache preventative trials, only female sex (OR 2.02, 95% CI 1.09-3.74, P =.025) was found to be significantly associated with treatment continuation. Conclusions: In the usual care setting, PD and EOB are not significantly associated with therapy continuation in patients receiving initial treatment with BTX for the prevention of CM. However, after considering sex, age, year of treatment, and number of previous headache preventives attempted, we found that female patients had twice the likelihood of continuing with BTX therapy compared to male patients with CM. © 2020 American Headache Society
Author Keywords
adult; botulinum toxins type A; chronic disease; humans; migraine disorders; neuromuscular agents
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Smoking cessation treatment for individuals with comorbid diabetes and serious mental illness in an integrated health care delivery system" (2020) Addictive Behaviors
Smoking cessation treatment for individuals with comorbid diabetes and serious mental illness in an integrated health care delivery system
(2020) Addictive Behaviors, art. no. 106697, .
Hwong, A.R.a , Schmittdiel, J.b , Schillinger, D.c d , Newcomer, J.W.e f , Essock, S.g , Zhu, Z.b , Dyer, W.b , Young-Wolff, K.C.a b , Mangurian, C.a c h
a University of California, San Francisco, Weill Institute of Neurosciences, Department of Psychiatry, United States
b Kaiser Permanente Northern California Division of Research, Oakland, CA, United States
c UCSF Center for Vulnerable Populations at Zuckerberg San Francisco General Hospital, United States
d UCSF Division of General Internal Medicine at Zuckerberg San, Francisco General Hospital, United States
e Thriving Mind South Florida, Miami, FL, United States
f Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, United States
g Columbia University, Department of Psychiatry, United States
h UCSF Philip R. Lee Institute for Health Policy Studies, United States
Abstract
Introduction: Smoking is a significant modifiable risk factor for mortality for persons with serious mental illness (SMI), who have a life expectancy 15–20 years shorter than the general population. Individuals with SMI and comorbid diabetes who are smokers face an even higher risk of cardiovascular complications and early death. Yet despite high rates of smoking among people with SMI, tobacco cessation interventions have not been broadly offered to this population. Methods: We conducted a retrospective cohort study using electronic health records from 2014 in a large integrated care delivery system to examine whether use of smoking cessation pharmacotherapy among smokers with type 2 diabetes varies by serious mental illness (SMI) diagnosis. We analyzed smoking cessation medication prescription fills among adult smokers with diabetes, comparing those with SMI (N = 634) and without SMI (N = 18,021). Risk ratios were adjusted for age, gender, race, urban area type, and medical facility. Results: Of the SMI group, 19.09% filled at least one smoking cessation prescription compared to 9.73% of the non-SMI group (adjusted risk ratio 1.80 [95% CI 1.52–2.13]; p < .001). For the SMI group, primary care providers wrote 80.24% of prescriptions, while psychiatrists wrote 8.81% of prescriptions. Conclusions: These findings offer an example of a delivery system with higher uptake of smoking cessation pharmacotherapy among people with SMI than without SMI, and highlight the opportunity to provide more smoking cessation interventions in mental health care settings. © 2020
Author Keywords
Diabetes; Serious mental illness; Smoking cessation
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Seizures Are Associated With Brain Injury in Infants Undergoing Extracorporeal Membrane Oxygenation" (2020) Journal of Child Neurology
Seizures Are Associated With Brain Injury in Infants Undergoing Extracorporeal Membrane Oxygenation
(2020) Journal of Child Neurology, .
Bauer Huang, S.L.a , Said, A.S.b , Smyser, C.D.a c , Lin, J.C.b , Guilliams, K.P.a b , Guerriero, R.M.a
a Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University in St LouisMO, United States
b Department of Pediatrics, Division of Critical Care Medicine, Washington University in St LouisMO, United States
c Department of Radiology, Washington University in St LouisMO, United States
Abstract
Objective: Determine seizure frequency and association with neurologic outcomes in infants undergoing extracorporeal membrane oxygenation. Identify patient or clinical factors associated with seizures or brain injury on imaging. Methods: Retrospective, single-center study including infants less than 1 year of age, who underwent extracorporeal membrane oxygenation between 2012 and 2017. Results: A total of 104 infants met study criteria including 45 patients with continuous electroencephalographic (EEG) monitoring during their extracorporeal membrane oxygenation run and 59 infants without EEG. Seizures (electrographic-only or electro-clinical) were identified in 18 of the 45 (40%). Among the 18 infants with seizures, 14 (78%) had moderate to severe brain injury, whereas only 44% of those without seizures (12 of 27) on EEG had moderate to severe brain injury (P =.03). Cardiopulmonary resuscitation prior to extracorporeal membrane oxygenation (ECPR), mode of extracorporeal membrane oxygenation, length of stay, survival to discharge, and congenital heart disease were not associated with seizures. One of 10 patients with cyanotic congenital heart disease due to hypoplastic left heart syndrome had seizures compared with 7 of 10 patients with non–hypoplastic left heart syndrome lesions (P =.02). Seizures were associated with moderate to severe brain injury, after adjusting for ECPR and congenital heart disease (P =.04). Conclusions: Electrographic seizures were common in patients undergoing extracorporeal membrane oxygenation and higher than previously reported. Seizures were associated with moderate to severe abnormalities on imaging, after adjusting for ECPR and congenital heart disease. This study adds to recent literature describing the risk of seizures in patients on extracorporeal membrane oxygenation and highlights the presence of brain injuries that may be identified by routine EEG surveillance. © The Author(s) 2020.
Author Keywords
congenital heart disease; electroencephalography; extracorporeal membrane oxygenation; neonatal; neurologic outcomes
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis" (2020) Muscle and Nerve
Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis
(2020) Muscle and Nerve, .
Paganoni, S.a b , Hendrix, S.c , Dickson, S.P.c , Knowlton, N.c , Macklin, E.A.d , Berry, J.D.a , Elliott, M.A.e , Maiser, S.f , Karam, C.g , Caress, J.B.h , Owegi, M.A.i , Quick, A.j , Wymer, J.k , Goutman, S.A.l , Heitzman, D.m , Heiman-Patterson, T.D.n , Jackson, C.E.o , Quinn, C.p , Rothstein, J.D.q , Kasarskis, E.J.r , Katz, J.s , Jenkins, L.s , Ladha, S.t , Miller, T.M.u , Scelsa, S.N.v , Vu, T.H.w , Fournier, C.N.x , Glass, J.D.x , Johnson, K.M.y , Swenson, A.z , Goyal, N.A.aa , Pattee, G.L.ab , Andres, P.L.ac , Babu, S.a , Chase, M.a , Dagostino, D.a , Hall, M.t , Kittle, G.t , Eydinov, M.a , McGovern, M.a , Ostrow, J.a , Pothier, L.a , Randall, R.t , Shefner, J.M.t , Sherman, A.V.a , St Pierre, M.E.a , Tustison, E.a , Vigneswaran, P.a , Walker, J.a , Yu, H.a , Chan, J.d , Wittes, J.ad , Yu, Z.-F.ad , Cohen, J.ae , Klee, J.ae , Leslie, K.ae , Tanzi, R.E.a , Gilbert, W.af , Yeramian, P.D.ae , Schoenfeld, D.d , Cudkowicz, M.E.a
a Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
b Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States
c Pentara Corporation, Millcreek, UT, United States
d Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
e Swedish Neuroscience Institute, Seattle, WA, United States
f Departments of Neurology and Medicine, Hennepin Healthcare, Minneapolis, MN, United States
g Department of Neurology, Oregon Health & Science University, Portland, OR, United States
h Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC, United States
i Department of Neurology, University of Massachusetts Memorial Medical Center, Worcester, MA, United States
j Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, United States
k Department of Neurology, University of Florida College of Medicine, Gainesville, FL, United States
l Department of Neurology, University of Michigan, Ann Arbor, MI, United States
m Texas Neurology, Dallas, TX, United States
n Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
o Department of Neurology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
p Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
q Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
r Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, United States
s California Pacific Medical Center Research Institute and Forbes Norris MDA/ALS Research and Treatment Center, San Francisco, CA, United States
t Department of Neurology, Gregory W. Fulton ALS Center, Barrow Neurological Institute, Phoenix, AZ, United States
u Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
v Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, United States
w Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
x Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta, GA, United States
y Department of Neurology, Ochsner Health System, New Orleans, LA, United States
z Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
aa Department of Neurology, University of California, Irvine School of Medicine, Irvine, CA, United States
ab Neurology Associates, Lincoln, NE, United States
ac Independent Consultant, Nobleboro, ME, United States
ad Statistics Collaborative, Inc., Washington, District of Columbia, United States
ae Amylyx Pharmaceuticals, Inc., Cambridge, MA, United States
af Harvard University, Cambridge, MA, United States
Abstract
An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P =.023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS. © 2020 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
Author Keywords
amyotrophic lateral sclerosis; CENTAUR; motor neuron disease; sodium phenylbutyrate-taurursodiol; survival analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
"Five-Year Cost-Effectiveness Modeling of Primary Care-Based, Nonmydriatic Automated Retinal Image Analysis Screening Among Low-Income Patients with Diabetes" (2020) Journal of Diabetes Science and Technology
Five-Year Cost-Effectiveness Modeling of Primary Care-Based, Nonmydriatic Automated Retinal Image Analysis Screening Among Low-Income Patients with Diabetes
(2020) Journal of Diabetes Science and Technology, .
Fuller, S.D.a , Hu, J.b , Liu, J.C.a , Gibson, E.a , Gregory, M.c , Kuo, J.a , Rajagopal, R.a
a John F. Hardesty Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, United States
b Shiley Eye Institute, University of California San Diego School of Medicine, La Jolla, CA, United States
c John T. Milliken Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Artificial intelligence-based technology systems offer an alternative solution for diabetic retinopathy (DR) screening compared with standard, in-office dilated eye examinations. We performed a cost-effectiveness analysis of Automated Retinal Image Analysis System (ARIAS)-based DR screening in a primary care medicine clinic that serves a low-income patient population. Methods: A model-based, cost-effectiveness analysis of two DR screening systems was created utilizing data from a recent study comparing adherence rates to follow-up eye care among adults ages 18 or older with a clinical diagnosis of diabetes. In the study, the patients were prescreened with an ARIAS-based, nonmydriatic (undilated), point-of-care tool in the primary care setting and were compared with patients with diabetes who were referred for dilated retinal screening without prescreening, as is the current standard of care. Using a Markov model with microsimulation resulting in a total of 600 000 simulated patient experiences, we calculated the incremental cost-utility ratio (ICUR) of the two screening approaches, with regard to five-year cost-effectiveness of DR screening and treatment of vision-threatening DR. Results: At five years, ARIAS-based screening showed similar utility as the standard of care screening systems. However, ARIAS reduced costs by 23.3%, with an ICUR of $258 721.81 comparing the current practice to ARIAS. Conclusions: Primary care-based ARIAS DR screening is cost-effective when compared with standard of care screening methods. © 2020 Diabetes Technology Society.
Author Keywords
artificial intelligence; cost-effectiveness analysis; diabetic retinopathy; healthcare economics; machine learning technology; public health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke" (2020) Cellular and Molecular Neurobiology
Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke
(2020) Cellular and Molecular Neurobiology, .
Liu, C.a , Xie, J.a , Sun, S.b , Li, H.a , Li, T.a , Jiang, C.c , Chen, X.d , Wang, J.d , Le, A.e , Wang, J.f , Li, Z.a , Wang, J.d , Wang, W.a
a Department of Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
b Department of Ultrasound Imaging, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
c Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
d Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Henan, 450000, China
e Washington University in St. Louis, Saint Louis, MO 63130, United States
f The Johns Hopkins University, Baltimore, MD 21218, United States
Abstract
Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Blood; Brain barrier; Hemorrhagic transformation; Ischemic stroke; Tissue plasminogen activator
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
"Prevalence and correlates of antisocial personality disorder in older adults" (2020) Aging and Mental Health
Prevalence and correlates of antisocial personality disorder in older adults
(2020) Aging and Mental Health, .
Holzer, K.J.a b , Vaughn, M.G.b c , Loux, T.M.d , Mancini, M.A.b , Fearn, N.E.b , Wallace, C.L.b
a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b School of Social Work, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
c Graduate School of Social Welfare, Yonsei University, Seoul, South Korea
d Department of Epidemiology and Biostatistics, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
Abstract
Objectives: There is a paucity of research on antisocial personality disorder (ASPD) in the geriatric population and the majority of knowledge on the disorder is drawn from young adult samples. Researchers posit that the prevalence of ASPD as well as other personality disorders (PDs) is underestimated among older adults. Using a nationally representative sample, the present study examines the prevalence and correlates of ASPD in adults ages 50 and older. Methods: We analyzed data from the National Epidemiologic Survey on Alcohol and Related Conditions Waves I and III. Multivariate logistic regression analyses were employed to investigate associations between ASPD and sociodemographic characteristics. A series of logistic regression analyses were also conducted to study associations between ASPD and medical conditions (liver and cardiovascular disease, arthritis, and stomach ulcer), major psychiatric disorders (lifetime major depressive disorder, mania, and generalized anxiety disorder), and substance use disorders (lifetime alcohol, marijuana, cocaine, heroin, and nicotine use disorders). Results: Findings indicated that the prevalence of ASPD increases through early adulthood, with a peak at 3.91% in younger adults and decline to 0.78% in adults ages ≥65. Older adults with ASPD are more likely to be diagnosed with a substance use disorder, major depression, mania, and generalized anxiety disorder as well as each medical condition. Conclusion: Older adults with ASPD experience increased rates of medical and psychiatric comorbidities. These conditions exacerbate the existing challenges associated with diagnosing and treating this population and may have serious consequences for the patient, their caregivers and society. © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
antisocial personality disorder; correlates; Older adult; prevalence; substance abuse
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks" (2020) Psychological Medicine
Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks
(2020) Psychological Medicine, .
Moran, E.K.a , Gold, J.M.b , Carter, C.S.c , Macdonald, A.W.d , Ragland, J.D.c , Silverstein, S.M.e , Luck, S.J.f , Barch, D.M.a g h
a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore, MD, United States
c Department of Psychiatry, University of California, Davis, CA, United States
d Department of Psychology, University of Minnesota, Minneapolis, MN, United States
e Department of Psychiatry, Rutgers Robert Wood Johnson Medical School Hospital, Piscataway, NJ, United States
f Department of Psychology, University of California, Davis, CA, United States
g Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
h Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
BackgroundSchizophrenia is a disorder characterized by pervasive deficits in cognitive functioning. However, few well-powered studies have examined the degree to which cognitive performance is impaired even among individuals with schizophrenia not currently on antipsychotic medications using a wide range of cognitive and reinforcement learning measures derived from cognitive neuroscience. Such research is particularly needed in the domain of reinforcement learning, given the central role of dopamine in reinforcement learning, and the potential impact of antipsychotic medications on dopamine function.MethodsThe present study sought to fill this gap by examining healthy controls (N = 75), unmedicated (N = 48) and medicated (N = 148) individuals with schizophrenia. Participants were recruited across five sites as part of the CNTRaCS Consortium to complete tasks assessing processing speed, cognitive control, working memory, verbal learning, relational encoding and retrieval, visual integration and reinforcement learning.ResultsIndividuals with schizophrenia who were not taking antipsychotic medications, as well as those taking antipsychotic medications, showed pervasive deficits across cognitive domains including reinforcement learning, processing speed, cognitive control, working memory, verbal learning and relational encoding and retrieval. Further, we found that chlorpromazine equivalency rates were significantly related to processing speed and working memory, while there were no significant relationships between anticholinergic load and performance on other tasks.ConclusionsThese findings add to a body of literature suggesting that cognitive deficits are an enduring aspect of schizophrenia, present in those off antipsychotic medications as well as those taking antipsychotic medications. Copyright © The Author(s), 2020. Published by Cambridge University Press.
Author Keywords
Antipsychotic medications; cognition; reinforcement learning; schizophrenia
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials" (2020) Therapeutic Advances in Neurological Disorders
Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials
(2020) Therapeutic Advances in Neurological Disorders, 13, .
Zhang, Y.a , Gonzalez Caldito, N.b , Shirani, A.c , Salter, A.d , Cutter, G.e , Culpepper, W., IIf , Wallin, M.g , Kosa, P.h , Bielekova, B.h , Lublin, F.a , Stϋve, O.i
a Department of Neurology, Icahn School of Medicine at Mount SinaiNY, United States
b Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, United States
c Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
f Department of Neurology, University of Maryland School of Medicine, VA Multiple Sclerosis Center of Excellence-East and VA Post Deployment Health Services, Washington, DC, United States
g Department of Neurology, George Washington University School of Medicine, Director, VA Multiple Sclerosis Center of Excellence-East, Washington, DC, United States
h Neuroimmunological Diseases Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
i Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd, Dallas, TX 75216, United States
Abstract
Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age. © The Author(s), 2020.
Author Keywords
aging; clinical trials; disease-modifying therapies; multiple sclerosis
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
"Pain relief after surgical decompression of the distal brachial plexus" (2020) Journal of Brachial Plexus and Peripheral Nerve Injury
Pain relief after surgical decompression of the distal brachial plexus
(2020) Journal of Brachial Plexus and Peripheral Nerve Injury, 15 (1), pp. E22-E32.
Morgan, R.a , Elliot, I.b , Banala, V.c , Dy, C.d , Harris, B.e , Ouellette, E.A.e
a Department of Physical Medicine and Rehabilitation, Larkin Community Hospital, Miami, FL, United States
b Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, United States
c Department of Orthopedic Surgery, Montefiore Medical Center, Bronx, NY, United States
d Department of Orthopedic Surgery, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Orthopedic Surgery, Miami Orthopedics and Sports Medicine Institute, Baptist Health Medical Group South Florida, Miami, FL, United States
Abstract
Background Brachial plexopathy causes pain and loss of function in the affected extremity. Entrapment of the brachial plexus terminal branches within the surrounding connective tissue, ormedial brachial fascial compartment,maymanifest in debilitating symptoms. Open fasciotomy and external neurolysis of the neurovascular bundle in the medial brachial fascial compartment were performed as a surgical treatment for pain and functional decline in the upper extremity. The aim of this study was to evaluate pain outcomes after surgery in patients diagnosed with brachial plexopathy. Methods We identified 21 patients who met inclusion criteria. Documents dated between 2005 and 2019 were reviewed from electronic medical records. Chart review was conducted to collect data on visual analog scale (VAS) for pain, Semmes-Weinstein monofilament test (SWMT), and Medical Research Council (MRC) scale for muscle strength. Pre- and postoperative data was obtained. A paired sample t-test was used to determine statistical significance of pain outcomes. Results Pain severity in the affected arm was significantly reduced after surgery (pre: 6.4 ± 2.5; post: 2.0 ± 2.5; p < 0.01). Additionally, there was an increased response to SWMT after the procedure. More patients achieved an MRC rating score ≥3 and ≥4 in elbow flexion after surgery. This may be indicative of improved sensory and motor function. Conclusion Open fasciotomy and external neurolysis at the medial brachial fascial compartment is an effective treatment for pain when nerve continuity is preserved. These benefits were evident in patients with a prolonged duration elapsed since injury onset. © 2020 Georg Thieme Verlag KG Stuttgart.
Author Keywords
Brachial plexopathy; Brachial plexus; Compression; Entrapment; Medial brachial fascial compartment; Neuropathy; Outcomes; Pain; Surgery
Document Type: Article
Publication Stage: Final
Source: Scopus
"Treatment and mortality outcomes in patients with other extrapulmonary cryptococcal disease compared with central nervous system disease" (2020) Mycoses
Treatment and mortality outcomes in patients with other extrapulmonary cryptococcal disease compared with central nervous system disease
(2020) Mycoses, .
Mejia-Chew, C.a , Abby, S.b , Larson, L.a , Powderly, W.G.a , Spec, A.a
a Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Determining the extent of cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localised pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. Methods: This is a retrospective, single-centre study of all hospitalised patients with nonpulmonary cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox regression analysis. Results: Of 193 patients analysed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, p =.9). In the comorbidity-adjusted multivariable Cox regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, p <.001). Conclusion: Patients with OE CD had similar 90-day mortality compared to those with CNS disease. Despite current guideline recommendations, patients with OE disease were less likely to receive appropriate induction therapy with AmB and flucytosine compared to patients with CNS disease. © 2020 Wiley-VCH GmbH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus