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2.
Theranostics ; 9(17): 4959-4970, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410194

RESUMO

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

5.
J Neurovirol ; 25(2): 284-287, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30864100

RESUMO

Therapy for progressive multifocal leukoencephalopathy (PML) remains challenging since there are no antiviral therapies available for JC virus. Immune reconstitution has improved the prognosis in many settings where PML occurs, but it often is not possible in PML patients with hematologic malignancies. We describe the first biopsy proven PML case where the PD-1 inhibitor nivolumab appears to have stimulated immune activation resulting in effective control of PML in a patient with hematologic malignancy. This report supports further investigation of the utility of checkpoint inhibitors for treating PML where other immune reconstitution options are not available.

6.
Proc Natl Acad Sci U S A ; 116(8): 3251-3255, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718410

RESUMO

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age-relative to their chronological age-compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.


Assuntos
Envelhecimento/fisiologia , Atenção/fisiologia , Encéfalo/fisiologia , Cognição/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Caracteres Sexuais , Adulto Jovem
7.
J Cereb Blood Flow Metab ; 39(10): 2096-2102, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29569986

RESUMO

Glucose and oxygen metabolism are tightly coupled in the human brain, with the preponderance of the brain's glucose supply used to generate ATP via oxidative phosphorylation. A fraction of glucose is consumed outside of oxidative phosphorylation despite the presence of sufficient oxygen to do so. We refer to this process as aerobic glycolysis. A recent positron emission tomography study reported that aerobic glycolysis is uniform within gray matter. Here, we analyze the same data and demonstrate robust regional differences in aerobic glycolysis within gray matter, a finding consistent with previously published data.

8.
Proc Natl Acad Sci U S A ; 115(41): E9727-E9736, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30254176

RESUMO

fMRI revolutionized neuroscience by allowing in vivo real-time detection of human brain activity. While the nature of the fMRI signal is understood as resulting from variations in the MRI signal due to brain-activity-induced changes in the blood oxygenation level (BOLD effect), these variations constitute a very minor part of a baseline MRI signal. Hence, the fundamental (and not addressed) questions are how underlying brain cellular composition defines this baseline MRI signal and how a baseline MRI signal relates to fMRI. Herein we investigate these questions by using a multimodality approach that includes quantitative gradient recalled echo (qGRE), volumetric and functional connectivity MRI, and gene expression data from the Allen Human Brain Atlas. We demonstrate that in vivo measurement of the major baseline component of a GRE signal decay rate parameter (R2t*) provides a unique genetic perspective into the cellular constituents of the human cortex and serves as a previously unidentified link between cortical tissue composition and fMRI signal. Data show that areas of the brain cortex characterized by higher R2t* have high neuronal density and have stronger functional connections to other brain areas. Interestingly, these areas have a relatively smaller concentration of synapses and glial cells, suggesting that myelinated cortical axons are likely key cortical structures that contribute to functional connectivity. Given these associations, R2t* is expected to be a useful signal in assessing microstructural changes in the human brain during development and aging in health and disease.


Assuntos
Encéfalo/metabolismo , Redes Reguladoras de Genes , Genoma Humano , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Encéfalo/irrigação sanguínea , Mapeamento Encefálico , Circulação Cerebrovascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
PLoS One ; 13(9): e0204242, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30248124

RESUMO

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


Assuntos
Encéfalo/fisiologia , Metabolismo dos Carboidratos , Glucose/metabolismo , Oxigênio/metabolismo , Descanso/fisiologia , Teorema de Bayes , Encéfalo/metabolismo , Feminino , Humanos , Ácido Láctico/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação Oxidativa , Consumo de Oxigênio , Adulto Jovem
11.
Neurol Clin Pract ; 8(4): 283-291, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30140579

RESUMO

Background: We sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance. Methods: We conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases. Results: T2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%-98.5%) and specific (100.0%; 95% CI 92.3%-100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age. Conclusions: With the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.

12.
Clin Neurol Neurosurg ; 172: 27-30, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29960103

RESUMO

OBJECTIVE: Computed tomographic angiography (CTA) is increasingly utilized to evaluate for traumatic cerebrovascular injury (TCVI). The purpose of this study was to determine the yield, management effect, and risk of stroke or poor outcome of a positive CTA in a large cohort of trauma patients. PATIENTS AND METHODS: A retrospective analysis was performed on 1290 consecutive trauma patients that underwent head and/or neck CTA at our level I trauma center from 2006 to 2015. Clinical variables assessed include mechanism of injury, neurological status, CTA findings, subsequent imaging results, patient management, and clinical outcomes. RESULTS: Among 1290 patients who underwent CTA, 200 (15.5%) were positive for TCVI, higher in blunt than penetrating trauma patients. In a generalized linear model, factors that increased likelihood of positive CTA included multiple cervical fractures, fractures with foraminal involvement, gunshot injury, Glasgow Coma Scale ≤ 13, and focal neurological deficit. Excluding cases with these factors lowered the positive rate to 4.3%. Of the 200 CTA-positives, 99 were treated for TCVI and 9 (4.5%) developed a subsequent stroke as compared to 5 (0.5%) in CTA-negative patients (odds ratio 10.2, Fisher exact test, p < 0.001). Risk of death or nursing facility discharge location was also higher in CTA-positive patients, correcting for age and presenting GCS (p < 0.01). CONCLUSION: CTA had a modest yield in identifying TCVI in this cohort. When positive, CTA influenced management and predicted an increased risk of subsequent stroke and poor outcome.


Assuntos
Angiografia Cerebral , Traumatismo Cerebrovascular/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital/métodos , Angiografia Cerebral/métodos , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Lesões do Pescoço/complicações , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Centros de Traumatologia , Ferimentos não Penetrantes/complicações
13.
Annu Rev Nutr ; 38: 381-399, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-29856933

RESUMO

Appraising success in meeting the world's nutritional needs has largely focused on infant mortality and anthropometric measurements with an emphasis on the first 1,000 days (conception to approximately age 2 years). This ignores the unique nutritional needs of the human brain. Although the intrauterine environment and the early postnatal years are important, equally critical periods follow during which the brain's intricate wiring is established for a lifetime of experience-driven remodeling. At the peak of this process during childhood, the human brain may account for 50% of the body's basal nutritional requirement. Thus, the consequences of proper nutritional management of the brain play out over a lifetime. Our motivation in preparing this review was to move the human brain into a more central position in the planning of nutritional programs. Here we review the macro- and micronutrient requirements of the human brain and how they are delivered, from conception to adulthood.


Assuntos
Encéfalo/crescimento & desenvolvimento , Longevidade , Fenômenos Fisiológicos da Nutrição , Necessidades Nutricionais , Humanos
14.
J Pediatr Gastroenterol Nutr ; 66 Suppl 3: S46-S49, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29762377

RESUMO

Adequate nutrition is critical for human brain development, which depends particularly upon glucose. The adult human brain accounts for 20% to 25% of total body resting glucose consumption, and studies indicate that the developing brain requires an even greater percentage of glucose. Here we critically review the currently available data on glucose requirements for early childhood brain development. Implications of these findings are then discussed in the context of childhood malnutrition and future areas of investigation.


Assuntos
Encéfalo/metabolismo , Desenvolvimento Infantil/fisiologia , Glucose/metabolismo , Encéfalo/crescimento & desenvolvimento , Criança , Glucose/administração & dosagem , Humanos , Necessidades Nutricionais
15.
Neurobiol Aging ; 67: 95-98, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29655050

RESUMO

Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Glicólise , Proteínas tau/metabolismo , Aerobiose , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas Amiloidogênicas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Glucose/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal , Consumo de Oxigênio , Tomografia por Emissão de Pósitrons
16.
Childs Nerv Syst ; 34(5): 901-910, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511809

RESUMO

PURPOSE: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. METHODS: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9-18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. RESULTS: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0-7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). CONCLUSION: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE.


Assuntos
Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/fisiopatologia , Lateralidade Funcional/fisiologia , Tempo de Reação/fisiologia , Descanso , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Imagem por Ressonância Magnética , Masculino , Oxigênio/sangue , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos
17.
Childs Nerv Syst ; 33(10): 1719-1726, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29149384

RESUMO

Age-dependent changes in brain metabolism may influence the response to and tolerance of secondary insults, potentially affecting outcomes. More complete characterization of brain metabolism across the clinical trajectory of severe pediatric TBI is needed to improve our ability to measure and better mitigate the impact of secondary insults. Better management of secondary insults will impact clinical care and the probability of success of future neuroprotective clinical trials. Improved bedside monitoring and imaging technologies will be required to achieve these goals. Effective and sustained integration of brain metabolism information into the pediatric critical care setting will be equally challenging and important.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/terapia , Encéfalo/metabolismo , Pediatria , Criança , Pré-Escolar , Cuidados Críticos , Humanos , Lactente
18.
Cell Metab ; 26(2): 353-360.e3, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768174

RESUMO

The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.


Assuntos
Envelhecimento/metabolismo , Encéfalo , Glucose/metabolismo , Glicólise , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Aerosp Med Hum Perform ; 87(8): 745-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27634611

RESUMO

INTRODUCTION: Visual Impairment and Intracranial Pressure Syndrome (VIIP) has caused symptomatology during and after long duration missions on the International Space Station (ISS). Only indirect measurements of intracranial pressure (ICP), such as ultrasound, have been performed on ISS. Discussion and interest has happened at NASA about performing lumbar puncture (LP) in microgravity. Only the "blind" palpation approach and the ultrasound-assisted approach have been discussed. This article, as proof of concept, discusses the possibility of portable radiography to assist lumbar punctures in microgravity. METHOD: An anthropomorphic radiological phantom of an adult lumbar spine was made containing a fluid-filled space in the spinal canal with a latex membrane which simulated the dural sac and cerebrospinal fluid. A portable direct-digital radiography system with wireless transmitting image receptor and screen was used to perform image-guided lumbar puncture. Using the same equipment and technique, this procedure was then performed on a cadaver for final proof of concept. RESULTS: Technical success was achieved in all approaches on the first try without needle redirection. There was no difference between the cadaver model and the phantom model in terms of difficulty in reaching the fluid space or visually confirming needle location. DISCUSSION: Portable radiography via proof of concept has the potential to guide lumbar puncture while minimizing volume and mass of equipment. This could be ideal for assisting in performing lumbar puncture in microgravity, as this is the standard of care on Earth for difficult or failed "blind" lumbar punctures. Lerner DJ, Parmet AJ, Don S, Shimony JS, Goyal MS. Technique for performing lumbar puncture in microgravity using portable radiography. Aerosp Med Hum Perform. 2016; 87(8):745-747.


Assuntos
Região Lombossacral/diagnóstico por imagem , Punção Espinal/métodos , Ausência de Peso , Adulto , Cadáver , Humanos , Imagens de Fantasmas , Radiografia/instrumentação
20.
Stroke ; 47(4): 1012-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26892282

RESUMO

BACKGROUND AND PURPOSE: Stroke mimics (SM) challenge the initial assessment of patients presenting with possible acute ischemic stroke (AIS). When SM is considered likely, intravenous tissue-type plasminogen activator (tPA) may be withheld, risking an opportunity to treat AIS. Although computed tomography is routinely used for tPA decision making, magnetic resonance imaging (MRI) may diagnose AIS when SM is favored but not certain. We hypothesized that a hyperacute MRI (hMRI) protocol would identify tPA-eligible AIS patients among those initially favored to have SM. METHODS: A streamlined hMRI protocol was designed based on barriers to rapid patient transport, MRI acquisition, and post-MRI tPA delivery. Neurologists were trained to order hMRI when SM was favored and tPA was being withheld. The use of hMRI for tPA decision making, door-to-needle times, and outcomes were compared before hMRI implementation (pre-hMRI: August 1, 2011 to July 31, 2013) and after (post-hMRI, August 1, 2013, to January 15, 2015). RESULTS: Post hMRI, 57 patients with suspected SM underwent hMRI (median MRI-order-to-start time, 29 minutes), of whom, 11 (19%) were diagnosed with AIS and 7 (12%) received tPA. Pre-hMRI, no tPA-treated patients were screened with hMRI. Post hMRI, 7 of 106 (6.6%) tPA-treated patients underwent hMRI to aid in decision making because of suspected SM (0% versus 6.6%; P=0.001). To ensure standard care was maintained after implementing the hMRI protocol, pre- versus post-hMRI tPA-treated cohorts were compared and did not differ: door-to-needle time (39 versus 37 minutes; P=0.63), symptomatic hemorrhage rate (4.5% versus 1.9%; P=0.32), and favorable discharge location (85% versus 89%; P=0.37). CONCLUSIONS: A streamlined hMRI protocol permitted tPA administration to a small, but significant, subset of AIS patients initially considered to have SM.


Assuntos
Isquemia Encefálica/patologia , Fibrinolíticos/uso terapêutico , Imagem por Ressonância Magnética/métodos , Acidente Vascular Cerebral/patologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Isquemia Encefálica/tratamento farmacológico , Tomada de Decisão Clínica , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento
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