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1.
PLoS One ; 16(7): e0254572, 2021.
Article in English | MEDLINE | ID: mdl-34252170

ABSTRACT

OBJECTIVE: While prior research shows that mental illness is associated with lower utilization of screening imaging, little is known about how mental illness impacts use of diagnostic imaging, other than for screening. This study explores the association between a history of anxiety or depression in the prior year and utilization of diagnostic imaging. METHODS: Commercial and Medicare Advantage health plan claims from 2017 and 2018 from patients with plans from one national organization were extracted. Exclusions were made for patients without continuous plan enrollment. History of anxiety or depression was determined using 2017 claims, and downstream diagnostic imaging was determined using 2018 claims. Univariate associations were assessed with Chi-square tests. A matched sample was created using Coarsened Exact Matching, with history of mental illness serving as the treatment variable. Logistic regressions were used to calculate adjusted odds ratios, before and after matching, controlling for age, sex, urbanicity, local income, comorbidities, claims history, region, and health plan characteristics. Associations between mental illness and chest imaging, neuroimaging, and emergency department imaging were also evaluated. RESULTS: The sample included 2,381,851 patients before matching. Imaging was significantly more likely for patients with a history of anxiety (71.1% vs. 55.7%, P < .001) and depression (73.2% vs. 55.3%, P < .001). The adjusted odds of any imaging were 1.24 (95% confidence interval [CI]: 1.22-1.26) for patients with a history of anxiety, and 1.43 (CI: 1.41-1.45) for patients with a history of depression before matching, and 1.18 (CI: 1.16-1.20) for a history of anxiety and 1.33 (CI: 1.32-1.35) for a history of depression after matching. Adjusted analyses found significant, positive associations between mental illness and chest imaging, neuroimaging, and emergency department imaging both before and after matching. DISCUSSION: In contrast to prior findings on screening, anxiety and depression were associated with greater likelihood of diagnostic imaging within the population studied.


Subject(s)
Anxiety/diagnostic imaging , Depression/diagnostic imaging , Diagnostic Imaging/methods , Aged , Humans , Logistic Models , Odds Ratio
2.
PLoS One ; 14(11): e0224735, 2019.
Article in English | MEDLINE | ID: mdl-31725755

ABSTRACT

OBJECTIVE: Combined computed tomography (CT) occurs when one anatomical area is simultaneously imaged both without and with contrast, or two overlapping anatomical areas are imaged concurrently. While this has been studied in a Traditional Medicare population, it has not been studied in other populations subject to prior authorization. This study explores between-facility variation in ordering and receiving orders to render combined CT in a mixed commercial and Medicare Advantage population. METHODS: Orders for CT abdomen (without/with contrast), CT thorax (without/with contrast), and concurrent CT brain and sinus authorized by a prior authorization company from 2013-2017, pertaining to patients with commercial or Medicare Advantage health plans from one national insurer, were extracted. Orders were issued and rendered by both hospitals and nonhospitals. The analysis was performed separately for each anatomical area in two ways: orders were grouped by ordering facility, and by designated rendering facility. For each facility, the ratio of combined to total orders was calculated, and analysis of variance was used to determine whether there were significant differences in this rate by year. The association between health plan type and combined imaging rates was assessed. RESULTS: Combined rates [ratio±standard deviation] for abdomen, thorax, and brain/sinus were 0.306±0.246, 0.089±0.142, and 0.002±0.01 respectively when the analysis was conducted according to ordering facility, and 0.311±0.178, 0.096±0.113, and 0.001±0.006 when the analysis was conducted according to designated rendering facility. Combined CT abdomen and CT thorax rates decreased monotonically from 2013 to 2017, decreases that were significant (P < .01) regardless of whether orders were grouped by ordering or rendering facility. Combined CT abdomen and CT thorax rates significantly differed between orders pertaining to people with commercial and Medicare Advantage plans. DISCUSSION: Variability was greater when orders were grouped by ordering facility, rather than rendering facility. Health plan type may influence whether a patient receives combined CT.


Subject(s)
Medicare Part C , Neuroimaging , Outpatients , Practice Patterns, Physicians' , Tomography, X-Ray Computed , Abdomen/diagnostic imaging , Female , Humans , Male , Thorax/diagnostic imaging , United States
3.
Drug Alcohol Depend ; 177: 244-248, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28622627

ABSTRACT

INTRODUCTION: Chronic alcohol abuse is associated with neurophysiological changes in brain activity; however, these changes are not well localized in humans. Non-human primate models of alcohol abuse enable control over many potential confounding variables associated with human studies. The present study utilized high-resolution magnetoencephalography (MEG) to quantify the effects of chronic EtOH self-administration on resting state (RS) brain function in vervet monkeys. METHODS: Adolescent male vervet monkeys were trained to self-administer ethanol (n=7) or an isocaloric malto-dextrin solution (n=3). Following training, animals received 12 months of free access to ethanol. Animals then underwent RS magnetoencephalography (MEG) and subsequent power spectral analysis of brain activity at 32 bilateral regions of interest associated with the chronic effects of alcohol use. RESULTS: demonstrate localized changes in brain activity in chronic heavy drinkers, including reduced power in the anterior cingulate cortex, hippocampus, and amygdala as well as increased power in the right medial orbital and parietal areas. DISCUSSION: The current study is the first demonstration of whole-head MEG acquisition in vervet monkeys. Changes in brain activity were consistent with human electroencephalographic studies; however, MEG was able to extend these findings by localizing the observed changes in power to specific brain regions. These regions are consistent with those previously found to exhibit volume loss following chronic heavy alcohol use. The ability to use MEG to evaluate changes in brain activity following chronic ethanol exposure provides a potentially powerful tool to better understand both the acute and chronic effects of alcohol on brain function.


Subject(s)
Alcohol Drinking/physiopathology , Alcohol Drinking/trends , Brain/drug effects , Brain/physiopathology , Ethanol/administration & dosage , Alcoholic Intoxication/physiopathology , Animals , Chlorocebus aethiops , Electroencephalography/drug effects , Electroencephalography/trends , Magnetoencephalography/drug effects , Magnetoencephalography/trends , Male , Primates , Self Administration
5.
AJR Am J Roentgenol ; 207(1): 121-5, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27064855

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate the impact of a collaborative radiology utilization management program on the disposition of cases according to provider specialty. MATERIALS AND METHODS: A utilization management program directed by a radiology benefit management company provided peer-to-peer decision support for providers ordering advanced outpatient imaging studies. After a radiologist reviewed the cases, based upon provider specialty, the rates of the following dispositions were analyzed: study approved by consensus, study changed by consensus, study not performed by consensus, study approved (no consensus), and study administratively not performed (no callback). Aggregated rates of study changed or not performed by consensus (withdrawals) were used to assess the effect of provider-radiologist collaboration. The rate of no callback was used to assess sentinel effect. The combined rate of withdrawals and no callback represented the overall impact of radiologist participation. The project period was 5 years. RESULTS: A total of 168,915 studies were reviewed: 58.6% were approved, 6.8% were changed, and 13.5% were withdrawn by consensus; 6.0% were approved without consensus; 15.2% were withdrawn because of no callback; 35.5% initially ordered were not performed at the time they were ordered. Family practice (25.3%) and internal medicine (23.8%) had the highest aggregated rates of study changed or withdrawn by consensus. Thoracic surgery (13.3%), neurosurgery (11.2%), and orthopedic surgery (9.3%) had the lowest rates. Internal medicine (18.0%), neurology (17.7%), and family practice (17.4%) had the highest rates of study withdrawn owing to no callback. Pediatrics (7.1%) and ophthalmology (7.3%) had the lowest rates. The overall impact was greatest for family practice (42.7%), internal medicine (41.8%), and neurology (33.4%) and least for orthopedic surgery (22.8%) and neurosurgery (24.0%). CONCLUSION: Radiologist participation had substantial impact regardless of provider specialty. The impact was greatest on primary care providers who are heavier users of radiology.


Subject(s)
Diagnostic Imaging/statistics & numerical data , Peer Review , Referral and Consultation , Consensus , Decision Support Techniques , Humans , Patient Selection , Practice Patterns, Physicians'/statistics & numerical data , Quality Assurance, Health Care , United States , Unnecessary Procedures/statistics & numerical data
6.
Neuroinformatics ; 14(2): 183-90, 2016 04.
Article in English | MEDLINE | ID: mdl-26643442

ABSTRACT

Current tools for automated skull stripping, normalization, and segmentation of non-human primate (NHP) brain MRI studies typically demonstrate high failure rates. Many of these failures are due to a poor initial estimate for the affine component of the transformation. The purpose of this study is to introduce a multi-atlas approach to overcome these limitations and drive the failure rate to near zero. A library of study-specific templates (SST) spanning three Old World primate species (Macaca fascicularis, M. mulatta, Chlorocebus aethiops) was created using a previously described unbiased automated approach. Several modifications were introduced to the methodology to improve initial affine estimation at the study-specific template level, and at the individual subject level. These involve performing multiple separate normalizations to a multi-atlas library of templates and selecting the best performing template on the basis of a covariance similarity metric. This template was then used as an initialization for the affine component of subsequent skull stripping and normalization procedures. Normalization failure rate for SST generation and individual-subject segmentation on a set of 150 NHP was evaluated on the basis of visual inspection. The previous automated template creation procedure results in excellent skull stripping, segmentation, and atlas labeling across species. Failure rate at the individual-subject level was approximately 1%, however at the SST generation level it was 17%. Using the new multi-atlas approach, failure rate was further reduced to zero for both SST generation and individual subject processing. We describe a multi-atlas library registration approach for driving normalization failures in NHP to zero. It is straightforward to implement, and can have application to a wide variety of existing tools, as well as in difficult populations including neonates and the elderly. This approach is also an important step towards developing fully automated high-throughput processing pipelines that are critical for future high volume multi-center NHP imaging studies for studies of drug abuse and brain health.


Subject(s)
Atlases as Topic , Brain Mapping , Brain/diagnostic imaging , Magnetic Resonance Imaging , Animals , Brain/anatomy & histology , Humans , Image Processing, Computer-Assisted , Primates
7.
Alcohol Clin Exp Res ; 39(4): 659-71, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25833027

ABSTRACT

BACKGROUND: Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol. Of particular interest was how chronic alcohol exposure may affect the resting state network. METHODS: Baseline resting state functional magnetic resonance imaging was acquired in a cohort of vervet monkeys. Animals underwent an induction period where they were exposed to an isocaloric maltose dextrin solution (control) or ethanol in escalating doses over three 30-day epochs. Following induction, animals were given ad libitum access to water and a maltose dextrin solution (control) or water and ethanol for 22 h/d over 12 months. Cross-sectional analyses examined region of interests in hubs and community structure across animals to determine differences between drinking and nondrinking animals after the 12-month free access period. RESULTS: Animals were classified as lighter (<2.0 g/kg/d) or heavier drinkers (≥2.0 g/kg/d) based on a median split of their intake pattern during the 12-month ethanol free access period. Statistical analysis of hub connectivity showed significant differences in heavier drinkers for hubs in the precuneus, posterior parietal cortices, superior temporal gyrus, subgenual cingulate, and sensorimotor cortex. Heavier drinkers were also shown to have less consistent communities across the brain compared to lighter drinkers. The different level of consumption between the lighter and heavier drinking monkeys suggests that differences in connectivity may be intake dependent. CONCLUSIONS: Animals that consume alcohol show topological differences in brain network organization, particularly in animals that drink heavily. Differences in the resting state network were linked to areas that are associated with spatial association, working memory, and visuomotor processing.


Subject(s)
Alcohol Drinking/physiopathology , Brain/drug effects , Brain/physiology , Ethanol/administration & dosage , Ethanol/pharmacology , Neural Pathways/drug effects , Neural Pathways/physiology , Animals , Brain/cytology , Chlorocebus aethiops , Functional Neuroimaging , Magnetic Resonance Imaging , Male , Self Administration
8.
Alcohol Clin Exp Res ; 38(7): 1973-81, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24942558

ABSTRACT

BACKGROUND: An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of ethanol (EtOH) and they metabolize it more rapidly than primates. METHODS: The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates, specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent per day) over long periods of time (12 to 30 months) with concomitant pathological changes in endocrine, hepatic, and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the EtOH-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. RESULTS: The MATRR is a unique postmortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer EtOH using a standardized experimental paradigm to the broader alcohol research community. CONCLUSIONS: This resource provides a translational platform from which we can better understand the disease processes associated with alcoholism.


Subject(s)
Alcoholism , Brain , Endocrine Glands , Liver , Tissue Banks , Animals , Computational Biology , Ethanol/administration & dosage , Female , Haplorhini , Male , Self Administration , Specimen Handling
9.
Neuroinformatics ; 12(4): 543-50, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24850577

ABSTRACT

Currently available non-human primate templates typically require input of a skull-stripped brain for structural processing. This can be a manually intensive procedure, and considerably limits their utility. The purpose of this study was to create a vervet MRI population template, associated tissue probability maps (TPM), and a label atlas to facilitate true fully automated Magnetic Resonance Imaging (MRI) structural analyses for morphometric analyses. Structural MRI scans of ten vervet monkeys (Chlorocebus aethiops) scanned at three time points were used in this study. An unbiased population average template was created using a symmetric diffeomorphic registration (SyN) procedure. Skull stripping, segmentation, and label map generation were performed using the publically available rhesus INIA19 MRI template and NeuroMap label atlas. A six-class TPM and a six-layer two-class normalization template was created from the vervet segmentation for use within the Statistical Parametric Mapping (SPM) framework. Fully automated morphologic processing of all of the vervet MRI scans was then performed using the vervet TPM and vervet normalization template including skull-stripping, segmentation and normalization. The vervet template creation procedure resulted in excellent skull stripping, segmentation, and NeuroMap atlas labeling with 720 structures successfully registered. Fully automated processing was accomplished for all vervet scans, demonstrating excellent skull-stripping, segmentation, and normalization performance. We describe creation of an unbiased vervet structural MRI population template and atlas. The template includes an associated six-class TPM and DARTEL six-layer two-class normalization template for true fully automated skull-stripping, segmentation, and normalization of vervet structural T1-weighted MRI scans. We provide the most detailed vervet label atlas currently available based on the NeuroMaps atlas with 720 labels successfully registered. We additionally describe a novel method for atlas label generation that capitalizes on previous work in this area using high-dimensional highly accurate image matching procedures for inter-species morphologic normalization.


Subject(s)
Algorithms , Brain Mapping/methods , Brain/anatomy & histology , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Animals , Chlorocebus aethiops
10.
Drug Alcohol Depend ; 136: 135-42, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24467872

ABSTRACT

BACKGROUND: Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. METHODS: Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [(3)H]MPPF, and the agonist, [(3)H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. RESULTS: An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. CONCLUSIONS: Chronic, ethanol self-administration up-regulates hippocampal 5-HT1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted.


Subject(s)
Alcoholism/metabolism , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Receptor, Serotonin, 5-HT1A/drug effects , 8-Hydroxy-2-(di-n-propylamino)tetralin , Alcoholism/genetics , Aminopyridines/metabolism , Animals , Autoradiography , DNA, Complementary/biosynthesis , DNA, Complementary/isolation & purification , Gene Expression/drug effects , Housing, Animal , Macaca fascicularis , Male , Piperazines/metabolism , Polymerase Chain Reaction , RNA/biosynthesis , RNA/isolation & purification , Receptor, Serotonin, 5-HT1A/genetics , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/metabolism , Self Administration , Serotonin Antagonists/metabolism , Serotonin Receptor Agonists
11.
Int J Stroke ; 9(5): 646-51, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24450819

ABSTRACT

RATIONALE: Intracerebral hemorrhage causes 15% of strokes annually in the United States, and there is currently no effective therapy. AIMS AND HYPOTHESIS: This is a clinical trial designed to study the safety, feasibility, and efficacy of a protocol of targeted temperature management to moderate hypothermia in intracerebral hemorrhage patients. METHODS: The targeted temperature management after intracerebral hemorrhage trial is a prospective, single-center, interventional, randomized, parallel, two-arm (1:1) phase-II clinical trial with blinded end-point ascertainment. Intracerebral hemorrhage patients will be randomized within 18 h of symptom onset to either 72 h of targeted temperature management to moderate hypothermia (32-34°C) followed by a controlled rewarming at of 0·05-0·1°C per hour or 72 h of targeted temperature management to normothermia (36-37°C) using endovascular or surface cooling. OUTCOMES: The primary outcome is the development of serious adverse events possibly and probably related to treatment. Secondary outcomes include in-hospital neurological deterioration between day 0-7, in-hospital mortality, functional outcome measured by the modified Rankin scale at discharge and 90 days, and effect of treatment allocation on cerebral edema and hematoma volume. DISCUSSION: Intracerebral hemorrhage remains the most severe form of stroke with limited options to improve survival. As the early resuscitation phase in the intensive care unit represents the greatest opportunity for impact on clinical outcome, it also appears to be the most promising window of opportunity to demonstrate a benefit when investigating aggressive treatments. CONCLUSION: More research of novel therapies to improve outcomes after intracerebral hemorrhage is desperately needed. The results of the targeted temperature management after intracerebral hemorrhage clinical trial may provide additional information on the applicability of targeted temperature management after intracerebral hemorrhage.


Subject(s)
Cerebral Hemorrhage/therapy , Clinical Protocols , Hypothermia, Induced/methods , Brain Edema/etiology , Brain Edema/pathology , Brain Edema/prevention & control , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/pathology , Critical Care/methods , Feasibility Studies , Humans , Hypothermia, Induced/adverse effects , Outcome Assessment, Health Care/methods , Patient Selection , Prospective Studies , Rewarming/methods , Stroke/complications , Stroke/pathology , Stroke/therapy
12.
Cell Tissue Bank ; 15(1): 99-110, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23709130

ABSTRACT

Appropriate animal models are critical to conduct translational studies of human disorders without variables that can confound clinical studies. Such analytic methods as patch-clamp electrophysiological and voltammetric recordings of neurons in brain slices require living brain tissue. In order to obtain viable tissue from nonhuman primate brains, tissue collection methods must be designed to preserve cardiovascular and respiratory functions for as long as possible. This paper describes a method of necropsy that has been used in three species of monkeys that satisfies this requirement. At necropsy, animals were maintained under a deep surgical plane of anesthesia while a craniotomy was conducted to expose the brain. Following the craniotomy, animals were perfused with ice-cold, oxygenated artificial cerebrospinal fluid to displace blood and to reduce the temperature of the entire brain. The brain was removed within minutes of death and specific brain regions were immediately dissected for subsequent in vitro electrophysiology or voltammetry experiments. This necropsy method also provided for the collection of tissue blocks containing all brain regions that were immediately frozen and stored for subsequent genomic, proteomic, autoradiographic and histological studies. An added benefit from the design of this necropsy method is that all major peripheral tissues were also collected and are now being utilized in a wide range of genomic, biochemical and histological assays. This necropsy method has resulted in the establishment and growth of a nonhuman primate alcohol tissue bank designed to distribute central nervous system and peripheral tissues to the larger scientific community.


Subject(s)
Brain/physiology , Tissue and Organ Harvesting/methods , Animals , Brain/cytology , Brain Mapping , Craniotomy , Electrophysiology , Macaca fascicularis , Tissue Banks
13.
Alcohol Clin Exp Res ; 37(11): 1891-900, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23905720

ABSTRACT

BACKGROUND: Animal studies have long been an important tool for basic research as they offer a degree of control often lacking in clinical studies. Of particular value is the use of nonhuman primates (NHPs) for neuroimaging studies. Currently, studies have been published using functional magnetic resonance imaging (fMRI) to understand the default-mode network in the NHP brain. Network science provides an alternative approach to neuroimaging allowing for evaluation of whole-brain connectivity. In this study, we used network science to build NHP brain networks from fMRI data to understand the basic functional organization of the NHP brain. We also explored how the brain network is affected following an acute ethanol (EtOH) pharmacological challenge. METHODS: Baseline resting-state fMRI was acquired in an adult male rhesus macaque (n = 1) and a cohort of vervet monkeys (n = 10). A follow-up scan was conducted in the rhesus macaque to assess network variability and to assess the effects of an acute EtOH challenge on the brain network. RESULTS: The most connected regions in the resting-state networks were similar across species and matched regions identified as the default-mode network in previous NHP fMRI studies. Under an acute EtOH challenge, the functional organization of the brain was significantly impacted. CONCLUSIONS: Network science offers a great opportunity to understand the brain as a complex system and how pharmacological conditions can affect the system globally. These models are sensitive to changes in the brain and may prove to be a valuable tool in long-term studies on alcohol exposure.


Subject(s)
Brain/drug effects , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Nerve Net/drug effects , Animals , Chlorocebus aethiops , Functional Neuroimaging , Macaca mulatta , Magnetic Resonance Imaging , Male , Neural Networks, Computer
14.
Int J Radiat Oncol Biol Phys ; 85(2): 321-8, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-22687197

ABSTRACT

PURPOSE: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/therapy , Chemoradiotherapy/methods , Dacarbazine/analogs & derivatives , Glioma/therapy , Neoplasm Recurrence, Local/therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/blood supply , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Chemoradiotherapy/adverse effects , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Female , Glioma/blood supply , Glioma/mortality , Glioma/pathology , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Proteins/blood , Neoplasm Recurrence, Local/blood supply , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/therapeutic use , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Radiotherapy Dosage , Sorafenib , Temozolomide , Vascular Endothelial Growth Factor A/blood
15.
J Neurosci ; 32(44): 15626-42, 2012 Oct 31.
Article in English | MEDLINE | ID: mdl-23115197

ABSTRACT

Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by "epigenetic" mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several "candidate genes" in the brain. This study examines whether randomized differential rearing (maternal vs surrogate-peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation.


Subject(s)
DNA Methylation/physiology , Maternal Deprivation , Prefrontal Cortex/metabolism , T-Lymphocytes/metabolism , Animals , Base Sequence , Chromosomes/genetics , DNA, Complementary/metabolism , Immunoprecipitation , In Situ Hybridization , Macaca mulatta , Male , Microarray Analysis , Molecular Sequence Data , RNA/biosynthesis , RNA/isolation & purification , Real-Time Polymerase Chain Reaction , Social Environment
16.
Alcohol ; 46(4): 371-6, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22445804

ABSTRACT

Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse.


Subject(s)
Alcohol Drinking/metabolism , Brain/metabolism , Ethanol/pharmacology , Hydroxyindoleacetic Acid/cerebrospinal fluid , Maternal Deprivation , Serotonin/metabolism , Alcohol Drinking/cerebrospinal fluid , Analysis of Variance , Animals , Chromatography , Disease Models, Animal , Hydroxyindoleacetic Acid/metabolism , Macaca mulatta , Male
17.
Dev Psychobiol ; 54(5): 546-55, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22072233

ABSTRACT

Adverse early experiences are associated with a range of deleterious health outcomes in humans, including higher risk for affective disorders. Studies using a long-standing model of nonhuman primate model of early adversity have demonstrated that nursery-reared (NR) monkeys exhibit alterations in multiple aspects of biobehavioral development; however, few studies have evaluated the persistence of socioaffective behavioral changes through adulthood. We evaluated the effects of early rearing experience on adult animals' response to a well-validated assessment of anxiety-like behavior, the human intruder paradigm (HIP). We tested 22 rhesus monkeys who were either nursery-reared (NR) or reared with their mothers (mother-reared; MR). NR monkeys were inhibited in their behavior compared to MR monkeys, with reduced locomotion and exploratory behaviors. NR animals showed a marginal increase in freezing. Together these findings demonstrate that the consequences of differential infant rearing experience on socioaffective behavior persist into adulthood, with evidence of greater inhibition in NR monkeys.


Subject(s)
Anxiety/psychology , Behavior, Animal/physiology , Macaca mulatta/physiology , Maternal Deprivation , Stress, Psychological , Analysis of Variance , Animals , Exploratory Behavior , Female , Macaca mulatta/psychology , Male , Time
18.
J Am Coll Radiol ; 8(10): 716-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21962787

ABSTRACT

PURPOSE: The aim of this study was to analyze variability in study withdrawal rates among academic neuroradiologists participating in a utilization management (UM) program. METHODS: The activities of 5 academic neuroradiologists participating in a UM program were assessed. The project period spanned 42 months. Participating neuroradiologists received identical training and used identical rule sets to evaluate the appropriateness of outpatient CT and MRI studies. Neuroradiologists could approve studies on the basis of available electronic data or contact referring physicians for further information. The rate of withdrawals (defined as "study not performed by consensus" or "study changed by consensus" with the referring physician) was compared among the neuroradiologists. RESULTS: A total of 5,256 studies were reviewed (mean, 1,051; median, 1,043). There were 573 studies (10.9%) not performed by consensus and 298 studies (5.7%) changed by consensus, resulting in a total of 871 withdrawals (16.6%). Among the neuroradiologists, withdrawal rates varied by approximately a factor of 2 (mean, 16.5%; median, 15.2%; range, 12.8%-23.5%). Although rate of studies not performed by consensus varied by approximately a factor of 2 (mean, 10.8%; median, 8.1%; range, 7.6%-18.0%), the rate of studies changed by consensus showed little variation (mean, 5.7%; median, 5.5%; range, 4.8%-6.6%). CONCLUSIONS: Variability in withdrawal rates was related to cases in which referring physicians were asked not to perform studies; there was little variation when referring physicians were asked to change studies. These data imply agreement among the neuroradiologists regarding appropriateness of rule sets but suggest that personality characteristics such as persuasiveness, persistence, and desire for conflict avoidance may play an important role in outcomes.


Subject(s)
Career Choice , Guideline Adherence/statistics & numerical data , Neuroradiography/statistics & numerical data , Personnel Turnover/statistics & numerical data , Practice Management/statistics & numerical data , Academic Medical Centers , Cross-Sectional Studies , Female , Humans , Magnetic Resonance Imaging/statistics & numerical data , Male , Observer Variation , Practice Patterns, Physicians'/trends , Tomography, X-Ray Computed/statistics & numerical data , United States
20.
J Am Coll Radiol ; 7(11): 854-8, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21040866

ABSTRACT

PURPOSE: The aim of this study was to analyze trends in the utilization of CT angiography (CTA) and MR angiography (MRA) of the head and neck in the Medicare population over a 6-year interval. METHODS: Nationwide Medicare Part B fee-for-service databases were reviewed. Current Procedural Terminology® codes for CTA and MRA of the head and neck were selected. MRA codes included studies without contrast, with contrast, and without and with contrast. Yearly and aggregate procedure volumes were compared for each Current Procedural Terminology code and modality. Data were also analyzed regarding contrast utilization and cost. RESULTS: From 2002 to 2007, the volume of head CTA increased by 827%, and the overall volume of head MRA increased by 39%. The year-to-year percentage increase in overall volume of head MRA declined throughout the study period; almost all of the increase in the overall volume of head MRA occurred from 2002 to 2005. The volume of neck CTA increased by 1,074%, and the overall volume of neck MRA increased by 31%. An 18% decrease in the volume of neck MRA without contrast was offset by a 104% increase in the volume of neck MRA using contrast. The year-to-year percentage increase in the overall volume of neck MRA declined from 2002 to 2005; there was a decrease in volume of 3% from 2005 to 2007. From 2002 to 2007, when considering all study types, procedure volume increased by 71%; aggregate allowable charges increased by $181 million. Examinations using contrast increased by 235%. In 2002, 23% of examinations used contrast; in 2007, 46% of examinations used contrast. CONCLUSIONS: The rate of growth for head and neck CTA was dramatically higher than for MRA. Neck MRA using contrast also showed substantial growth. The Medicare population is now receiving more contrast material and radiation to noninvasively assess the arterial vasculature of the head and neck.


Subject(s)
Head/diagnostic imaging , Head/pathology , Magnetic Resonance Angiography/statistics & numerical data , Medicare Part B/statistics & numerical data , Neck/diagnostic imaging , Neck/pathology , Tomography, X-Ray Computed/statistics & numerical data , Humans , United States/epidemiology
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