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The assessment and subsequent management of a potentially neoplastic bone lesion seen at diagnostic radiography is often complicated by diagnostic uncertainty and inconsistent management recommendations. Appropriate clinical management should be directed by risk of malignancy. Herein, the ACR-sponsored Bone Reporting and Data System (Bone-RADS) Committee, consisting of academic leaders in the fields of musculoskeletal oncology imaging and orthopedic oncology, presents the novel Bone-RADS scoring system to aid in risk assignment and provide risk-aligned management suggestions. When viewed in the proper clinical context, a newly identified bone lesion can be risk stratified as having very low, low, intermediate, or high risk of malignancy. Radiographic features predictive of risk are reviewed include margination, pattern of periosteal reaction, depth of endosteal erosion, pathological fracture, and extra-osseous soft tissue mass. Other radiographic features predictive of histopathology are also briefly discussed. To apply the Bone-RADS scoring system to a potentially neoplastic bone lesion, radiographic features predictive of risk are each given a point value. Point values are summed to yield a point total, which can be translated to a Bone-RADS score (1-4) with corresponding risk assignment (very low, low, intermediate, high). For each score, evidence-based and best practice consensus management suggestions are outlined. Examples of each Bone-RADS scores are presented, and a standardized diagnostic radiography report template is provided. [ABSTRACT FROM AUTHOR]

Developmental dysplasia of the hip (DDH) is an important contributor to musculoskeletal morbidity, but effective strategies to screen for DDH remain controversial. The current utilization of hip ultrasound (US) screening for DDH in the United States is not defined. This study utilized Optum's de-identified Clinformatics® Data Mart, a large commercial and Medicare Advantage claims database. The frequency of DDH and hip US utilization was estimated using billing data on an average of 2.9 million relevant beneficiaries included annually from 2007 through 2017. A total of 6806 DDH cases were identified with an average annual prevalence of 1.7 per 1000 infants, which was stable during the study period. Girls were more likely to be screened and diagnosed with DDH, comprising 72% of DDH cases with an OR of 2.55 (95% CI 2.42–2.69), p < 0.001. Hip US screening was employed in 0.9% of the infant population on average but increased substantially from 2007 (0.4%) to 2017 (2.2%). Most common billing diagnoses included hip deformity (27.4%), breech delivery (20.4%), and physical exam abnormality (17.7%). The average imaging costs per patient for all screened children was $108.94. Insurance claims reflect the current American practice of selective hip US with relative adherence to American Academy of Pediatrics guidelines based on reported diagnoses. While hip US utilization increased during the study period, prevalence of DDH diagnoses did not increase. Our results suggest that expansion of hip US screening may not effectively increase DDH detection although further investigation is needed to ascertain optimal screening strategies to improve patient outcomes. • Hip ultrasound utilization increased in young children between 2007 and 2017. • Despite increased hip ultrasound utilization, frequency of developmental dysplasia of the hip did not increase. • Common reasons for hip ultrasound included hip deformity, breech delivery and physical exam abnormality. Claims reflected selective screening practice adhering to AAP guidelines. • Claims reflected selective screening practice adhering to AAP guidelines. [ABSTRACT FROM AUTHOR]

Physical and mental stressors on radiologists can result in burnout. Although current efforts seek to target the issues of burnout and stress for radiologists, the impact of their physical workspace is often overlooked. By combining evidence-based design, human factors, and the architectural concept of the Eudaimonia Machine, we have developed a redesign of the radiology reading room that aims to create an optimal workspace for the radiologist. Informed by classical principles of well-being and contemporary work theory, Eudaimonia integrates concerns for individual wellness and efficiency to create an environment that fosters productivity. This layout arranges a work environment into purposeful spaces, each hosting tasks of varying degrees of intensity. The improved design addresses the radiologist's work requirements while also alleviating cognitive and physical stress, fatigue, and burnout. This new layout organizes the reading room into separate areas, each with a distinct purpose intended to support the range of radiologists' work, from consultation with other health care providers to reading images without interruption. The scientific principles that undergird evidence-based design and human factors considerations ensure that the Eudaimonia Radiology Machine is best suited to support the work of the radiologists and the entire radiology department. [ABSTRACT FROM AUTHOR]

To assess magnetic resonance spectroscopy (MRS) bone marrow fat fractions' ability to discern between untreated Gaucher disease patients and healthy controls based on assessment of bone marrow infiltration and evaluate response to enzyme replacement therapy (ERT) on serial imaging. This retrospective case-controlled study compared conventional MRI and bone marrow MRS findings in six pediatric and young adult Gaucher disease patients with age- and sex-matched controls, examining femoral neck and lumbar spine bone marrow fat fractions and bone marrow burden (BMB) scores. Separate analysis of six patients with serial imaging on ERT was performed with analysis of fat fractions, BMB scores, organ volumes, and serum chitotriosidase. Untreated patients had significantly lower femoral and lumbar spine fat fractions than controls (0.32 versus 0.67, p = 0.041 and 0.17 versus 0.34, p = 0.041, respectively). Total BMB scores were significantly higher in patients (8.0 versus 3.5, p = 0.015). In patients on ERT with average follow-up of 3.5 years, femoral neck fat fraction was the sole significant predictor of treatment duration (R square: 0.804, p < 0.001) when adjusted for age. Femoral neck fat fraction also correlated with lumbar spine fat fraction, liver volume and chitotriosidase (p < 0.05). MRS test-retest reliability was excellent (Pearson correlations: 0.96, 0.99; p -values <0.001). BMB inter-rater reliability was good overall with an intra-class correlation coefficient of 0.79 for total score, although lumbar spine score reliability was poor at 0.45. MRS-derived bone marrow fat fractions appear capable of detecting Gaucher disease severity and monitoring treatment-related changes as a predictor of ERT duration in pediatric and young adult patients. • Pediatric Gaucher disease patients had significantly lower MRS femoral and lumbar spine fat fractions compared to controls. • Femoral fat fractions corresponded with duration of treatment and reflected liver volume and chitotriosidase. • MRS may be an alternative to chemical shift imaging for Gaucher disease response to therapy, pending further validation. [ABSTRACT FROM AUTHOR]

Objective: To systematically review all published cost-effectiveness analyses (CEAs) of imaging technologies in children.Methods: We identified all CEAs involving fetal and pediatric imaging included in a publicly available repository of CEAs published since 1976. Information on publication characteristics, methods, costs, quality of life weights, and incremental cost-effectiveness ratios (ICERs) was recorded for each article.Results: Of 480 diagnostic CEAs, only 10 focused on fetal and pediatric imaging. The 10 studies reported 43 quality of life weights based on previously published adult data (n = 20, 46.5%); pregnant women perspective (n = 11, 25.6%), and treating physician perspective (n = 12, 27.9%). None of the studies elicited quality of life weights from children nor took into consideration the postnatal impact of disease on family's quality of life. All studies used a health care payer perspective without incorporating patients' incurred cost such as loss wages or travel related cost. Of 37 ICERs, 7 (18.9%) were cost saving and 6 (16.2%) were more expensive and less effective. The remaining ICERs ranged from $1,400 per quality-adjusted life-year (MRI versus ultrasound in newborns with moderate risk of occult spinal dysraphism) to $10,000,000 per quality-adjusted life-year (CT versus no imaging in children at low risk for craniosynostosis).Conclusion: There is a striking paucity of cost-effectiveness studies evaluating imaging technologies in children. Existing studies do not incorporate the patient and family perspectives regarding utilities (eg, impact of child's disease on families' quality of life) or cost (eg, loss wages, travel, time off). Future studies should elicit and incorporate the impact of disease on families to better reflect real-world scenarios. [ABSTRACT FROM AUTHOR]

Introduction: Nonradiologist providers increasingly perform diagnostic imaging examinations and imaging-guided interventions traditionally performed by radiologists, which have raised concerns regarding appropriate utilization and self-referral. The purpose of this study was to assess the contribution of imaging studies to Medicare reimbursements for highly compensated nonradiologist providers in specialties often performing imaging studies.Methods: The Medicare Provider Utilization and Payment Database was queried for provider information regarding overall reimbursement for providers in anesthesiology, cardiology, emergency medicine, neurology, obstetrics and gynecology, orthopedic surgery, neurology, and vascular surgery. Information regarding imaging studies reported and payment amounts were extracted for the 25 highest-reimbursed providers. Data were analyzed for relative contribution of imaging payments to overall medical Medicare payments.Results: Significant differences between numbers of imaging studies, types of imaging, and payment amounts were noted based on provider specialty (p < 0.001). Highest-reimbursed cardiologists received the greatest percentage of Medicare payments from imaging (18.3%) followed by vascular surgery (11.6%), obstetrics and gynecology (10.9%), orthopedic surgery (9.6%), emergency medicine (8.7%), neurology (7.8%), and anesthesiology (3.2%) providers. Mean imaging payments amongst highly reimbursed nonradiologists were greatest for cardiology ($578,265), vascular surgery ($363,912), and orthopedic surgery ($113,634). Amongst highly reimbursed specialists, most common nonradiologist imaging payments were from ultrasound (45%) and cardiac nuclear medicine studies (40%).Conclusions: Nonradiologist performed imaging payments comprised substantial proportions of overall Medicare reimbursement for highly reimbursed physicians in several specialties, especially cardiology, vascular surgery, and orthopedic surgery. Further investigation is needed to better understand the wider economic implications of nonradiologist imaging study performance and self-referral beyond the Medicare population. [ABSTRACT FROM AUTHOR]

Interpretation of increasingly complex imaging studies involves multiple intricate tasks requiring visual evaluation, cognitive processing, and decision-making. At each stage of this process, there are opportunities for error due to human factors including perceptual and ergonomic conditions. Investigation into the root causes of interpretive error in radiology first began over a century ago. In more recent work, there has been increasing recognition of the limits of human image perception and other human factors and greater acknowledgement of the role of the radiologist's environment in increasing the risk of error. This article reviews the state of research on perceptual and interpretive error in radiology. This article focuses on avenues for further error examination, and strategies for mitigating these errors are discussed. The relationship between artificial intelligence and interpretive error is also considered. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Aneurysm wall enhancement (AWE) on magnetic resonance vessel wall imaging has been proposed as an imaging marker of aneurysm wall inflammation and instability. We performed a systematic review and meta-analysis to summarize the association between AWE and aneurysm rupture.Materials and Methods: We performed a comprehensive literature search of studies evaluating the association between AWE and aneurysm rupture. We abstracted the following study data: study design, patient demographics, aneurysm characteristics, MRI protocols, and AWE assessment. We performed meta-analysis using a random-effects model. Study heterogeneity was assessed by using the Cochrane Q and I2 statistic, and publication bias was examined by using the Begg-Mazumdar test.Results: Five studies with 492 subjects met eligibility for systematic review. We found a significant positive overall association between AWE and aneurysm rupture, with an odds ratio (OR) of 34.26 (95% confidence interval [CI] 10.20-115.07, p < 0.001). No significant heterogeneity (Q = 5.38, p = 0.25; I2 = 26%) or publication bias (p = 1.000) was present. In the separate analysis of circumferential AWE and aneurysm rupture, we identified marked heterogeneity across studies (Q = 21.23, p < 0.001; I2 = 86%). Further subgroup analysis considering the effect of aneurysm size showed that the strength of association between circumferential AWE and aneurysm rupture was significant in small aneurysms (<7 mm), with an OR of 26.12 (95% CI 6.11-111.75, p < 0.001), but limited in large aneurysms (OR = 0.56, 95% CI [0.21, 1.44], p = 0.23).Conclusion: AWE on magnetic resonance vessel wall imaging is significantly and independently associated with aneurysm rupture and may become a promising imaging marker to predict aneurysm behavior and identify high-risk aneurysms. [ABSTRACT FROM AUTHOR]

Partial liquid ventilation is proposed as an alternative ventilation strategy to reduce surface tension, increase alveolar recruitment, and decrease inflammation. Studied in acute respiratory distress and other indications, liquid ventilation is being revisited for infants with bronchopulmonary dysplasia. Perfluorooctyl bromide used for liquid ventilation is radiopaque, allowing radiographic visualization of lung liquid ventilation patterns that may provide additional insight into pulmonary pathophysiology. Current protocols utilize reduced liquid dosing, resulting in unique imaging features. We discuss optimal radiographic technique and report initial ultrasound evaluation results. With renewed interest in partial liquid ventilation, it may be helpful for pediatric radiologists to familiarize themselves with the clinical use and radiographic appearance of liquid ventilation material. [ABSTRACT FROM AUTHOR]

Bilateral agenesis of the cruciate ligaments is a rare congenital anomaly. We report a unique case of a young girl who had congenital short femur and diagnosed with polyarticular juvenile idiopathic arthritis (JIA) and later discovered to have congenital absence of both anterior and posterior cruciate ligaments and meniscal dysplasia in both the knees when MRI was performed at 11 years of age. The MRI was performed to evaluate knee laxity and persistent symptoms despite medical management and multiple steroid injections for arthritis treatment. This patient is one of the youngest with congenital absence of both the cruciate ligaments to be treated with ACL reconstruction. We highlight the unique radiographic imaging manifestations of congenital cruciate ligament agenesis and emphasize the role of MRI to confirm and depict additional intraarticular abnormalities. [ABSTRACT FROM AUTHOR]

Objective Assessment of tumor response to chemotherapy is essential in managing malignant pediatric bone tumors prior to resection. Subjects and methods Pre-chemotherapy and post-chemotherapy osteosarcoma and Ewing sarcoma cases (n = 18) were analyzed with apparent diffusion coefficient (ADC) values measured by two readers. Results Treated tumors demonstrated significantly greater ADC values compared to untreated tumors ( p < 0.001). Intraclass correlation coefficients ranged between 0.858 and 0.935. No significant tumor volume differences were observed. Regression analysis demonstrated average ADC as the best predictor of treatment. Conclusions Our study suggests that ADC values may be useful for evaluating chemotherapeutic response of malignant pediatric bone tumors. [ABSTRACT FROM AUTHOR]

Funding for research has become increasingly difficult to obtain in an environment of decreasing clinical revenue, increasing research costs, and growing competition for federal and nonfederal funding sources. This paper identifies critical requirements to build and sustain a successful radiology research program (eg, key personnel and leadership, research training and mentorship, infrastructure, institutional and departmental funding or support), reviews the current state of available funding for radiology (including federal, nonfederal, philanthropy, crowdfunding, and industry), and describes promising opportunities for future funding (eg, health services, comparative effectiveness, and patient-centered outcomes research). The funding climate, especially at the federal level, changes periodically, so it is important to have radiology-specific organizations such as the American College of Radiology and the Academy of Radiology Research serving as our key advocates. Key to obtaining any funding, no matter what the source, is a well-formulated grant proposal, so a review of opportunities specifically available to radiologists to develop and hone their grant-writing skills is provided. Effective and sustained funding for radiology research has the potential to cultivate young researchers, bolster quality research, and enhance health care. Those interested in pursuing research need to be aware of the ever-changing funding landscape, research priority areas, and the resources available to them to succeed. To succeed, radiology researchers need to think about diversification and flexibility in their interests, developing multidisciplinary and multi-institutional projects, and engaging a broader base of stakeholders that includes patients. [ABSTRACT FROM AUTHOR]

Purpose: Vertebral fractures have a substantial impact on the health and quality of life of elderly individuals as one of the most common complications of osteoporosis. Vertebral augmentation procedures including vertebroplasty and kyphoplasty have been supported as means of reducing pain and mitigating disability associated with these fractures. However, use of vertebroplasty is debated, with negative randomized controlled trials published in 2009 and divergent clinical guidelines. The effect of changing evidence and guidelines on different practitioners' utilization of both kyphoplasty and vertebroplasty in the years after these developments and publication of data supporting their use is poorly understood.Methods: Using national aggregate Medicare claims data from 2002 through 2014, vertebroplasty and kyphoplasty procedures were identified by provider type. Changes in utilization by procedure type and provider were studied.Results: Total vertebroplasty billing increased 101.6% from 2001 (18,911) through 2008 (38,123). Total kyphoplasty billing frequency increased 17.2% from 2006 (54,329) through 2008 (63,684). Vertebroplasty billing decreased 60.9% from 2008 through 2014 to its lowest value (14,898). Kyphoplasty billing decreased 8.4% from 2008 (63,684) through 2010 (58,346), but then increased 7.6% from 2010 to 2013 (62,804).Conclusions: Vertebroplasty billing decreased substantially beginning in 2009 and continued to decrease through 2014 despite publication of more favorable studies in 2010 to 2012, suggesting studies published in 2009 and AAOS guidelines in 2010 may have had a persistent negative effect. Kyphoplasty did not decrease as substantially and increased in more recent years, suggesting a clinical practice response to favorable studies published during this period. [ABSTRACT FROM AUTHOR]

Summary Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer’s disease (AD) pathology. We sought to understand whether mGluR5’s role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP C ) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5’s role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window. [ABSTRACT FROM AUTHOR]

Schizophrenia is a serious illness that affects millions of patients and has been associated with N -methyl- d -aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32 , a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses. [ABSTRACT FROM AUTHOR]

Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse. [ABSTRACT FROM AUTHOR]

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK 1 R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK 1 R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK 1 R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK 1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11–84%) via dose selection. [ABSTRACT FROM AUTHOR]

Abstract: Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability. [Copyright &y& Elsevier]

Abstract: Purpose: Previous studies reporting relaxation times within atherosclerotic plaque have typically used dedicated small-bore high-field systems and small sample sizes. This study reports quantitative T1, T2 and T2 ⁎ relaxation times within plaque tissue at 1.5 T using spatially co-matched histology to determine tissue constituents. Methods: Ten carotid endarterectomy specimens were removed from patients with advanced atherosclerosis. Imaging was performed on a 1.5-T whole-body scanner using a custom built 10-mm diameter receive-only solenoid coil. A protocol was defined to allow subsequent computation of T1, T2 and T2 ⁎ relaxation times using multi-flip angle spoiled gradient echo, multi-echo fast spin echo and multi-echo gradient echo sequences, respectively. The specimens were subsequently processed for histology and individually sectioned into 2-mm blocks to allow subsequent co-registration. Each imaging sequence was imported into in-house software and displayed alongside the digitized histology sections. Regions of interest were defined to demarcate fibrous cap, connective tissue and lipid/necrotic core at matched slice-locations. Relaxation times were calculated using Levenberg-Marquardt''s least squares curve fitting algorithm. A linear-mixed effect model was applied to account for multiple measurements from the same patient and establish if there was a statistically significant difference between the plaque tissue constituents. Results: T2 and T2 ⁎ relaxation times were statistically different between all plaque tissues (P=.026 and P=.002 respectively) [T2: lipid/necrotic core was lower 47±13.7 ms than connective tissue (67±22.5 ms) and fibrous cap (60±13.2 ms); T2 ⁎: fibrous cap was higher (48±15.5ms) than connective tissue (19±10.6 ms) and lipid/necrotic core (24±8.2 ms)]. T1 relaxation times were not significantly different (P=.287) [T1: Fibrous cap: 933±271.9 ms; connective tissue (1002±272.9 ms) and lipid/necrotic core (1044±304.0 ms)]. We were unable to demarcate hemorrhage and calcium following histology processing. Conclusions: This study demonstrates that there is a significant difference between qT2 and qT2 ⁎ in plaque tissues types. Derivation of quantitative relaxation times shows promise for determining plaque tissue constituents. [Copyright &y& Elsevier]

Abstract: The calcitonin gene-related peptide (CGRP) receptor has been implicated in the pathogenesis of migraine. A class of urethanamide derivatives has been identified as potent inhibitors of the CGRP receptor. Compound 20 was found to be among the most potent (IC50 =17pM). It was shown to retain excellent aqueous solubility (>50mg/mL, pH 7) while dramatically improving solution stability as compared to our previously disclosed development candidate, BMS-694153 (1). [Copyright &y& Elsevier]

A pre-PLV chest radiograph revealed chronic lung disease of prematurity as well as atelectasis of the right upper lobe (Fig. These findings suggest that chest radiographs are helpful in these patients to ascertain the distribution of the liquid to infer ventilation patterns. Initial chest X-ray (A) shows chronic lung disease and right upper lobe atelectasis. [Extracted from the article]

Abstract: Objective: Intraplaque hemorrhage is an increasingly recognized contributor to plaque instability. Neovascularization of plaque is believed to facilitate the entry of inflammatory and red blood cells (RBC). Under physiological conditions, neovessels are subject to mechanical loading from the deformation of atherosclerotic plaque by blood pressure and flow. Local mechanical environments around neovessels and their relevant pathophysiologic significance have not yet been examined. Methods and results: Four carotid plaque samples removed at endarcterectomy were collected for histopathological examination. Neovessels and other components were manually segmented to build numerical models for mechanical analysis. Each component was assumed to be non-linear isotropic, piecewise homogeneous and incompressible. The results indicated that local maximum principal stress and stretch and their variations during one cardiac cycle were greatest around neovessels. Neovessels surrounded by RBC underwent a much larger stretch during systole than those without RBCs present nearby (median [inter quartile range]; 1.089 [1.056, 1.131] vs. 1.034 [1.020, 1.067]; p <0.0001) and much larger stress (5.3kPa [3.4, 8.3] vs. 3.1kPa [1.6, 5.5]; p <0.0001) and stretch (0.0282 [0.0190, 0.0427] vs. 0.0087 [0.0045, 0.0185]; p <0.0001) variations during the cardiac cycle. Conclusions: Local critical mechanical conditions may lead to the rupture of neovessels resulting in the formation and expansion of intraplaque hemorrhage. [Copyright &y& Elsevier]

Background and aims Recent development of high resolution MRI techniques have enabled imaging of intracranial atherosclerotic plaque in vivo . However, identifying plaque composition remains challenging given the small size and the lack of histological validation. This study aims to quantify the relaxation times of intracranial plaque components ex vivo at 3 T and to determine whether multi-contrast MRI could classify intracranial plaque according to the American Heart Association classification with histological validation. Methods A total of 53 intracranial arteries with atherosclerotic plaques from 20 cadavers (11 male, age 73.8 ± 10.9) were excised. Quantitative T 1 /T 2 /T 2 * mapping sequences and multi-contrast fast-spin echo sequences (T 1 , T 2 , proton-density weighted and short time inversion recovery) were acquired. Plaque components including: fibrous cap, lipid core, fibrous tissue, calcification, and healthy wall were segmented on histology, and their relaxation times were derived from quantitative images. Two radiologists independently classified plaque type blinded to the histology results. Results Relaxation times of plaque components are distinct and different. T 2 and T 2 * values of lipid core are lower than fibrous cap (p = 0.026 & p < 0.0001), but are comparable with fibrous tissue and healthy wall (p = 0.76 & p = 0.42). MRI reliably classified plaque type compared with histology (κ = 0.69) with an overall accuracy of 80.7%. The sensitivity and specificity using MRI to identify fibro-lipid atheroma (type IV-V) was 94.8% and 77.1%, respectively. Inter-observer agreement was excellent (κ = 0.77). Conclusion Intracranial plaque components have distinct and different relaxation times at 3 T. High-resolution MRI is able to characterize intracranial plaque composition and classify plaque types ex vivo at 3 T. [ABSTRACT FROM AUTHOR]

Abstract: Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%). [Copyright &y& Elsevier]

Abstract: A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK1/SERT affinity. Optimization based on NK1/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK1/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression. [Copyright &y& Elsevier]