Attenuation of Experimental Aortic Aneurysm Formation in P-Selectin Knockout Mice

The aim of this study was to determine the role of P-selectin, an adhesion molecule found on the surface of activated platelets and endothelial cells during experimental aortic aneurysm formation. Infrarenal abdominal aortas of C57 black wild-type (WT) mice and P-selectin knockout (PKO) mice were measured in situ and then perfused with porcine pancreatic elastase (0.332 U mL). Whole blood was drawn from the tail artery on day 2 pre-perfusion to determine total and differential white blood cell (WBC) counts. On day 14 postperfusion, aortic diameters (AD) of WT mice ( N 19) and PKO mice ( N 9) were measured. An aortic aneurysm was defined as a 100 or greater increase in AD from pre-perfusion measurement. Immunohistochemistry, including H&E, trichrome and von Gieson staining, was performed on harvested aortic tissue. Statistical analysis was performed by t -test and Fisher's exact test. There were no significant differences in peripheral leukocyte counts at baseline between the two groups. WT mice had significantly larger AD compared to PKO mice at day 14 postperfusion (116 vs. 38 , P < 0.001). Aortic aneurysm penetrance was 52 in WT mice, while 0 ( P 0.01) of PKO mice formed aneurysms. On histologic examination, WT mouse aortas were associated with a significant inflammatory response and degradation of elastin and collagen fibers, while PKO mouse aortas lacked signs of inflammation or vessel wall injury. P-selectin deficiency attenuates aneurysm formation in the elastase aortic perfusion model. This was associated with a blunting of the inflammatory response and preserved vessel wall intergrity following elastase perfusion in the P-selectin knockout mice. Further investigation to elucidate the independent contributions of endothelial cell and platelet P-selectin in experimental aortic aneurysm formation is required.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73125/1/annals.1383.014.pd

The first definitive carcharodontosaurid (Dinosauria:Theropoda) from Asia and the delayed ascent of tyrannosaurids

Little is known about the evolution of large-bodied theropod dinosaurs during the Early to mid Cretaceous in Asia. Prior to this time, Asia was home to an endemic fauna of basal tetanurans, whereas terminal Cretaceous ecosystems were dominated by tyrannosaurids, but the intervening 60 million years left a sparse fossil record. Here, we redescribe the enigmatic large-bodied Chilantaisaurus maortuensis from the Turonian of Inner Mongolia, China. We refer this species to a new genus, Shaochilong, and analyze its systematic affinities. Although Shaochilong has previously been allied with several disparate theropod groups (Megalosauridae, Allosauridae, Tyrannosauroidea, Maniraptora), we find strong support for a derived carcharodontosaurid placement. As such, Shaochilong is the first unequivocal Asian member of Carcharodontosauridae, which was once thought to be restricted to Gondwana. The discovery of an Asian carcharodontosaurid indicates that this clade was cosmopolitan in the Early to mid Cretaceous and that Asian large-bodied theropod faunas were no longer endemic at this time. It may also suggest that the ascent of tyrannosaurids into the large-bodied dinosaurian predator niche was a late event that occurred towards the end of the Cretaceous,between the Turonian and the Campanian

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report

Objective The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78048/1/27580_ftp.pd

2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative

Objective The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct “rheumatoid arthritis.” Results In the new criteria set, classification as “definite RA” is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct “rheumatoid arthritis.”Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78045/1/27584_ftp.pd

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The Biogeography of Coelurosaurian Theropods and Its Impact on Their Evolutionary History

The Coelurosauria are a group of mostly feathered theropods that gave rise to birds, the only dinosaurians that survived the Cretaceous-Paleogene extinction event and are still found today. Between their first appearance in the Middle Jurassic up to the end Cretaceous, coelurosaurians were party to dramatic geographic changes on the Earth’s surface, including the breakup of the supercontinent Pangaea, and the formation of the Atlantic Ocean. These plate tectonic events are thought to have caused vicariance or dispersal of coelurosaurian faunas, influencing their evolution. Unfortunately, few coelurosaurian biogeographic hypotheses have been supported by quantitative evidence. Here, we report the first, broadly sampled quantitative analysis of coelurosaurian biogeography using the likelihood-based package BioGeoBEARS. Mesozoic geographic configurations and changes are reconstructed and employed as constraints in this analysis, including their associated uncertainties. We use a comprehensive time-calibrated coelurosaurian evolutionary tree produced from the Theropod Working Group phylogenetic data matrix. Six biogeographic models in the BioGeoBEARS package with different assumptions about the evolution of spatial distributions are tested against geographic constraints. Our results statistically favor the DIVALIKE+J and DEC+J models, which allow vicariance and founder events, supporting continental vicariance as an important factor in coelurosaurian evolution. Ancestral range estimation indicates frequent dispersal events via the Apulian route (connecting Europe and Africa during the Early Cretaceous) and the Bering land bridge (connecting North America and Asia during the Late Cretaceous). These quantitative results are consistent with commonly inferred Mesozoic dinosaurian dispersals and continental-fragmentation-induced vicariance events. In addition, we recognize the importance of Europe as a dispersal center and gateway in the Early Cretaceous, as well as other vicariance events such as those triggered by the disappearance of land bridges