Infarct evolution in a large animal model of middle cerebral artery occlusion

Mechanical thrombectomy for the treatment of ischemic stroke shows high rates of recanalization; however, some patients still have a poor clinical outcome. A proposed reason for this relates to the fact that the ischemic infarct growth differs significantly between patients. While some patients demonstrate rapid evolution of their infarct core (fast evolvers), others have substantial potentially salvageable penumbral tissue even hours after initial vessel occlusion (slow evolvers). We show that the dog middle cerebral artery occlusion model recapitulates this key aspect of human stroke rendering it a highly desirable model to develop novel multimodal treatments to improve clinical outcomes. Moreover, this model is well suited to develop novel image analysis techniques that allow for improved lesion evolution prediction; we provide proof-of-concept that MRI perfusion-based time-to-peak maps can be utilized to predict the rate of infarct growth as validated by apparent diffusion coefficient-derived lesion maps allowing reliable classification of dogs into fast versus slow evolvers enabling more robust study design for interventional research

Acute thrombus formation on phosphorilcholine surface modified flow diverters

PURPOSE: Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED). METHODS: Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent. RESULTS: Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p \u3c 0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198). CONCLUSION: In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device

Quantitative assessment of device-clot interaction for stent retriever thrombectomy

PURPOSE: Rapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device-clot interaction as a potential mechanism for efficient embolectomy. METHODS: Two different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF). RESULTS: The CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004-0.007). CONCLUSIONS: This study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot-device integration increased in both clot models by waiting 5 min

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE)

Health and Pleasure in Consumers' Dietary Food Choices: Individual Differences in the Brain's Value System

Taking into account how people value the healthiness and tastiness of food at both the behavioral and brain levels may help to better understand and address overweight and obesity-related issues. Here, we investigate whether brain activity in those areas involved in self-control may increase significantly when individuals with a high body-mass index (BMI) focus their attention on the taste rather than on the health benefits related to healthy food choices. Under such conditions, BMI is positively correlated with both the neural responses to healthy food choices in those brain areas associated with gustation (insula), reward value (orbitofrontal cortex), and self-control (inferior frontal gyrus), and with the percent of healthy food choices. By contrast, when attention is directed towards health benefits, BMI is negatively correlated with neural activity in gustatory and reward-related brain areas (insula, inferior frontal operculum). Taken together, these findings suggest that those individuals with a high BMI do not necessarily have reduced capacities for self-control but that they may be facilitated by external cues that direct their attention toward the tastiness of healthy food. Thus, promoting the taste of healthy food in communication campaigns and/or food packaging may lead to more successful self-control and healthy food behaviors for consumers with a higher BMI, an issue which needs to be further researched

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).This project was funded by the National Health and Medical Research Council (NHMRC; 1093017), the Walking On Sunshine Foundation, Anne Stanton, Nicola Laws and Lloyd Owen in Memorial and Civic Solutions. This study was also funded by Fight for Sight, Denmark. A.L.P. is supported by Highland Island Enterprise (HMS9353763). This work was supported by an NHMRC Program Grant (G.V.L., G.J.M., R.A.S. and N.K.H.). G.V.L. is supported by an NHMRC Practitioner Fellowship and The University of Sydney, Medical Foundation. R.A.S. is supported by an NHMRC Practitioner Fellowship. Support from Melanoma Institute Australia and The Ainsworth Foundation is also gratefully acknowledged. J.S.W. is supported by a NHMRC early career fellowship (1111678). N.W. is supported by an NHMRC Senior Research Fellowship (1139071). N.K.H. is supported by an NHMRC Senior Principal Research Fellowship (1117663)

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant