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siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration — intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) — and 2 dosing regimens — single and repetitive via an implanted reservoir device — on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS.

For thousands of years, the volcanic activity present along the Andes Mountain range has generated a large amount of pyroclastic material. As a result, around 60 percent of the soils present in Chile have a volcanic origin, of which, we can find soils derived from volcanic ash. These correspond to soils whose origin is the weathering of volcanic ash, which generates minerals such as allophane, imogolite, and halloysite. The presence of these minerals gives these soils unique geotechnical properties, such as high plasticity, low dry unit weight, and a unique internal structure. Subjecting these soils to extreme temperatures like those needed to perform standard laboratory tests produces changes in their structures, and thus in their geotechnical behavior. These changes are important to be aware of with respect to slope stability problems, embankment conformation, surface foundations, etc. In the present study, a type of soil found in Chile originating from the weathering of volcanic ash and locally named Trumao was studied. Due to its age and formation processes, the main minerals found in the soil are allophane and imogolite, and hence it belongs to the allophanic soil type. The material was studied in its natural state (undisturbed) and, after being oven-dried using common geotechnical tests, the behaviors of both samples were compared. The study shows that some properties are affected significantly by the oven-drying process, and thus it is not recommended to expose the material to high temperatures during geotechnical laboratory testing to avoid misleading results.

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.\ud \ud

Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington’s disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders. A divalent siRNA architecture enables sustained silencing of gene expression in deep regions of the brain.

Operational ocean forecasts are typically produced by modelling systems run using a forced mode approach. The evolution of the ocean state is not directly influenced by surface waves, and the ocean dynamics are driven by an external source of meteorological data which are independent of the ocean state. Model coupling provides one approach to increase the extent to which ocean forecast systems can represent the interactions and feedbacks between ocean, waves, and the atmosphere seen in nature. This paper demonstrates the impact of improving how the effect of waves on the momentum exchange across the ocean–atmosphere interface is represented through ocean–wave coupling on the performance of an operational regional ocean prediction system. This study focuses on the eddy-resolving (1.5 km resolution) Atlantic Margin Model (AMM15) ocean model configuration for the north-west European Shelf (NWS) region. A series of 2-year duration forecast trials of the Copernicus Marine Environment Monitoring Service (CMEMS) north-west European Shelf regional ocean prediction system are analysed. The impact of including ocean–wave feedbacks via dynamic coupling on the simulated ocean is discussed. The main interactions included are the modification of surface stress by wave growth and dissipation, Stokes–Coriolis forcing, and wave-height-dependent ocean surface roughness. Given the relevance to operational forecasting, trials with and without ocean data assimilation are considered. Summary forecast metrics demonstrate that the ocean–wave coupled system is a viable evolution for future operational implementation. When results are considered in more depth, wave coupling was found to result in an annual cycle of relatively warmer winter and cooler summer sea surface temperatures for seasonally stratified regions of the NWS. This is driven by enhanced mixing due to waves, and a deepening of the ocean mixed layer during summer. The impact of wave coupling is shown to be reduced within the mixed layer with assimilation of ocean observations. Evaluation of salinity and ocean currents against profile measurements in the German Bight demonstrates improved simulation with wave coupling relative to control simulations. Further, evidence is provided of improvement to simulation of extremes of sea surface height anomalies relative to coastal tide gauges.

PurposeThe USDA’s Risk Management Agency (RMA) made several changes to the crop insurance products available to organic growers for the 2014 crop year. Most notably, a 5 percent premium surcharge was removed and organic-specific transitional yields (t-yields) were issued for the first time. The purpose of this paper is to use farm-level organic crop yield data to analyze the impact of these reforms on producer insurance outcomes and compare the insurance options for new organic growers.Design/methodology/approachThis study uses a unique panel data set of organic corn and soybean yields to analyze the impact of organic crop insurance reforms. Actual Production History values and premium rates are calculated for each farm and crop yield sequence. Producer loss ratios and subsidized premium wedges are compared for yield, revenue and area-risk products before and after the instituted reforms.FindingsResults indicate that RMA succeeded in improving the actuarial soundness of the organic insurance program, though further refinement of organic t-yields may be necessary to accurately reflect the yield potential of organic producers and avoid reductions in program participation.Originality/valueThis paper provides insight into the effectiveness of reforms intended to improve the actuarial soundness of organic crop insurance and demonstrates the effect that the reforms are likely to have on new and existing organic farms. Because this analysis uses data collected independently of RMA and includes farms that may or may not have purchased crop insurance, it avoids the self-selection problems that might affect analyses using crop insurance program data.

A new software tool called BitFlows has been developed to support creativity, collaboration, performance and innovation in New Media. New Media practitioners already have a diverse range of tools at their disposal. This range of tools is constantly growing fueled by hardware and software hacks, which allow individuals to creatively use and abuse consumer products in ways not intended by their original creators. Software such as Ableton Live, MaxiMSP and VVVV give creators the ability to perform and demonstrate works in a live setting. Influenced by Csikszentmihalyi's concept of Flow in creative work (Csikszentmihalyi, 1996) and Shneiderman's suggestion that creativity can be aided by smoother flow between applications (Shneiderman, 2000a), BitFlows provides a simple means for users to mash-up the data-flows from all of these diverse pieces of hardware and software, over the network, in single or collaborative settings.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N=518) design. We assessed 98 single nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate gene-studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

When people experience a near-death or life-threatening incident, they sometimes report an altered state of consciousness in which they have the perception of being out of or away from their physical body. During such an experience these individuals at times have the impression of encountering a spiritual personage who offers them a choice to stay or return to their physical life and/or attempts to motivate them to willingly do so, sometimes conflicting with a simultaneous desire to stay in that altered state of consciousness they perceive as the afterlife. This paper discusses how self-determination theory (SDT) is relevant to this process by meeting the experient’s three basic psychological needs for relatedness, competence, and autonomy, resulting in various degrees of effectiveness. It concludes with a postulation that by doing so it may foster a continuing intrinsic motivation to live life well, resulting in a greater overall condition of psychological wellbeing.

Oceanography has entered an era of new observing platforms, such as biogeochemical-Argo floats and gliders, some of which will provide three-dimensional maps of essential ecosystem variables on the North-West European (NWE) Shelf. In a foreseeable future operational centers will use multi-platform assimilation to integrate those valuable data into ecosystem reanalysis and forecast systems. Here we address some important questions related to glider biogeochemical data assimilation (DA) and introduce multi-platform DA in a preoperational model of the NWE Shelf sea ecosystem. We test the impact of the different multi-platform system components (glider vs. satellite, physical vs. biogeochemical) on the simulated biogeochemical variables. To characterize the model performance, we focus on the period around the phytoplankton spring bloom, since the bloom is a major ecosystem driver on the NWE Shelf. We found that the timing and magnitude of the phytoplankton bloom is insensitive to the physical DA, which is explained in the study. To correct the simulated phytoplankton bloom one needs to assimilate chlorophyll observations from glider or satellite Ocean Color (OC) into the model. Although outperformed by the glider chlorophyll assimilation, we show that OC assimilation has mostly desirable impact on the sub-surface chlorophyll. Since the OC assimilation updates chlorophyll only in the mixed layer, the impact on the sub-surface chlorophyll is the result of the model dynamical response to the assimilation. We demonstrate that the multi-platform assimilation combines the advantages of its components and always performs comparably to its best performing component.

The importance of oceans for atmospheric forecasts as well as climate simulations is being increasingly recognised with the advent of coupled ocean / atmosphere forecast models. Having comparable resolutions in both domains maximises the benefits for a given computational cost. The Met Office has recently upgraded its operational global ocean-only model from an eddy permitting 1/4 degree tripolar grid (ORCA025) to the eddy resolving 1/12 degree ORCA12 configuration while retaining 1/4 degree data assimilation. We will present a description of the ocean-only ORCA12 system, FOAM-ORCA12, alongside some initial results. Qualitatively, FOAM-ORCA12 seems to represent better (than FOAM-ORCA025) the details of mesoscale features in SST and surface currents. Overall, traditional statistical results suggest that the new FOAM-ORCA12 system performs similarly or slightly worse than the pre-existing FOAM-ORCA025. However, it is known that comparisons of models running at different resolutions suffer from a double penalty effect, whereby higher-resolution models are penalised more than lower-resolution models for features that are offset in time and space. Neighbourhood verification methods seek to make a fairer comparison using a common spatial scale for both models and it can be seen that, as neighbourhood sizes increase, ORCA12 consistently has lower continuous ranked probability scores (CRPS) than ORCA025. CRPS measures the accuracy of the pseudo-ensemble created by the neighbourhood method and generalises the mean absolute error measure for deterministic forecasts. The focus over the next year will be on diagnosing the performance of both the model and assimilation. A planned development that is expected to enhance the system is the update of the background-error covariances used for data assimilation.

Introduction: The ADAPT technique uses large bore aspiration catheters for mechanical thrombectomy. Several aspiration catheters are now available. We report a bench-top exploration of a beveled-tip catheter, and our experience in treating large vessel occlusions using next-generation aspiration catheters. Methods: Twenty experiments were conducted with either a Sofia Plus or a Zoom71 using a vascular phantom in which a clot model was introduced. Rate of ingestion, complete recanalization after a single attempt, and pressure at the catheter tip for both devices were recorded. A retrospective analysis from a prospectively-maintained database was performed. Patient demographics, periprocedural metrics, discharge and 90-day modified Rankin Scales were collected. Patients were divided into two groups based on which aspiration catheter was used. Results: In our bench-top experiment, complete ingestion of the clot occurred in 90% of beveled tip and 20% of control device experiments (p=0.006). Our clinical data demonstrated no significant difference in age, gender, IV tPA administration, admission NIHSS, baseline mRS, or LVO location between the beveled tip and flat tip groups. With the beveled tip, TICI 2C or better recanalization was more frequent (93.2% vs 74.2%, p-value 0.017), stent retriever usage was lower (9.1% versus 29%, p-value 0.024), and patients had lower mRS on discharge (median 3 vs 4, p less than 0.001) and at 90 days (median 2 vs 4, p=0.008). Conclusion: The beveled tip design leads to more frequent clot ingestion in a bench top model, which may translate into a more efficacious thrombectomy device with improved outcomes.

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2’-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds.

Expansions of a G4C2 repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Proposed disease mechanisms include a gain of toxic functions of the G4C2 repeats, implying that selective reduction in levels of the repeat-containing transcripts would represent a treatment strategy for this disorder. In the present study, using C9-ALS/FTD patient derived cells and C9ORF72 BAC transgenic mice, we have generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G4C2 repeat containing transcripts in both the sense and anti-sense strands of C9ORF72 and effectively suppress tissue levels of polyGP dipeptides. In a single patient harboring mutant C9ORF72 with the G4C2 repeat expressions, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of CSF polyGP.

Copernicus Marine Service - North West-European Shelf Monitoring and Forecasting Centre. This document refers to the following real-time CMEMS products: NORTHWESTSHELF-ANALYSIS-FORECAST-PHYS-004-013. The physical component of the North West European Analysis and Forecast system at ~1.5 km horizontal resolution and 33 vertical levels. &nbsp

Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies., This study was supported by a grant from the National Institute of Mental Health (R01MH092293 to GAH and JAT) and by a grant from the New Jersey Center for Tourette Syndrome (to GAH and JAT). This study was also supported by grants from the National Institute of Mental Health (K08MH099424 to TVF) and the National Institute for Environmental Health Science (R01 ES021462 for YSK and BLL). PM has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña, and the Jaques and Gloria Gossweiler Foundation. AM has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. AM has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1, and FOR 2698). AJW received a Young Investigator Award from Tourette Association of America. IH declares that all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

A series of observing system simulation experiments (OSSEs) have been carried out using the Met Office global Forecasting Ocean Assimilation Model (FOAM) to provide insights on the current and future design of the in situ observing network for ocean monitoring and forecasting. Synthetic observations are generated from a Nature Run (NR) that represents the true ocean state in the experiments. These observations are assimilated in FOAM and the results are compared to the NR to assess the impact of the observations, as well as assessing the effectiveness of the data assimilation system. The NR and FOAM based OSSEs have different resolutions and are driven by different surface forcing. The results show that assimilating observations equivalent to the current observing system allows the system to produce a realistic representation of the ocean state. Additional Argo profiles in some of the Western Boundary Current (WBC) regions and along the Equator improve the performance of FOAM by reducing the root mean square error (RMSE) against the Nature Run by ~10% for temperature and salinity fields in the upper ocean. Assimilating additional Deep Argo floats leads to ~20% RMSE reduction in basin scale regions and the reduction rate is up to 80% in the Labrador Sea below 2,500 m. An experiment withdrawing mooring profiles indicates the impact of moorings is localized and on average the analysis shows ~5% degradation without the mooring observations. The additional Argo profiles in the WBC regions and deep ocean also have impacts on the representation of the Ocean Heat Content (OHC) and the Atlantic Meridional Overturning Circulation (AMOC), with the deep Argo observations correcting the model drift in OHC below 2,000 m. The results highlight the necessity of a well-designed and coordinated in situ observing network globally, as well as requirements for future model and assimilation developments to achieve the best use of the additional in situ observations.

The benefits of applying data assimilation to a regional wave model for the northwest European continental shelf have been assessed. The assimilation method uses a 3D variational scheme commonly used in ocean model data assimilation, NEMOVAR, coupled to a regional configuration of WAVEWATCH III deployed on a Spherical Multiple-Cell grid with rotated pole. Significant wave height forecast skill was positively impacted over lead times of up to 12 hours, in both offshore and coastal areas of the model. Assimilation experiments tested the impacts of applying both satellite altimeter and in-situ platform observations of significant wave height as the state variable. Addition of in-situ data introduced an improvement in model skill versus assimilating altimeter measurements only, but these improvements were relatively short-lived in lead time (on the order of a few hours). Extending observation coverage into the coastal zone introduced a benefit for only the first 1-2 hours of forecast lead time at coastal sites. Although impacts on significant wave height forecasts were substantial at short lead times, the relatively short ‘system memory’ of the assimilation suggests that, in the case of the northwest European shelf region, the best application of wave data assimilation is in a rapidly cycling short range forecast system used to generate nowcasts, or for a reanalysis product.

Introduction Animal models of saccular aneurysms are stable following creation, and do not actively remodel or rupture. Recently, rodent models of aneurysm wall remodeling and rupture have been described by surgical grafting of decellularized arterial tissue.1 We sought to 1) develop and apply a modified in situ decellularization approach, not require complex grafting procedures, in a large animal model of saccular aneurysms and 2) investigate modified aneurysmal expansion and inflammation using in vivo imaging. Methods 18 New Zealand White rabbits (3.0–3.5 kg) underwent standard elastinolysis aneurysm creation of the right common carotid artery. The animals were randomized 2:1 to receive isolated vessel SDS treatment (perfusion with 1% solution for 45 min) or nothing. Every two weeks until week 8, three of the rabbits (2 SDS+elastase, 1 elastase), were subjected to MR imaging,2 followed by contrast injection with stable macrocyclic gadolinium(III)-based contrast agent that has been shown to selectively enhance the areas of vessel wall myeloperoxidase (MPO) accumulation.3 4 The MRI was repeated at 3 hours post contrast injection and the enhancement ratio (ER) was calculated. All aneurysms were measured for size by digital subtraction angiography. Results Of the 17 rabbits included in the study, 11 were treated in situ with SDS following elastase incubation and 6 served as controls. One SDS-treated rabbit was excluded due to rupture of the carotid artery during recovery. During follow-up MR imaging the ER was greater than 1 for all SDS-treated animals, whereas the controls had an ER of greater than 1 only at the two-week timepoint (consistent with the expected healing process). Average ER for SDS-treated animals was 1.63±0.20, while control animals had an ER of 1.02±0.06 (p Conclusions During the 12 weeks post aneurysm creation, MPO-mediated MR signal enhancement was continuously detected within the wall of the aneurysm, and other than at 2 weeks, only in the SDS-treated animals. This novel modified large animal aneurysm model is expected to be useful for testing of new therapies that rely on not only the mechanical properties of the aneurysm but also the biological processes that make aneurysms vulnerable to rupture. References Stroke 2014;45:248–254. AJNR2015;36:146–52. Radiology 2009;252:696–703. Sci Rep 2018;8:7687. Disclosures R. King: None. J. Caroff: 1; C; FullBright. A. Leopardi: None. A. Bogdanov: None. M. Gounis: None.

Introduction Neuroprotective strategies represent a significant opportunity to delay infarct progression in patients suffering a Large Vessel Occlusion (LVO), allowing more time for treatment by mechanical thrombectomy. Oxygen carrier therapy has the potential to deliver oxygen to hypoxic tissues, allowing for a longer window of treatment before cell death. Methods Twenty-three dogs were used in this study, with an additional 14 historical controls. Autologous clot was injected into the left MCA, confirmed on DSA, and the dog was transferred to a 3T MRI. In order to determine infarct evolution rate, Perfusion Weighted Imaging was performed and relative Time to Peak (rTTP) maps were generated.1 Based on the initial infarct evolution pathway (slow or rapid progressors), animals were randomized to either receive oxygen carrier or vehicle control. Regardless of evolution pathway, or treatment group, IV bolus was given 45 minutes after clot placement. Following bolus, diffusion weighted imaging (DWI) was performed every 30 minutes to assess infarct evolution. After 5 hours, dogs were removed from the MR, euthanized and the brain was explanted for histological processing. To calculate the true infarct volume, apparent diffusion coefficient (ADC) was calculated from the DWI images, and a threshold value of 0.533 × 10-3 mm2/s was used to differentiate infarct. The predicted final infarct size was taken from rTTP maps as the area with greater than 4.5s delay and used to normalize infarct volume. Results Of the 23 dogs used in the active group, 5 were excluded due to spontaneous recanalization or lack of sufficient infarct on DWI. From the included 18 dogs, 11 were identified as rapid progressors, and 7 as slow. The figure shows the average infarct growth rate for the four groups, showing the oxygen carrier increasing the time needed for the infarct to reach 50% of its expected size by approximately 45 minutes in the rapid group, and 30 minutes in the slow. Overall the final infarct size was reduced in both the rapid and slow groups, 0.99 vs 0.87 control versus treatment, and 0.97 vs 0.92 control versus treatment, respectively (p Conclusions Oxygen carrier therapy shows promise to slow down the infarct growth after an LVO, allowing for more time to perform mechanical thrombectomy. Not only was the time to 50% infarct increased, but after 5 hours, the infarct in the oxygen carrier groups still showed an area of penumbra. Reference Transl Stroke Res. 2019 Sep 3. Disclosures R. King: None. M. Shazeeb: None. J. Kolstad: None. C. Raskett: None. J. Winger: 5; C; Omniox Inc. L. Kelly: 5; C; Omniox Inc. Z. Vardar: None. A. Kraitem: None. V. Anagnostakou: None. A. Krtolica: 5; C; Omniox Inc. N. Henninger: 1; C; K08NS091499. M. Gounis: None.

Introduction High Frequency Optical Coherence Tomography (HF-OCT)1 is an intra-vascular imaging technique to assess device-vessel interactions and neointimal tissue growth at unprecedented spatial resolution (~10µm). In this study, we tested the hypothesis that an adequately deployed (as visualized by HF-OCT) Woven EndoBridge (WEB, Microvention, Aliso Viejo, CA) will lead to a higher aneurysm occlusion rate at 12-week follow-up in an animal model of aneurysms. Methods Elastase-induced rabbit aneurysms (n=24) were treated with the WEB device. HF-OCT (Vis-M; Gentuity LLC, Sudbury MA) and DSA were performed after WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion and malapposition were binary coded (0- present, 1- absent; 0- malapposed, 1- neck apposition >50%), respectively, on HF-OCT and DSA. A device was considered adequately deployed if it was scored as 1 on both metrics. Aneurysm healing on DSA was interpreted using the 4-point WEB occlusion score (WOS)2; with A-B considered a positive outcome. HF-OCT images acquired at 12 weeks were analyzed and neointimal coverage quantified. Scanning electron microscopy (SEM) was performed of the explanted specimens. Results Discrepancy between HF-OCT and DSA was found: HF-OCT classified as adequately deployed a total of 5 cases, whereas 8 cases were classified as adequately deployed by DSA images. Acceptable WOS grade at 12 weeks was seen in 21% of cases (n=5): 80% of those cases (n=4) were classified as adequately deployed based by HF-OCT; whereas only 60% of those cases (n=3) classified adequate by DSA. A significant interaction between adequate deployment on HF-OCT and positive outcome was confirmed (p=0.007). However, there was no statistically significant relationship between good outcome and adequate deployment based on DSA images (p=0.289). Based on HF-OCT images, the absence of the protrusion was related with a positive outcome (p=0.006); however, malapposition had no significant interaction with positive outcome (p=0.19). The area of neointimal tissue quantified by HF-OCT showed a strong correlation with SEM assessment (R²=0.96; p Conclusion HF-OCT may be valuable prognosticate adequate aneurysm occlusion with the WEB and can be used to monitor aneurysm healing longitudinally. Absence of protrusion was associated with subsequent aneurysm occlusion; however, malapposition alone did not show an effect on the rate of aneurysm healing. Reference Stroke. 2018:Nov29:STROKEAHA118022315 2. AJNR 2014;35:432–8. Disclosures Z. Vardar: None. R. King: None. A. Kraitem: None. E. Langan: None. L. Peterson: None. B. Duncan: None. C. Raskett: None. V. Anagnostakou: None. M. Gounis: None. A. Puri: None. G. Ughi: None.

Background The new generation of intrasaccular flow disruptors offers several potential advantages in aneurysm treatment.1 2 However, questions regarding risks for thromboembolic complications3 4 and long-term treatment durability remain. We study the safety and effectiveness of three Galaxy Therapeutics Seal© intrasaccular prototypes: A, B, and C (Galaxy Therapeutics LLC, Brookfield, WI). Methods Aneurysms were created in thirteen rabbits and one of 3 Seal devices were implanted. High frequency optical coherence tomography (HF-OCT) and Digital Subtraction Angiography (DSA) was performed 4- and 12-weeks post-implant. After 12 weeks, the parent vessel and the aneurysm were explanted for histological analysis. One rabbit developed symptoms consistent with a lumbar spine injury and was euthanized and explanted at day 56. Results 12-week DSA and OCT images demonstrated 8 animals had a satisfactory aneurysm occlusion (group 1: complete blood flow disruption or contrast filling in marker recess) and 4 into group 2 (residual neck or aneurysm). The percentage of neointimal coverage of the device at four-weeks was greater for group 1 (78±22.6%) than for group 2 (37 ±4.7%) (p=0.006) which persisted at 12-weeks (87.5± 14% vs. 41±3.1% respectively; p=0.004). There was no statistical difference between groups 1 and 2 in either baseline neck gap areas (0.8±0.64 mm2 vs. 2.6±1.42 mm2, respectively; p=0.808) nor in baseline neck gap volumes (26±26 mm3 vs. 113.11±134.17 mm3, respectively; p=0.361). Representative examples of pathology are shown in the figure 1. Conclusion Preliminary evidence in this preclinical study highlight advantages of a new generation of intrasaccular aneurysm embolization technology in terms of flexibility and optimization of healing features, particularly in the A and C cohorts. References Radiology 2014;273:194–201. J Neurointerv Surg 2019;11:1150–1154. World Neurosurg 2018;109:e183–e193. J Neurointerv Surg 2018;10:553–559. Disclosures A. Kraitem: None. M. Gounis: 1; C; Research grant to institution to fund experiments by Galaxy Therapeutics. Z. Vardar: None. R. King: None. E. Langan: None. T. Wolfe: 4; C; Founder, Galaxy Therapeutics. A. Badruddin: 4; C; Founder, Galaxy Therapeutics. E. Periera: 4; C; Founder, Galaxy Therapeutics. B. Follmer: 5; C; Galaxy Therapeutics. A. Rosqueta: 5; C; Galaxy Therapeutics. O. Zaidat: 4; C; Founder, Galaxy Therapeutics.

ObjectiveTo investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation.Methods18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks. Every 2 weeks, three of the rabbits (two elastase + SDS, one control) underwent MRI, followed by contrast injection with myeloperoxidase (MPO)-sensing contrast agent. MRI was repeated 3 hours after contrast injection and the enhancement ratio (ER) was calculated. Following MRI, aneurysms were explanted and subjected to immunohistopathology.ResultsDuring follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (pConclusionsIn situ decellularization of a large animal model of saccular aneurysms reproduces features of unstable aneurysms, such as chronic inflammation (up to 12 weeks) and active aneurysm wall remodeling, leading to continued growth over 8 weeks.

In 2015, multiple randomized clinical trials showed an unparalleled treatment benefit of stent-retriever thrombectomy as compared to standard medical therapy for the treatment of a large artery occlusion causing acute ischemic stroke. A short time later, the HERMES collaborators presented the patient-level pooled analysis of five randomized clinical trials, establishing class 1, level of evidence A for stent-retriever thrombectomy, in combination with intravenous thrombolysis when indicated to treat ischemic stroke. In the years following, evidence continues to mount for expanded use of this therapy for a broader category of patients. The enabling technology that changed the tide to support endovascular treatment of acute ischemic stroke is the stent-retriever. This review summarizes the history of intra-arterial treatment of stroke, introduces the biomechanics of embolus extraction with stent-retrievers, describes technical aspects of the intervention, provides a description of hemodynamic implications of stent-retriever embolectomy, and proposes future directions for a more comprehensive, multi-modal endovascular approach for the treatment of acute ischemic stroke.

Finite nutrients, including P and K, are required in large quantities for many warm-season forages. However, native perennial grasses such as switchgrass (Panicum virgatum L.) have less of an affinity for fertilizers, although recommended P and K rates are largely unknown. Objectives were to test switchgrass forage yield response to P and K rates representative of warm-season forages and identify compositional impacts for developing switchgrass forage fertilizer recommendations. Switchgrass cv. Alamo was subjected to two harvests per year after applications of 0, 28, 56, 112, and 224 kg P ha⁻¹, and split applications of 0, 134, 269, 404, and 538 kg K ha⁻¹ yr⁻¹, from 2014 to 2016. Two sets of controls were used, a “nutrient control” (0 P and K with supplemental rates of N and S) and a “control” (no fertilizer). Harvest timing (first or second cuts) did not influence (P ≥ 0.05) P or K removal or forage yields. For all study years, the control (no supplemental fertilizer) resulted in substantially lower (P ≤ 0.05) yields than the nutrient control, meaning yield did benefit (44 and 49% increases) from supplemental nutrient applications. Therefore, minimal P and K inputs are required for a yield response, as there were very few detectable yield increases beyond the lowest tested application rates (134 kg K ha⁻¹ and 28 kg P ha⁻¹). Results indicate P and K are required in low amounts and that N is a more limiting nutrient in switchgrass forage systems on marginal soils of the southeast.

Granitic residual soils are soils formed by the in situ weathering of intrusive granitic rocks and are present in different parts of the world. Due to their large presence, many civil engineering projects are carried out on and within these soils. Therefore, a correct characterization of the slopes is necessary for slope stability studies. This investigation aims to study the influence of the values of geomechanical parameters (specific weight, cohesion, and friction angle) and the geometry of a slope (height and inclination) on slope stability of residual granitic soils in dry and static conditions. To this end, an automatic system was developed for the numerical study of cases using the finite element method with limit analysis. The system allows modeling, through Monte Carlo simulation and different slope configurations. With this system, the safety factors of 5000 cases were obtained. The results of the models were processed through the SAFE toolbox, performing a Regional Sensitivity Analysis (RSA). The results of this research concluded that the order of influence of the factors were: slope angle > slope height > cohesion > friction angle > unit weight (β > H > c > ϕ > γ).

To evaluate the difference in overall survival (OS) in patients with retromolar trigone squamous cell carcinoma (RMT SCC) treated with surgery alone versus surgery plus postoperative radiotherapy (PORT) versus surgery plus postoperative chemoradiotherapy (POCRT).Retrospective cohort study of patients from 1,500 US facilities reporting to the National Cancer Database (NCDB) registry. Participants were adult patients treated with surgery as primary treatment modality for RMT SCC (n = 2,877). Exposures were primary definitive surgery versus surgery + PORT versus surgery + POCRT. Outcomes included OS after diagnosis and treatment of RMT SCC. A multivariate Cox proportional hazards model was constructed to compare survival between the three treatment modalities. Subgroup analysis was performed by T classification and overall staging.There were 1,415 (50%) patients treated with surgery alone, 870 (30%) patients treated with surgery + PORT, and 572 (20%) treated with surgery + POCRT. Treatment with surgery + PORT was associated with improved OS compared to surgery alone (relative hazard: 1.25, 95% CI: 1.01, 1.54, p = 0.042). Patients treated with surgery + POCRT also had improved OS compared with surgery alone (relative hazard: 1.89, 95% CI 1.45, 2.43, p 0.001). Patients with T3/4 tumors had improved OS when treated with surgery + PORT (relative hazard 1.39, 95% CI: 1.05, 1.84, p = 0.022) or surgery + POCRT (relative hazard 2.27, 95% CI: 1.66, 3.15, p 0.001). Patients with T1 or T2 disease had no significant difference in survival in both the surgery + PORT (p = 0.331) and surgery + POCRT treatment groups (p = 0.134). Therefore, there was no difference in OS for patients with stage I or II disease treated with surgery + PORT (p = 0.451), nor with surgery + POCRT (p = 0.853).Treatment with surgery + PORT +/- chemotherapy appears to be associated with significantly improved OS compared to surgery alone for advanced RMT SCCa.