Coupled Dynamic Flow and Geomechanical Simulations for an Integrated Assessment of CO2 Storage Impacts in a Saline Aquifer

Pore pressure variation resulting from geological CO2 storage may compromise reservoir, caprock and fault integrity. Therefore, we investigate the mechanical impact of industrial-scale CO2 storage at a prospective Danish site by coupled 3D hydro-mechanical simulations carried out by two independent modelling groups. Even though the two chosen modelling strategies are not identical, simulation results demonstrate that storage integrity is maintained at any time. Vertical displacements are mainly determined by hydraulic fault conductivity influencing spatial pore pressure elevation. The introduced fault zone implementation in the hydro- mechanical model allows for localization of potential leakage pathways for formation fluids along the fault plane

The history of hydrocarbon filling of Danish chalk fields

In an oil reservoir, the geometry of the interface between water and oil is critical in determining the volume of oil trapped below the top seal. If the interface is planar and horizontal, the volume calculation is fairly simple, but if the interface is tilted or undulating, estimation of the volume of the trapped oil is complex as it depends on the combined structural and fluid contact geometry. Since accumulation of the oil may take place over a time span of several million years, while the reservoir is experiencing burial and compaction, the charge history must be studied using dynamic methods that account for these changes and for flow in both the oil and water phases. These processes have been studied quantitatively at the Geological Survey of Denmark and Greenland (GEUS) in a project that has combined the burial model with a fluid flow simulator. The modelling study shows that filling of a chalk reservoir can have a very long and complex history dominated by very low fluid flow rates (cm/year). The resulting modelled present-day situation exhibits a very irregular oil distribution and a non-planar geometry of the fluid contacts, and shows marked similarities to that shown by the field data

Face validity of a proposed tool for staging canine osteoarthritis: Canine OsteoArthritis Staging Tool (COAST)

Abstract Osteoarthritis (OA) is a common, progressive degenerative disease of synovial joints. It can develop subsequent to an acquired disorder such as joint trauma but is primarily driven by developmental orthopedic disease in young dogs. Therefore, it is essentially characterised as an early onset but lifelong disease that worsens with age. Early intervention using a multi-modal drug and non-drug approach, with or without surgery as required, has the greatest potential for the most effective management of the disease. Timely implementation of a continuing care plan provides an opportunity to slow the rate of deterioration by reducing the negative impacts of OA-associated pain, encouraging appropriate levels of activity and improving strength and posture. Unfortunately, many dogs are presented to veterinary clinics only when marked behavioural changes are observed and substantial deterioration of the musculoskeletal and somatosensory systems has already occurred. To assist veterinarians with early and stage-specific diagnosis of OA in dogs, the authors present a proposed, practical diagnostic aid called 'COAST' (Canine OsteoArthritis Staging Tool) with face validity. As indicated by the successful implementation of staging systems for other companion animal diseases, it is expected that standardized staging of OA in dogs will help guide disease management plans and improve monitoring. The items used to construct COAST have been developed using consensus opinion of international experts from nine countries, who are actively working in the fields of small animal orthopaedics, anaesthesia and pain management. Further validation (test-retest, discriminatory ability, responsiveness, criterion validation) of the tool under field conditions is now required and the authors invite input

Proximity ligation assay reveals both pre- A nd postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain

Background: Synaptic degeneration and accumulation of amyloid \u3b2-peptides (A\u3b2) are hallmarks of the Alzheimer diseased brain. A\u3b2 is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the \u3b2-secretase BACE1 and by \u3b3-secretase. If APP is instead cleaved by the \u3b1-secretase ADAM10, A\u3b2 will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons. Results: Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- A nd postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- A nd postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density. Conclusions: We show that the \u3b1-secretase ADAM10 and the \u3b2-secretase BACE1 are located in both the pre- A nd postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies

Functions of behavior change interventions when implementing multi-professional teamwork at an emergency department: a comparative case study

BACKGROUND While there is strong support for the benefits of working in multi-professional teams in health care, the implementation of multi-professional teamwork is reported to be complex and challenging. Implementation strategies combining multiple behavior change interventions are recommended, but the understanding of how and why the behavior change interventions influence staff behavior is limited. There is a lack of studies focusing on the functions of different behavior change interventions and the mechanisms driving behavior change. In this study, applied behavior analysis is used to analyze the function and impact of different behavior change interventions when implementing multi-professional teamwork. METHODS A comparative case study design was applied. Two sections of an emergency department implemented multi-professional teamwork involving changes in work processes, aimed at increasing inter-professional collaboration. Behavior change interventions and staff behavior change were studied using observations, interviews and document analysis. Using a hybrid thematic analysis, the behavior change interventions were categorized according to the DCOM® model. The functions of the behavior change interventions were then analyzed using applied behavior analysis. RESULTS The two sections used different behavior change interventions, resulting in a large difference in the degree of staff behavior change. The successful section enabled staff performance of teamwork behaviors with a strategy based on ongoing problem-solving and frequent clarification of directions. Managerial feedback initially played an important role in motivating teamwork behaviors. Gradually, as staff started to experience positive outcomes of the intervention, motivation for teamwork behaviors was replaced by positive task-generated feedback. CONCLUSIONS The functional perspective of applied behavior analysis offers insight into the behavioral mechanisms that describe how and why behavior change interventions influence staff behavior. The analysis demonstrates how enabling behavior change interventions, managerial feedback and task-related feedback interact in their influence on behavior and have complementary functions during different stages of implementation.Mandus Frykman, Henna Hasson, Åsa Muntlin Athlin, and Ulrica von Thiele Schwar

APP depletion alters selective pre- and post-synaptic proteins

The normal role of Alzheimer's disease (AD)-linked amyloid precursor protein (APP) in the brain remains incompletely understood. Previous studies have reported that lack of APP has detrimental effects on spines and electrophysiological parameters. APP has been described to be important in synaptic pruning during development. The effect of APP knockout on mature synapses is complicated by this role in development. We previously reported on differential changes in synaptic proteins and receptors in APP mutant AD transgenic compared to wild-type neurons, which revealed selective decreases in levels of pre- and post-synaptic proteins, including of surface glutamate receptors. In the present study, we undertook a similar analysis of synaptic composition but now in APP knockout compared to wild-type mouse neurons. Here we demonstrate alterations in levels of selective pre- and post-synaptic proteins and receptors in APP knockout compared to wild-type mouse primary neurons in culture and brains of mice in youth and adulthood. Remarkably, we demonstrate selective increases in levels of synaptic proteins, such as GluA1, in neurons with APP knockout and with RNAi knockdown, which tended to be opposite to the reductions seen in AD transgenic APP mutant compared to wild-type neurons. These data reinforce that APP is important for the normal composition of synapses

Multicenter Evaluation of the Fully Automated PCR-Based Idylla EGFR Mutation Assay on Forman-Fixed, Paraffin-Embedded Tissue of Human Lung Cancer

Before initiating treatment of advanced non-small-cell lung cancer with tyrosine kinase inhibitors (eg, erlotinib, gefitinib, osimertinib, and afatinib), which inhibit the catalytic activity of epidermal growth factor receptor (EGFR), clinical guidelines require determining the EGFR mutational status for activating (EGFR exons 18, 19, 20, or 21) and resistance (EGFR exon 20) mutations. The EGFR resistance mutation T790M should be monitored at cancer progression. The Idylla EGFR Mutation Assay, performed on the Idylla molecular diagnostics platform, is a fully automated (<2.5 hours turnaround time) sample-to-result molecular test to qualitatively detect 51 EGFR oncogene point mutations, deletions, or insertions. In a 15-center evaluation, Idylla results on 449 archived formalin-fixed, paraffin-embedded tissue sections, originating from non-small-cell lung cancer biopsies and resection specimens, were compared with data obtained earlier with routine reference methods, including next-generation sequencing, Sanger sequencing, pyrosequencing, mass spectrometry, and PCR-based assays. When results were discordant, a third method of analysis was performed, when possible, to confirm test results. After confirmation testing and excluding invalids/errors and discordant results by design, a concordance of 97.6% was obtained between Idylla and routine test results. Even with <10 mm(2) of tissue area, a valid Idylla result was obtained in 98.9% of the cases. The Idylla EGFR Mutation Assay enables sensitive detection of most relevant EGFR mutations in concordance with current guidelines, with minimal molecular expertise or infrastructure

Multidimensional analysis of the frequencies and rates of cytokine secretion from single cells by quantitative microengraving

The large diversity of cells that comprise the human immune system requires methods that can resolve the individual contributions of specific subsets to an immunological response. Microengraving is process that uses a dense, elastomeric array of microwells to generate microarrays of proteins secreted from large numbers of individual live cells ([similar]10⁴–10⁵ cells/assay). In this paper, we describe an approach based on this technology to quantify the rates of secretion from single immune cells. Numerical simulations of the microengraving process indicated an operating regime between 30 min–4 h that permits quantitative analysis of the rates of secretion. Through experimental validation, we demonstrate that microengraving can provide quantitative measurements of both the frequencies and the distribution in rates of secretion for up to four cytokines simultaneously released from individual viable primary immune cells. The experimental limits of detection ranged from 0.5 to 4 molecules/s for IL-6, IL-17, IFNγ, IL-2, and TNFα. These multidimensional measures resolve the number and intensities of responses by cells exposed to stimuli with greater sensitivity than single-parameter assays for cytokine release. We show that cells from different donors exhibit distinct responses based on both the frequency and magnitude of cytokine secretion when stimulated under different activating conditions. Primary T cells with specific profiles of secretion can also be recovered after microengraving for subsequent expansion in vitro. These examples demonstrate the utility of quantitative, multidimensional profiles of single cells for analyzing the diversity and dynamics of immune responses in vitro and for identifying rare cells from clinical samples.National Institute of Allergy and Infectious Diseases (U.S.) (Award no. 5U19AI050864-07)National Institute of Allergy and Infectious Diseases (U.S.) (Award no. F32AI651003)National Institute of Allergy and Infectious Diseases (U.S.) (Award no. U19AI070352)National Institute of Allergy and Infectious Diseases (U.S.) (Award no. U19AI046130)National Institute of Allergy and Infectious Diseases (U.S.) (Award no. P01AI045757)National Institute of Neurological Disorders and Stroke (U.S.) (Jacob Javits Merit Award (NS2427))Massachusetts Institute of Technology (Texaco- Mangelsdorf Career Development Professor