The Influence Of Particle Size And Frictional/Cohesional Shear Strength Components On UK Salt Marsh Substrate Stability

Salt marshes and tidal flats contribute valuable ecosystem services, by providing habitats, storing pollutants and reducing flood and erosion risk in the coastal hinterland. However, salt marsh areal extent is decreasing both globally and regionally (e.g. in Northwest Europe). While we know that salt marshes are retreating, this could be occurring due to biological, geochemical and geotechnical properties of the marsh and tidal flat, and/or due to changes in hydrodynamic forcing. Until now, very few studies have assessed how substrate geotechnical properties influence both the erosion processes and the erodibility of the marsh edge and tidal flat surface. Here, we compare frictional and cohesional strength components at two hydrodynamically-similar but sedimentologically-different salt marshes and tidal flats in the UK. As such, we assess how sediment composition and behavior may influence marsh resistance to hydrodynamic forcing.This work was funded by a NERC PhD studentship (LCAG/329; 2016-2020), and a Collaborative Award in Science and Engineering with the British Geological Survey (LCAG/352)

Overcoming Cloud Concerns with Trusted Execution Environments? Exploring the Organizational Perception of a Novel Security Technology in Regulated Swiss Companies

Trusted execution environments are a new approach for isolating data, specific parts of code, or an entire application within untrusted cloud environments. This emerging security technology could also enable the migration to cloud infrastructures for organizations working with highly sensitive data. As current research does not address the organizational perception of trusted execution environments (TEEs), we conducted an explorative study to clarify the technological, environmental, and organizational views on this technology by health care, life sciences, and banking companies in Switzerland. The interview findings show that in these industries, missing technological knowledge as well as privacy and process regulation are perceived to be the most critical driver for organizational adoption of TEEs. The identified low intrinsic motivation to adopt novel technologies permits us to conclude that clarifying the regulatory impact of TEEs could drive future adoption by organizations

Instructing human macrophage polarization by stiffness and glycosaminoglycan functionalization in 3D collagen networks

Dynamic alterations of composition and mechanics of the extracellular matrix (ECM) are suggested to modulate cellular behavior including plasticity of macrophages (MPhs) during wound healing. In this study, engineered 3D fibrillar matrices based on naturally occurring biopolymers (collagen I, glycosaminoglycans (GAGs)) were used to mimic matrix stiffening as well as modification by sulfated and non-sulfated GAGs at different stages of wound healing. Human MPhs were found to sensitively respond to these microenvironmental cues in terms of polarization towards pro-inflammatory or wound healing phenotypes over 6 days in vitro. MPhs exhibited a wound healing phenotype in stiffer matrices as determined by protein and gene expression of relevant cytokines (IL10, IL12, TNF). Presence of sulfated and non-sulfated GAGs inhibited this polarization effect. Furthermore, control experiments on 2D matrices stressed the relevance of using stiffness-controlled 3D matrices, as MPhs showed a reciprocal polarization behavior depending on GAG presence. Hence, the results indicate a strong influence of dimensionality, stiffness, and GAG presence of the biomaterial scaffold on MPh polarization and emphasize the need for matrices closely mimicking the 3D in vivo context with a variable stiffness and GAG composition in in vitro studies

Geotechnical Properties of Salt Marsh and Tidal Flat Substrates at Tillingham, Essex, UK.

Salt marshes and, to a lesser extent, tidal flats, attenuate incoming hydrodynamic energy, thus reducing flood and erosion risk in the coastal hinterland. However, marshes are declining in aerial extent both globally and regionally (e.g. the Northwest European region). In order to comprehend why a reduction in salt marsh extent due to marsh edge erosion is occurring, we need to understand the resistance of salt marshes to incoming hydrodynamic energy. This resistance depends on marsh biological, geochemical and geotechnical properties. However, there currently exists no systematic study of marsh geotechnical properties and how these may impact both marsh edge and marsh surface erosion processes (e.g. surface removal, cliff undercutting, gravitational slumping). This has led to an oversimplification of marsh evolution models. Here, we present the initial results of a systematic study of salt marsh and tidal flat geotechnical properties (shear strength, plasticity and particle size) at Tillingham marsh, Essex, UK.Department of Geograph

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Design and Measurements Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily ‘toothbrush’ regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. Conclusion A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure

Virasoro Algebra for Particles with Higher Derivative Interactions

In this paper we show that the worldline reparametrization for particles with higher derivative interactions appears as a higher dimensional symmetry, which is generated by the truncated Virasoro algebra. We also argue that for generic nonlocal particle theories the fields on the worldline may be promoted to those living on a two dimensional worldsheet, and the reparametrization symmetry becomes locally the same as the conformal symmetry.Comment: 10 page

Engaging learners with games–Insights from functional near-infrared spectroscopy

The use of game elements in learning tasks is thought to facilitate emotional and behavioral responses as well as learner engagement. So far, however, little is known about the underlying neural mechanisms of game-based learning. In the current study, we added game elements to a number line estimation task assessing fraction understanding and compared brain activation patterns to a non-game-based task version. Forty-one participants performed both task versions in counterbalanced order while frontal brain activation patterns were assessed using near-infrared spectroscopy (within-subject, cross-sectional study design). Additionally, heart rate, subjective user experience, and task performance were recorded. Task performance, mood, flow experience, as well as heart rate did not differ between task versions. However, the game-based task-version was rated as more attractive, stimulating and novel compared to the non-game-based task version. Additionally, completing the game-based task version was associated with stronger activation in frontal brain areas generally involved in emotional and reward processing as well as attentional processes. These results provide new neurofunctional evidence substantiating that game elements in learning tasks seem to facilitate learning through emotional and cognitive engagement.Peer reviewe

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor