Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Geotechnical monitoring using a combination of LIDAR, real-time dGPS, and electrical tomography to assess geotechnical risk of a coastal landslide.

The Antrim Coast Road stretching from the seaport of Larne in the East of Northern Ireland has a well-deserved reputation for being one of the most spectacular roads in Europe (Day, 2006). However the problematic geology; Jurassic Lias Clay and Triassic Mudstone overlain by Cretaceous Limestone and Tertiary Basalt, and environmental variables result in frequent instances of slope instability manifested in both shallow debris flows and occasional massive rotational movements, creating a geotechnical risk to this highway. This paper describes how a variety of techniques are being used to both assess instability and monitor movement of these active slopes near one site at Straidkilly Point, Glenarm. An in-depth understanding of the geology was obtained via boreholes, resistivity surveys and laboratory testing. Environmental variables recorded by an on-site weather station were correlated with measured pore water pressure and soil moisture infiltration data. Terrestrial LiDAR (TLS), with surveys carried out on a bi-monthly basis allowed for the generation of Digital Elevation Models (DEMs) of difference, highlighting areas of recent movement, accumulation and depletion. Morphology parameters were generated from the DEMs and include slope, curvature and multiple measures of roughness. Changes in the structure of the slope coupled with morphological parameters were characterised and linked to progressive failures from the temporal monitoring. In addition to TLS monitoring, Aerial LiDAR datasets were used for the spatio-morphological characterisation of the slope on a macro scale. A Differential Global Positioning System (dGPS) was also deployed on site to provide a real-time warning system for gross movements, which were also correlated with environmental conditions. Frequent electrical resistivity tomography (ERT) surveys were also implemented to provide a better understanding of long-term changes in soil moisture and help to define the complex geology. The paper describes how the data obtained via a diverse range of methods has been combined to facilitate a more informed management regime of geotechnical risk by the Northern Ireland Roads Service.

Context-dependent Combination of Sensor Information in Dempster-Shafer Theory for BDI

There has been much interest in the belief–desire–intention (BDI) agent-based model for developing scalable intelligent systems, e.g. using the AgentSpeak framework. However, reasoning from sensor information in these large-scale systems remains a significant challenge. For example, agents may be faced with information from heterogeneous sources which is uncertain and incomplete, while the sources themselves may be unreliable or conflicting. In order to derive meaningful conclusions, it is important that such information be correctly modelled and combined. In this paper, we choose to model uncertain sensor information in Dempster–Shafer (DS) theory. Unfortunately, as in other uncertainty theories, simple combination strategies in DS theory are often too restrictive (losing valuable information) or too permissive (resulting in ignorance). For this reason, we investigate how a context-dependent strategy originally defined for possibility theory can be adapted to DS theory. In particular, we use the notion of largely partially maximal consistent subsets (LPMCSes) to characterise the context for when to use Dempster’s original rule of combination and for when to resort to an alternative. To guide this process, we identify existing measures of similarity and conflict for finding LPMCSes along with quality of information heuristics to ensure that LPMCSes are formed around high-quality information. We then propose an intelligent sensor model for integrating this information into the AgentSpeak framework which is responsible for applying evidence propagation to construct compatible information, for performing context-dependent combination and for deriving beliefs for revising an agent’s belief base. Finally, we present a power grid scenario inspired by a real-world case study to demonstrate our work.

Face recogniton based on the optimal combination of neural networks, eigenfaces and least squares matching methods

Report of a research project of the Fachhochschule Hannover, University of Applied Sciences and Arts, Department of Information Technologies. Automatic face recognition increases the security standards at public places and border checkpoints. The picture inside the identification documents could widely differ from the face, that is scanned under random lighting conditions and for unknown poses. The paper describes an optimal combination of three key algorithms of object recognition, that are able to perform in real time. The camera scan is processed by a recurrent neural network, by a Eigenfaces (PCA) method and by a least squares matching algorithm. Several examples demonstrate the achieved robustness and high recognition rate.

Selection and combination of biomarkers to control and prevent the risk of occupational exposure to the mixture of lead, arsenic and manganese

Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2014

Self-adaptive combination of global tabu search and local search for nonlinear equations

Solving systems of nonlinear equations is a very important task since the problems emerge mostly through the mathematical modelling of real problems that arise naturally in many branches of engineering and in the physical sciences. The problem can be naturally reformulated as a global optimization problem. In this paper, we show that a self-adaptive combination of a metaheuristic with a classical local search method is able to converge to some difficult problems that are not solved by Newton-type methods.

Unilever food solutions new digital CRM platform- what is the combination of tools, processes and content that will help Unilever food solutions grow his business?

Unilever Food Solutions new digital CRM1 Platform - What is the combination of tools, processes and content that will help Unilever Food Solutions grow his business? Unilever Food Solutions (UFS) intend to create a new online platform to enable it to communicate with segments of the markets, which have previously been too difficult to reach. Specifically targeted at Chefs and other food professionals, the aim is to create an interactive website, which delivers value to its intended users by providing a variety of relevant content and functions, while simultaneously opening up a potential transactional channel to those same users.

Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma.

Taking advantage of homeostatic mechanisms to boost tumor-specific cellular immunity is raising increasing interest in the development of therapeutic strategies in the treatment of melanoma. Here, we have explored the potential of combining homeostatic proliferation, after transient immunosuppression, and antigenic stimulation of Melan-A/Mart-1 specific CD8 T-cells. In an effort to develop protocols that could be readily applicable to the clinic, we have designed a phase I clinical trial, involving lymphodepleting chemotherapy with Busulfan and Fludarabine, reinfusion of Melan-A specific CD8 T-cell containing peripheral blood mononuclear cells (exempt of growth factors), and Melan-A peptide vaccination. Six patients with advanced melanoma were enrolled in this outpatient regimen that demonstrated good feasibility combined with low toxicity. Consistent depletion of lymphocytes with persistent increased CD4/CD8 ratios was induced, although the proportion of circulating CD4 regulatory T-cells remained mostly unchanged. The study of the immune reconstitution period showed a steady recovery of whole T-cell numbers overtime. However, expansion of Melan-A specific CD8 T-cells, as measured in peripheral blood, was mostly inconsistent, accompanied with marginal phenotypic changes, despite vaccination with Melan-A/Mart-1 peptide. On the clinical level, 1 patient presented a partial but objective antitumor response following the beginning of the protocol, even though a direct effect of Busulfan/Fludarabine cannot be completely ruled out. Overall, these data provide further ground for the development of immunotherapeutic approaches to be both effective against melanoma and applicable in clinic.

Slow and Smooth: A Bayesian Theory for the Combination of Local Motion Signals in Human Vision

In order to estimate the motion of an object, the visual system needs to combine multiple local measurements, each of which carries some degree of ambiguity. We present a model of motion perception whereby measurements from different image regions are combined according to a Bayesian estimator --- the estimated motion maximizes the posterior probability assuming a prior favoring slow and smooth velocities. In reviewing a large number of previously published phenomena we find that the Bayesian estimator predicts a wide range of psychophysical results. This suggests that the seemingly complex set of illusions arise from a single computational strategy that is optimal under reasonable assumptions.

Ex Vivo Construction of an Artificial Ocular Surface by Combination of Corneal Limbal Epithelial Cells and a Compressed Collagen Scaffold Containing Keratocytes

We have investigated the use of a laminin coated compressed collagen gel containing corneal fibroblasts (keratocytes) as a novel scaffold to support the growth of corneal limbal epithelial stem cells. The growth of limbal epithelial cells was compared between compressed collagen gel and a clinically proven conventional substrate, denuded amniotic membrane. Following compression of the collagen gel, encapsulated keratocytes remained viable and scanning electron microscopy showed that fibres within the compressed gel were dense, homogeneous and similar in structure to those within denuded amniotic membrane. Limbal epithelial cells were successfully expanded upon the compressed collagen resulting in stratified layers of cells containing desmosome and hemidesmosome structures. The resulting corneal constructs of both the groups shared a high degree of transparency, cell morphology and cell stratification. Similar protein expression profiles for cytokeratin 3 and cytokeratin 14 and no significant difference in cytokeratin 12 mRNA expression levels by real time PCR were also observed. This study provides the first line of evidence that a laminin coated compressed collagen gel containing keratocytes can adequately support limbal epithelial cell expansion, stratification and differentiation to a degree that is comparable to the leading conventional scaffold, denuded amniotic membrane.

Relationship between sublethal injury and microbial inactivation by the combination of high hydrostatic pressure and citral or tert-butyl hydroquinone

The aim was to investigate (i) the occurrence of sublethal injury in Listeria monocytogenes, Escherichia coli, and Saccharomyces cerevisiae after high hydrostatic pressure (HHP) treatment as a function of the treatment medium pH and composition and (ii) the relationship between the occurrence of sublethal injury and the inactivating effect of a combination of HHP and two antimicrobial compounds, tert-butyl hydroquinone (TBHQ) and citral. The three microorganisms showed a high proportion of sublethally injured cells (up to 99.99% of the surviving population) after HHP. In E. coli and L. monocytogenes, the extent of inactivation and sublethal injury depended on the pH and the composition of the treatment medium, whereas in S. cerevisiae, inactivation and sublethal injury were independent of medium pH or composition under the conditions tested. TBHQ alone was not lethal to E. coli or L. monocytogenes but acted synergistically with HHP and 24-h refrigeration, resulting in a viability decrease of >5 log(10) cycles of both organisms. The antimicrobial effect of citral depended on the microorganism and the treatment medium pH. Acting alone for 24 h under refrigeration, 1,000 ppm of citral caused a reduction of 5 log(10) cycles of E. coli at pH 7.0 and almost 3 log(10) cycles of L. monocytogenes at pH 4.0. The combination of citral and HHP also showed a synergistic effect. Our results have confirmed that the detection of sublethal injury after HHP may contribute to the identification of those treatment conditions under which HHP may act synergistically with other preserving processes.