Oral medication delivery in impaired swallowing: thickening liquid medications for safe swallowing alters dissolution characteristics

Acetaminophen (paracetamol) is available in a wide range of oral formulations designed to meet the needs of the population across the age-spectrum, but for people with impaired swallowing, i.e. dysphagia, both solid and liquid medications can be difficult to swallow without modification. The effect of a commercial polysaccharide thickener, designed to be added to fluids to promote safe swallowing by dysphagic patients, on rheology and acetaminophen dissolution was tested using crushed immediate-release tablets in water, effervescent tablets in water, elixir and suspension. The inclusion of the thickener, comprised of xanthan gum and maltodextrin, had a considerable impact on dissolution; acetaminophen release from modified medications reached 12–50% in 30?min, which did not reflect the pharmacopeia specification for immediate release preparations. Flow curves reflect the high zero-shear viscosity and the apparent yield stress of the thickened products. The weak gel nature, in combination with high G' values compared to G'' (viscoelasticity) and high apparent yield stress, impact drug release. The restriction on drug release from these formulations is not influenced by the theoretical state of the drug (dissolved or dispersed), and the approach typically used in clinical practice (mixing crushed tablets into pre-prepared thickened fluid) cannot be improved by altering the order of incorporation or mixing method.     

The privileged sensing framework: A principled approach to improved human-autonomy integration

ABSTRACT

A primary goal for human-autonomy integration (HAI) is to balance the strengths of human and autonomy in order to achieve performance objectives more efficiently and robustly than either the human or autonomous agents would independently. This paper proposes the Privileged Sensing Framework (PSF) as a novel approach to HAI. This approach is based on the concept of dynamically ‘privileging’ information during the process of integration by dynamically bestowing special rights based on the characteristics of each individual agent, the task context, and the performance goals. The proposed framework is tested through a series of simulation experiments that provide a clear demonstration of increased accuracy and throughput of human-autonomy performance. These proof-of-concept simulations provide initial evidence of the utility of the PSF. Continued development of this approach has the potential to revolutionise capabilities of multi-agent cooperative teams across a broad range of applications.     

Design of synthetic materials for intracellular delivery of RNAs: From siRNA-mediated gene silencing to CRISPR/Cas gene editing

Ribonucleic acids (RNAs) possess great therapeutic potential and can be used to treat a variety of diseases. The unique biophysical properties of RNAs, such as high molecular weight, negative charge, hydrophilicity, low stability, and potential immunogenicity, require chemical modification and development of carriers to enable intracellular delivery of RNAs for clinical use. A variety of nanomaterials have been developed for the effective in vivo delivery of short/ small RNAs, messenger RNAs, and RNAs required for gene editing technologies including clustered regularly interspaced palindromic repeat (CRISPR)/Cas. This review outlines the challenges of delivering RNA therapeutics, explores the chemical synthesis of RNA modifications and carriers, and describes the efforts to design nanomaterials that can be used for a variety of clinical indications.     

Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors

A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.     

Melting and Vaporization of the 1223 Phase in the System (Tl-Pb-Ba-Sr-Ca-Cu-O)

The melting and vaporization of the 1223 [(Tl,Pb):(Ba,Sr):Ca:Cu] oxide phase in the system (Tl-Pb-Ba-Sr-Ca-Cu-O) have been investigated using a combination of dynamic methods (differential thermal analysis, thermogravimetry, effusion) and post-quenching characterization techniques (powder x-ray diffraction, scanning electron microscopy, energy dispersive x-ray spectrometry). Vaporization rates, thermal events, and melt compositions were followed as a function of thallia loss from a 1223 stoichiometry. Melting and vaporization equilibria of the 1223 phase are complex, with as many as seven phases participating simultaneously. At a total pressure of 0.1 MPa the 1223 phase was found to melt completely at (980 ± 5) °C in oxygen, at a thallia partial pressure (p_Tl2O) of (4.6 ± 0.5) kPa, where the quoted uncertainties are standard uncertainties, i.e., 1 estimated standard deviation. The melting reaction involves five other solids and a liquid, nominally as follows: 1223→1212+(Ca,Sr)2CuO3+(Sr,Ca)CuO2+BaPbO3+(Ca,Sr)O+LiquidStoichiometries of the participating phases have been determined from microchemical analysis, and substantial elemental substitution on the 1212 and 1223 crystallographic sites is indicated. The 1223 phase occurs in equilibrium with liquids from its melting point down to at least 935 °C. The composition of the lowest melting liquid detected for the bulk compositions of this study has been measured using microchemical analysis. Applications to the processing of superconducting wires and tapes are discussed.     

Review Paper: A critical review of the present and future prospects for electronic paper

Abstract— The commercial success of monochrome electronic paper (e‐Paper) is now propelling the development of next‐generation flexible, video, and color e‐Paper products. Unlike the early battles in the 1980s and 1990s between transmissive and emissive display technologies, there is a extraordinary diversity of technologies vying to become the next generation of e‐Paper. A critical review of all major e‐Paper technologies, including a technical breakdown of the performance limitations based on device physics and commentary on possible future breakthroughs, is presented. In addition, the visual requirements for color e‐Paper are provided and compared to standards used in conventional print. It is concluded that researchers have much work remaining in order to bridge the significant gap between reflective electronic displays and print‐on‐paper.     

Feature-based statistical analysis of combustion simulation data

We present a new framework for feature-based statistical analysis of large-scale scientific data and demonstrate its effectiveness by analyzing features from Direct Numerical Simulations (DNS) of turbulent combustion. Turbulent flows are ubiquitous and account for transport and mixing processes in combustion, astrophysics, fusion, and climate modeling among other disciplines. They are also characterized by coherent structure or organized motion, i.e. nonlocal entities whose geometrical features can directly impact molecular mixing and reactive processes. While traditional multi-point statistics provide correlative information, they lack nonlocal structural information, and hence, fail to provide mechanistic causality information between organized fluid motion and mixing and reactive processes. Hence, it is of great interest to capture and track flow features and their statistics together with their correlation with relevant scalar quantities, e.g. temperature or species concentrations. In our approach we encode the set of all possible flow features by pre-computing merge trees augmented with attributes, such as statistical moments of various scalar fields, e.g. temperature, as well as length-scales computed via spectral analysis. The computation is performed in an efficient streaming manner in a pre-processing step and results in a collection of meta-data that is orders of magnitude smaller than the original simulation data. This meta-data is sufficient to support a fully flexible and interactive analysis of the features, allowing for arbitrary thresholds, providing per-feature statistics, and creating various global diagnostics such as Cumulative Density Functions (CDFs), histograms, or time-series. We combine the analysis with a rendering of the features in a linked-view browser that enables scientists to interactively explore, visualize, and analyze the equivalent of one terabyte of simulation data. We highlight the utility of this new framework for combustion science; however, it is applicable to many other science domains.     

BallotMaps: detecting name bias in alphabetically ordered ballot papers

The relationship between candidates' position on a ballot paper and vote rank is explored in the case of 5000 candidates for the UK 2010 local government elections in the Greater London area. This design study uses hierarchical spatially arranged graphics to represent two locations that affect candidates at very different scales: the geographical areas for which they seek election and the spatial location of their names on the ballot paper. This approach allows the effect of position bias to be assessed; that is, the degree to which the position of a candidate's name on the ballot paper influences the number of votes received by the candidate, and whether this varies geographically. Results show that position bias was significant enough to influence rank order of candidates, and in the case of many marginal electoral wards, to influence who was elected to government. Position bias was observed most strongly for Liberal Democrat candidates but present for all major political parties. Visual analysis of classification of candidate names by ethnicity suggests that this too had an effect on votes received by candidates, in some cases overcoming alphabetic name bias. The results found contradict some earlier research suggesting that alphabetic name bias was not sufficiently significant to affect electoral outcome and add new evidence for the geographic and ethnicity influences on voting behaviour. The visual approach proposed here can be applied to a wider range of electoral data and the patterns identified and hypotheses derived from them could have significant implications for the design of ballot papers and the conduct of fair elections.     

Development of quantitative structure-activity relationships for explanatory modeling of fast reacting (meth)acrylate monomers bearing novel functionality

The photoinitiated polymerization of (meth)acrylate monomers bearing novel carbamate functionality exhibits significantly greater reaction rate when compared to more traditional acrylate monomers undergoing similar polymerization. This unusually fast reactivity has been the subject of much investigation. In order to suggest an explanatory mechanism for the enhanced polymerization rates we have conducted quantitative structure-activity relationship investigations of these novel monomers. These studies have resulted in statistically sound models with coefficients of multiple determination of R(2)>0.93. Principal component and k nearest neighbor similarity analysis were also conducted on the multiple regression models. These results are discussed in light of published experimental investigations of the photopolymerization reactivity of the novel monomers.