The difficult-to-treat, therapy-resistant cough: Why are current cough treatments not working and what can we do?

Cough can persist despite exhaustive diagnostic and therapeutic effort and has been termed 'idiopathic' or 'unexplained' but perhaps 'difficult to treat' cough is a more appropriate description. In this article the reasons for poor treatment response are discussed. These include a lack of physician fidelity to management guidelines, patient non-adherence and the lack of effective medicines. A number of randomized controlled trials have been undertaken including low dose opiate therapy, the use of a speech pathology intervention, oral antibiotics and antidepressants. The success or otherwise of such interventions will be discussed. A number of approaches to deal with the problem of 'difficult to treat cough' will be considered.

Photodynamic antimicrobial polymers for infection control

Hospital-acquired infections pose both a major risk to patient wellbeing and an economic burden on global healthcare systems, with the problem compounded by the emergence of multidrug resistant and biocide tolerant bacterial pathogens. Many inanimate surfaces can act as a reservoir for infection, and adequate disinfection is difficult to achieve and requires direct intervention. In this study we demonstrate the preparation and performance of materials with inherent photodynamic, surface-active, persistent antimicrobial properties through the incorporation of photosensitizers into high density poly(ethylene) (HDPE) using hot-melt extrusion, which require no external intervention except a source of visible light. Our aim is to prevent bacterial adherence to these surfaces and eliminate them as reservoirs of nosocomial pathogens, thus presenting a valuable advance in infection control. A two-layer system with one layer comprising photosensitizer-incorporated HDPE, and one layer comprising HDPE alone is also described to demonstrate the versatility of our approach. The photosensitizer-incorporated materials are capable of reducing the adherence of viable bacteria by up to 3.62 Log colony forming units (CFU) per square centimeter of material surface for methicillin resistant Staphylococcus aureus (MRSA), and by up to 1.51 Log CFU/cm2 for Escherichia coli. Potential applications for the technology are in antimicrobial coatings for, or materials comprising objects, such as tubing, collection bags, handrails, finger-plates on hospital doors, or medical equipment found in the healthcare setting.

Universal tight binding model for chemical reactions in solution and at surfaces. II. Water

A revised water model intended for use in condensed phase simulations in the framework of the self consistent polarizable ion tight binding theory is constructed. The model is applied to water monomer, dimer, hexamers, ice, and liquid, where it demonstrates good agreement with theoretical results obtained by more accurate methods, such as DFT and CCSD(T), and with experiment. In particular, the temperature dependence of the self diffusion coefficient in liquid water predicted by the model, closely reproduces experimental curves in the temperature interval between 230 K and 350 K. In addition, and in contrast to standard DFT, the model properly orders the relative densities of liquid water and ice. A notable, but inevitable, shortcoming of the model is underestimation of the static dielectric constant by a factor of two. We demonstrate that the description of inter and intramolecular forces embodied in the tight binding approximation in quantum mechanics leads to a number of valuable insights which can be missing from ab initio quantum chemistry and classical force fields. These include a discussion of the origin of the enhanced molecular electric dipole moment in the condensed phases, and a detailed explanation for the increase of coordination number in liquid water as a function of temperature and compared with ice-leading to insights into the anomalous expansion on freezing. The theory holds out the prospect of an understanding of the currently unexplained density maximum of water near the freezing point. 

Universal tight binding model for chemical reactions in solution and at surfaces. III. Stoichiometric and reduced surfaces of titania and the adsorption of water

We demonstrate a model for stoichiometric and reduced titanium dioxide intended for use in molecular dynamics and other atomistic simulations and based in the polarizable ion tight binding theory. This extends the model introduced in two previous papers from molecular and liquid applications into the solid state, thus completing the task of providing a comprehensive and unified scheme for studying chemical reactions, particularly aimed at problems in catalysis and electrochemistry. As before, experimental results are given priority over theoretical ones in selecting targets for model fitting, for which we used crystal parameters and band gaps of titania bulk polymorphs, rutile and anatase. The model is applied to six low index titania surfaces, with and without oxygen vacancies and adsorbed water molecules, both in dissociated and non-dissociated states. Finally, we present the results of molecular dynamics simulation of an anatase cluster with a number of adsorbed water molecules and discuss the role of edge and corner atoms of the cluster. (C) 2014 AIP Publishing LLC.

Universal tight binding model for chemical reactions in solution and at surfaces. I. Organic molecules

As is now well established, a first order expansion of the Hohenberg-Kohn total energy density functional about a trial input density, namely, the Harris-Foulkes functional, can be used to rationalize a non self consistent tight binding model. If the expansion is taken to second order then the energy and electron density matrix need to be calculated self consistently and from this functional one can derive a charge self consistent tight binding theory. In this paper we have used this to describe a polarizable ion tight binding model which has the benefit of treating charge transfer in point multipoles. This admits a ready description of ionic polarizability and crystal field splitting. It is necessary in constructing such a model to find a number of parameters that mimic their more exact counterparts in the density functional theory. We describe in detail how this is done using a combination of intuition, exact analytical fitting, and a genetic optimization algorithm. Having obtained model parameters we show that this constitutes a transferable scheme that can be applied rather universally to small and medium sized organic molecules. We have shown that the model gives a good account of static structural and dynamic vibrational properties of a library of molecules, and finally we demonstrate the model's capability by showing a real time simulation of an enolization reaction in aqueous solution. In two subsequent papers, we show that the model is a great deal more general in that it will describe solvents and solid substrates and that therefore we have created a self consistent quantum mechanical scheme that may be applied to simulations in heterogeneous catalysis.

Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces

Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers.

Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research.

Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.

Synthesis and release kinetics of polymerisable ester drug conjugates towards pH-responsive infection-resistant urinary biomaterials

Herein we report the synthesis, characterisation and hydrolytic release kinetics of a suite of novel, polymerisable ester quinolone conjugates with varying alkenyl chain lengths. Hydrolysis was shown to proceed up to 17-fold faster upon elevation of pH from neutral to pH 9.29, making these conjugates attractive for the development of 'designer' infection-resistant urinary biomaterials exploiting the increase in urine pH reported at the onset of catheter-associated infection to trigger drug release. (C) 2013 Elsevier Ltd. All rights reserved.

A markerless deletion method for genetic manipulation of Burkholderia cenocepacia and other multidrug-resistant gram-negative bacteria

Genetic manipulation of multidrug-resistant bacteria is often difficult and hinders progress in understanding their physiology and pathogenesis. This book chapter highlights advances in genetic manipulation of Burkholderia cenocepacia, which are also applicable to other members of the Burkholderia cepacia complex and multidrug-resistant gram-negative bacteria of other genera. The method detailed here is based on the I-SceI homing endonuclease system, which can be efficiently used for chromosomal integration, deletion, and genetic replacement. This system creates markerless mutations and insertions without leaving a genetic scar and thus can be reused successively to generate multiple modifications in the same strain.

Hot deformation characteristics of a nitride strengthened martensitic heat resistant steel

Constitutive equations including an Arrhenius term have been applied to analyze the hot deformation behavior of a nitride-strengthened (NS) martensitic heat resistant steel in temperature range of 900–1200 °C and strain rate range of 0.001–10 /s. On the basis of analysis of the deformation data, the stress–strain curves up to the peak were divided into four regions, in sequence, representing four processes, namely hardening, dynamic recovery (DRV), dynamic strain induced transformation (DSIT), and dynamic recrystallization (DRX), according to the inflection points in ∂θ/∂σ∂θ/∂σ and ∂(∂θ/∂σ)/∂σ∂(∂θ/∂σ)/∂σ curves. Some of the inflection points have their own meanings. For examples, the minimum of ∂θ/∂σ∂θ/∂σ locates the start of DRV and the maximum of it indicates the start of DRX. The results also showed that the critical strain of DRX was sensitive to ln(Z) below 40, while the critical stress of DRX was sensitive to it above 40. The final microstructures under different deformation conditions were analyzed in terms of softening processes including DRV, DRX, metadynamic crystallization (MDRX) and DSIT.

Analysis of deformation behavior and workability of advanced 9Cr-Nb-V ferritic heat resistant steels

Hot compression tests were carried out on 9Cr–Nb–V heat resistant steels in the temperature range of 600–1200 °C and the strain rate range of 10−2–100 s−1 to study their deformation characteristics. The full recrystallization temperature and the carbon-free bainite phase transformation temperature were determined by the slope-change points in the curve of mean flow stress versus the inverse of temperature. The parameters of the constitutive equation for the experimental steels were calculated, including the stress exponent and the activation energy. The lower carbon content in steel would increase the fraction of precipitates by increasing the volume of dynamic strain-induced (DSIT) ferrite during deformation. The ln(εc) versus ln(Z) and the ln(σc) versus ln(Z) plots for both steels have similar trends. The efficiency of power dissipation maps with instability maps merged together show excellent workability from the strain of 0.05 to 0.6. The microstructure of the experimental steels was fully recrystallized upon deformation at low Z value owing to the dynamic recrystallization (DRX), and exhibited a necklace structure under the condition of 1050 °C/0.1 s−1 due to the suppression of the secondary flow of DRX. However, there were barely any DRX grains but elongated pancake grains under the condition of 1000 °C/1 s−1 because of the suppression of the metadynamic recrystallization (MDRX).

Constitutive modeling, microstructure evolution, and processing map for a nitride-strengthened heat-resistant steel

A constitutive equation was established to describe the deformation behavior of a nitride-strengthened (NS) steel through isothermal compression simulation test. All the parameters in the constitutive equation including the constant and the activation energy were precisely calculated for the NS steel. The result also showed that from the stress-strain curves, there existed two different linear relationships between critical stress and critical strain in the NS steel due to the augmentation of auxiliary softening effect of the dynamic strain-induced transformation. In the calculation of processing maps, with the change of Zener-Hollomon value, three domains of different levels of workability were found, namely excellent workability region with equiaxed-grain microstructure, good workability region with “stripe” microstructure, and the poor workability region with martensitic-ferritic blend microstructure. With the increase of strain, the poor workability region first expanded, then shrank to barely existing, but appeared again at the strain of 0.6.

Reconfigurable frequency selective surfaces with interleaved spiral slots

A new type of active frequency selective surface (AFSS) is proposed to realise a voltage controlled bi-state (transparent and reflecting) response at the specified frequencies. The bi-state switching is achieved by combining a passive array of interleaved spiral slots in conducting screens and active dipole arrays with integrated pin diodes at the opposite sides of a thin dielectric substrate. Simulation results show that such active surfaces have high isolation between the transparency and reflection states, while retaining the merits of substantially sub-wavelength response of the unit cell and large fractional bandwidths (FBWs) inherent to the original passive interwoven spiral arrays. Potential applications include reconfigurable and controllable electromagnetic architecture of buildings.

Active singly and dual polarised interwoven spiral frequency selective surfaces

Reconfigurable bi-state interwoven spiral FSSs are explored in this work. Their switching capability is realized by pin diodes that enable the change of the electromagnetic response between transparent and reflecting modes at the specified frequencies in both singly and dual polarised unit cell configurations. The proposed topologies are single layer FSS with their elements acting also as dc current carrying conductors supplying the bias signal for switching pin diodes between the on and off states, thus avoiding the need of external bias lines that can cause parasitic resonances and affect the response at oblique incidence. The presented simulation results show that such active FSSs have potentially good isolation between the transmission and reflection states, while retaining the substantially subwavelength response of the unit cell with large fractional bandwidths (FBWs) inherent to the original passive FSSs.