The Debrisoft ® monofilament debridement pad for use in acute or chronic wounds: A NICE medical technology guidance

As part of its Medical Technology Evaluation Programme, the National Institute for Health and Care Excellence (NICE) invited a manufacturer to provide clinical and economic evidence for the evaluation of the Debrisoft ® monofilament debridement pad for use in acute or chronic wounds. The University of Birmingham and Brunel University, acting as a consortium, was commissioned to act as an External Assessment Centre (EAC) for NICE, independently appraising the submission. This article is an overview of the original evidence submitted, the EAC’s findings and the final NICE guidance issued. The sponsor submitted a simple cost analysis to estimate the costs of using Debrisoft® to debride wounds compared with saline and gauze, hydrogel and larvae. Separate analyses were conducted for applications in home and applications in a clinic setting. The analysis took an UK National Health Service (NHS) perspective. It incorporated the costs of the technologies and supplementary technologies (such as dressings) and the costs of their application by a district nurse. The sponsor concluded that Debrisoft® was cost saving relative to the comparators. The EAC made amendments to the sponsor analysis to correct for errors and to reflect alternative assumptions. Debrisoft® remained cost saving in most analyses and savings ranged from £77 to £222 per patient compared with hydrogel, from £97 to £347 compared with saline and gauze, and from £180 to £484 compared with larvae depending on the assumptions included in the analysis and whether debridement took place in a home or clinic setting. All analyses were severely limited by the available data on effectiveness, in particular a lack of comparative studies and that the effectiveness data for the comparators came from studies reporting different clinical endpoints compared with Debrisoft®. The Medical Technologies Advisory Committee made a positive recommendation for adoption of Debrisoft® and this has been published as a NICE medical technology guidance (MTG17).The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

Non-polynomial Worst-Case Analysis of Recursive Programs

We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of nonrecursive programs. First, we apply ranking functions to recursion, resulting in measure functions. We show that measure functions provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in nonpolynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas' Lemma, and Handelman's Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form $\mathcal{O}(n\log n)$ as well as $\mathcal{O}(n^r)$ where $r$ is not an integer. We present experimental results to demonstrate that our approach can obtain efficiently worst-case bounds of classical recursive algorithms such as (i) Merge-Sort, the divide-and-conquer algorithm for the Closest-Pair problem, where we obtain $\mathcal{O}(n \log n)$ worst-case bound, and (ii) Karatsuba's algorithm for polynomial multiplication and Strassen's algorithm for matrix multiplication, where we obtain $\mathcal{O}(n^r)$ bound such that $r$ is not an integer and close to the best-known bounds for the respective algorithms.Comment: 54 Pages, Full Version to CAV 201

Varicella-Zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells

Active Site Mutations Change the Cleavage Specificity of Neprilysin

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential

RON5 is critical for organization and function of the Toxoplasma moving junction complex

Apicomplexans facilitate host cell invasion through formation of a tight-junction interface between parasite and host plasma membranes called the moving junction (MJ). A complex of the rhoptry neck proteins RONs 2/4/5/8 localize to the MJ during invasion where they are believed to provide a stable anchoring point for host penetration. During the initiation of invasion, the preformed MJ RON complex is injected into the host cell where RON2 spans the host plasma membrane while RONs 4/5/8 localize to its cytosolic face. While much attention has been directed toward an AMA1-RON2 interaction supposed to occur outside the cell, little is known about the functions of the MJ RONs positioned inside the host cell. Here we provide a detailed analysis of RON5 to resolve outstanding questions about MJ complex organization, assembly and function during invasion. Using a conditional knockdown approach, we show loss of RON5 results in complete degradation of RON2 and mistargeting of RON4 within the parasite secretory pathway, demonstrating that RON5 plays a key role in organization of the MJ RON complex. While RON8 is unaffected by knockdown of RON5, these parasites are unable to invade new host cells, providing the first genetic demonstration that RON5 plays a critical role in host cell penetration. Although invasion is not required for injection of rhoptry effectors into the host cytosol, parasites lacking RON5 also fail to form evacuoles suggesting an intact MJ complex is a prerequisite for secretion of rhoptry bulb contents. Additionally, while the MJ has been suggested to function in egress, disruption of the MJ complex by RON5 depletion does not impact this process. Finally, functional complementation of our conditional RON5 mutant reveals that while proteolytic separation of RON5 N- and C-terminal fragments is dispensable, a portion of the C-terminal domain is critical for RON2 stability and function in invasion

Development and validation of A quasi-dimensional model for (M)Ethanol-Fuelled SI engines

RESEARCH OBJECTIVE - The use of methanol and ethanol in spark-ignition engines forms an interesting approach to decarbonizing transport and securing domestic energy supply. Experimental work has produced promising results, however, the full potential of light alcohols in modern engine technology remains to be explored. Today, this can be addressed at low cost using system simulations of the whole engine, provided that the employed models account for the effect of the fuel on engine operation. The goal of current work is to develop an engine cycle model that can accurately predict performance, efficiency, pollutant emissions and knock onset in state-of-the-art neat alcohol engines. METHODOLOGY - Two-zone thermodynamic engine modeling, in combination with 1D gas dynamics, is put forward as a useful tool for cheap and fast optimization of engines. Typically, this model class derives the mass burning rate of fuel from turbulent combustion models. A fundamental building block of turbulent combustion models is an expression for the laminar burning velocity of the fuel-air-residuals mixture at instantaneous cylinder pressure and temperature. This physicochemical property basically groups the contribution of the chemical reactions (of the fuel) to combustion. Consequently, an important part of our study consisted of calculating (using chemical kinetics) and measuring the laminar burning velocity of methanol and ethanol at engine-like conditions. In order to validate the developed engine model, its predictions were compared against a database of experimental results obtained on three different flex-fuel and dedicated alcohol engines. RESULTS - Comparison of the experimental and simulated cylinder, intake and exhaust pressure traces confirmed the predictive power of our engine model for methanol-fuelled engines. A wide variety of engine operating points were accurately reproduced thanks to a new laminar burning velocity correlation, which correctly accounts for changes in pressure, temperature, mixture richness and residual ratio. The Flame Closure Model of Zimont-Lipatnikov emerged as the most widely applicable model from a comparison of several turbulent combustion models. With regard to the gas dynamics it proved necessary to include a fuel puddling submodel to take the cooling effect due to alcohol injection into consideration. LIMITATIONS - The developed model was successfully validated for normal combustion in port-injected neat methanol engines. The validation of the routines for ethanol combustion and engines with direct injection is part of ongoing work. Now that normal combustion can be accurately simulated, further work will look at the prediction of pollutant emissions and knock onset in these engines. NOVELTY - This paper presents the first recent attempt to model the application of neat alcohols in modern and anticipated future engine technologies. Compared to previous work the effects of in-cylinder and mixture conditions on the combustion are more accurately predicted thanks to the inclusion of a new and widely validated laminar burning velocity correlation. In contrast to other studies, the current experimental database also includes measurements on turbocharged, high compression ratio engines with elevated amounts of EGR, which is representative of future dedicated alcohol engines. CONCLUSIONS - The current work focused on adapting the various submodels of quasi-dimensional engine codes to the properties of light alcohols. The developed simulation tools can be used with confidence to optimize current and future engines running on neat methanol and ethanol. This work also forms the starting point for an extension of the modelling concepts to alcohol-gasoline blends, which hold more industrial relevance

ruvA Mutants that resolve Holliday junctions but do not reverse replication forks

RuvAB and RuvABC complexes catalyze branch migration and resolution of Holliday junctions (HJs) respectively. In addition to their action in the last steps of homologous recombination, they process HJs made by replication fork reversal, a reaction which occurs at inactivated replication forks by the annealing of blocked leading and lagging strand ends. RuvAB was recently proposed to bind replication forks and directly catalyze their conversion into HJs. We report here the isolation and characterization of two separation-of-function ruvA mutants that resolve HJs, based on their capacity to promote conjugational recombination and recombinational repair of UV and mitomycin C lesions, but have lost the capacity to reverse forks. In vivo and in vitro evidence indicate that the ruvA mutations affect DNA binding and the stimulation of RuvB helicase activity. This work shows that RuvA's actions at forks and at HJs can be genetically separated, and that RuvA mutants compromised for fork reversal remain fully capable of homologous recombination