EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article has been made available through the Brunel Open Access Publishing Fund.A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

Molecular dynamics simulations of vibrated granular gases

We present molecular dynamics simulations of mono- or bidisperse inelastic granular gases driven by vibrating walls, in two dimensions (without gravity). Because of the energy injection at the boundaries, a situation often met experimentally, density and temperature fields display heterogeneous profiles in the direction perpendicular to the walls. A general equation of state for an arbitrary mixture of fluidized inelastic hard spheres is derived and successfully tested against numerical data. Single-particle velocity distribution functions with non-Gaussian features are also obtained, and the influence of various parameters (inelasticity coefficients, density...) analyzed. The validity of a recently proposed Random Restitution Coefficient model is assessed through the study of projected collisions onto the direction perpendicular to that of energy injection. For the binary mixture, the non-equipartition of translational kinetic energy is studied and compared both to experimental data and to the case of homogeneous energy injection (``stochastic thermostat''). The rescaled velocity distribution functions are found to be very similar for both species

Genetic basis of thermal nociceptive sensitivity and brain weight in a BALB/c reduced complexity cross

Thermal nociception involves the transmission of temperature-related noxious information from the periphery to the CNS and is a heritable trait that could predict transition to persistent pain. Rodent forward genetics complement human studies by controlling genetic complexity and environmental factors, analysis of end point tissue, and validation of variants on appropriate genetic backgrounds. Reduced complexity crosses between nearly identical inbred substrains with robust trait differences can greatly facilitate unbiased discovery of novel genes and variants. We found BALB/cByJ mice showed enhanced sensitivity on the 53.5°C hot plate and mechanical stimulation in the von Frey test compared to BALB/cJ mice and replicated decreased gross brain weight in BALB/cByJ versus BALB/cJ. We then identified a quantitative trait locus (QTL) on chromosome 13 for hot plate sensitivity (LOD = 10.7; p < 0.001; peak = 56 Mb) and a QTL for brain weight on chromosome 5 (LOD = 8.7; p < 0.001). Expression QTL mapping of brain tissues identified H2afy (56.07 Mb) as the top transcript with the strongest association at the hot plate locus (FDR = 0.0002) and spliceome analysis identified differential exon usage within H2afy associated with the same locus. Whole brain proteomics further supported decreased H2AFY expression could underlie enhanced hot plate sensitivity, and identified ACADS as a candidate for reduced brain weight. To summarize, a BALB/c reduced complexity cross combined with multiple-omics approaches facilitated identification of candidate genes underlying thermal nociception and brain weight. These substrains provide a powerful, reciprocal platform for future validation of candidate variants

Diffusion of impurities in a granular gas

Diffusion of impurities in a granular gas undergoing homogeneous cooling state is studied. The results are obtained by solving the Boltzmann--Lorentz equation by means of the Chapman--Enskog method. In the first order in the density gradient of impurities, the diffusion coefficient $D$ is determined as the solution of a linear integral equation which is approximately solved by making an expansion in Sonine polynomials. In this paper, we evaluate $D$ up to the second order in the Sonine expansion and get explicit expressions for $D$ in terms of the restitution coefficients for the impurity--gas and gas--gas collisions as well as the ratios of mass and particle sizes. To check the reliability of the Sonine polynomial solution, analytical results are compared with those obtained from numerical solutions of the Boltzmann equation by means of the direct simulation Monte Carlo (DSMC) method. In the simulations, the diffusion coefficient is measured via the mean square displacement of impurities. The comparison between theory and simulation shows in general an excellent agreement, except for the cases in which the gas particles are much heavier and/or much larger than impurities. In theses cases, the second Sonine approximation to $D$ improves significantly the qualitative predictions made from the first Sonine approximation. A discussion on the convergence of the Sonine polynomial expansion is also carried out.Comment: 9 figures. to appear in Phys. Rev.

The Reverse Brazil Nut Problem: Competition between Percolation and Condensation

In the Brazil nut problem (BNP), hard spheres with larger diameters rise to the top. There are various explanations (percolation, reorganization, convection), but a broad understanding or control of this effect is by no means acheived. A theory is presented for the crossover from the BNP to the reverse Brazil nut problem (RBNP) based on a competition between the percolation effect and the condensation of hard spheres. The crossover condition is determined, and the theoretical predictions are compared to Molecular Dynamics simulations in two and three dimensions.Comment: 9 pages which includes 7 figure

Fruit-Surface Flavonoid Accumulation in Tomato Is Controlled by a SlMYB12-Regulated Transcriptional Network

The cuticle covering plants' aerial surfaces is a unique structure that plays a key role in organ development and protection against diverse stress conditions. A detailed analysis of the tomato colorless-peel y mutant was carried out in the framework of studying the outer surface of reproductive organs. The y mutant peel lacks the yellow flavonoid pigment naringenin chalcone, which has been suggested to influence the characteristics and function of the cuticular layer. Large-scale metabolic and transcript profiling revealed broad effects on both primary and secondary metabolism, related mostly to the biosynthesis of phenylpropanoids, particularly flavonoids. These were not restricted to the fruit or to a specific stage of its development and indicated that the y mutant phenotype is due to a mutation in a regulatory gene. Indeed, expression analyses specified three R2R3-MYB–type transcription factors that were significantly down-regulated in the y mutant fruit peel. One of these, SlMYB12, was mapped to the genomic region on tomato chromosome 1 previously shown to harbor the y mutation. Identification of an additional mutant allele that co-segregates with the colorless-peel trait, specific down-regulation of SlMYB12 and rescue of the y phenotype by overexpression of SlMYB12 on the mutant background, confirmed that a lesion in this regulator underlies the y phenotype. Hence, this work provides novel insight to the study of fleshy fruit cuticular structure and paves the way for the elucidation of the regulatory network that controls flavonoid accumulation in tomato fruit cuticle

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r2 = 0.554, P = 0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean ± s.d., 2736 ± 597) than those patients in whom IFO was administered by continuous infusion (1453 ± 730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data