Surrogate Accelerated Bayesian Inversion for the Determination of the Thermal Diffusivity of a Material

Determination of the thermal properties of a material is an important task in many scientific and engineering applications. How a material behaves when subjected to high or fluctuating temperatures can be critical to the safety and longevity of a system's essential components. The laser flash experiment is a well-established technique for indirectly measuring the thermal diffusivity, and hence the thermal conductivity, of a material. In previous works, optimization schemes have been used to find estimates of the thermal conductivity and other quantities of interest which best fit a given model to experimental data. Adopting a Bayesian approach allows for prior beliefs about uncertain model inputs to be conditioned on experimental data to determine a posterior distribution, but probing this distribution using sampling techniques such as Markov chain Monte Carlo methods can be incredibly computationally intensive. This difficulty is especially true for forward models consisting of time-dependent partial differential equations. We pose the problem of determining the thermal conductivity of a material via the laser flash experiment as a Bayesian inverse problem in which the laser intensity is also treated as uncertain. We introduce a parametric surrogate model that takes the form of a stochastic Galerkin finite element approximation, also known as a generalized polynomial chaos expansion, and show how it can be used to sample efficiently from the approximate posterior distribution. This approach gives access not only to the sought-after estimate of the thermal conductivity but also important information about its relationship to the laser intensity, and information for uncertainty quantification. We also investigate the effects of the spatial profile of the laser on the estimated posterior distribution for the thermal conductivity

Proceedings From the Symposium on Kidney Disease in Older People: Royal Society of Medicine, London, January 19, 2017

People are living longer. On the whole, they have healthier lives and many of the problems previously seen at a younger age now appear in their later years. Kidneys, like other organs, age, and kidney disease in the aged is a prime example. In the United Kingdom, as in other developed countries, the prevalence of end stage kidney disease is highest in the 70- to 79-year-old age group. There are many older people who require renal replacement and are now considered for dialysis. While older patients with end-stage renal disease invariably aspire for a better quality of life, this needs a specialized approach and management. In January 2017, the Royal Society of Medicine held a seminar in London on “Kidney Disease in Older People” with presentations from a multidisciplinary body of experts speaking on various aspects of kidney problems in this age group and its management. The objectives were to increase awareness and improve the understanding of nephrology in the context of geriatric medicine but also geriatrics in its interface with nephrology, especially in the area of chronic kidney disease

NMDA-receptor antibodies alter cortical microcircuit dynamics

NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities-or even seizures-is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab-related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to dat

Psychological factors associated with uptake of the childhood influenza vaccine and perception of post-vaccination side-effects : a cross-sectional survey in England

Objectives To identify predictors of: uptake of the childhood influenza vaccine in the 2015–2016 influenza season, parental perceptions of side-effects from the influenza vaccine and intention to vaccinate one's child for influenza in the 2016–2017 influenza season. Design Cross-sectional online survey. Setting Data were collected in England shortly after the end of the 2015–2016 immunization campaign. Participants 1001 parents or guardians of children aged between two and seven. Main outcome measures Self-reported uptake of the childhood influenza vaccine in the 2015–2016 influenza season, perception of side-effects from the influenza vaccine and intention to vaccinate one's child in the 2016–2017 influenza season. Results Self-reported uptake of the childhood influenza vaccine was 52.8%. Factors strongly positively associated with uptake included the child having previously been vaccinated against influenza, perceiving the vaccine to be effective and perceiving the child to be susceptible to flu. Factors strongly negatively associated with uptake included perceiving the vaccine to be unsafe, to cause short-term side-effects or long-term health problems and believing that yearly vaccination may overload the immune system. Predictors of intended vaccine uptake in 2016–2017 were similar. Participants who perceived side-effects after the 2015–2016 vaccination reported being less likely to vaccinate their child next year. Side-effects were more likely to be reported in first-born children, by participants who knew another child who had side-effects, those who thought that the vaccine would interact with medication that the child was currently taking, and those who believed the vaccine causes short-term side-effects. Conclusions Perceptions about the childhood influenza vaccine show strong associations with uptake, intended uptake and perception of side-effects. Attempts to improve uptake rates from their current low levels must address these perceptions

NAFLD exacerbates the effect of dietary sugar on liver fat and development of an atherogenic lipoprotein phenotype

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer.${\bf Aims/hypothesis:}$ We aimed to test the hypothesis that the effects of dietary sugar on lipoprotein metabolism are influenced by non-alcoholic fatty liver disease (NAFLD). ${\bf Methods:}$ The effect of two 12 week, iso-energetic diets, high and low in non-milk extrinsic sugars (26% and 6% total energy), matched for macronutrient content, was examined in a randomised, cross-over study in men with NAFLD (n=11) and controls (n= 14). Lipoprotein kinetics and the sources of fatty acids for triacylglycerol (TAG) production were measured using stable isotope tracers. ${\bf Results:}$ Liver fat was higher after the high versus low-sugar diet in both groups (p<0.02), but men with NAFLD showed a relatively greater response than controls (p<0.05). After the high versus low-sugar diet, VLDL1-TAG production rate was higher in the controls (p <0.002) due to a greater contribution from splanchnic fatty acids (p<0.02) and de novo lipogenesis (p <0.002), whereas in NAFLD, VLDL2-TAG production rate was higher (p <0.05), due to a greater contribution from splanchnic fatty acids (p<0.02). There was no difference in the contribution of systemic NEFA to VLDL1 and VLDL2-TAG production rate between diets in either group. Intermediate density lipoprotein (IDL), LDL2 and LDL3-apolipoprotein B production rates and post-heparin hepatic lipase activity were all higher (p<0.05) on the high-sugar diet in NAFLD. ${\bf Conclusions:}$ A high sugar intake promoted a greater accumulation of liver fat in NAFLD than controls and increased VLDL-TAG production in both groups, due mainly to an increased contribution of fatty acids from splanchnic sources, which includes hepatic TAG storage pools. These effects may drive the formation of atherogenic lipoproteins.The work was supported by a UK government grant from the Biological Biotechnology Scientific Research Council (Grant no. BB/G009899/1); University of Surrey PhD scholarship for AM; Medical Research Council (body composition measurements) and infrastructure support from the National Institute of Health Research at the Cambridge Biomedical Research Centre

Field-deployable, quantitative, rapid identification of active Ebola virus infection in unprocessed blood

The West African Ebola virus outbreak underlined the importance of delivering mass diagnostic capability outside the clinical or primary care setting in effectively containing public health emergencies caused by infectious disease. Yet, to date, there is no solution for reliably deploying at the point of need the gold standard diagnostic method, real time quantitative reverse transcription polymerase chain reaction (RT- qPCR), in a laboratory infrastructure-free manner. In this proof of principle work, we demonstrate direct performance of RT-qPCR on fresh blood using far-red fluorophores to resolve fluorogenic signal inhibition and controlled, rapid freeze/thawing to achieve viral genome extraction in a single reaction chamber assay. The resulting process is entirely free of manual or automated sample pre-processing, requires no microfluidics or magnetic/mechanical sample handling and thus utilizes low cost consumables. This enables a fast, laboratory infrastructure-free, minimal risk and simple standard operating procedure suited to frontline, field use. Developing this novel approach on recombinant bacteriophage and recombinant human immunodeficiency virus (HIV; Lentivirus), we demonstrate clinical utility in symptomatic EBOV patient screening using live, infectious Filoviruses and surrogate patient samples. Moreover, we evidence assay co-linearity independent of viral particle structure that may enable viral load quantification through pre-calibration, with no loss of specificity across an 8 log- linear maximum dynamic range. The resulting quantitative rapid identification (QuRapID) molecular diagnostic platform, openly accessible for assay development, meets the requirements of resource- limited countries and provides a fast response solution for mass public health screening against emerging biosecurity threats