In vivo "real-time" monitoring of glucose in the brain with an amperometric enzyme-based biosensor based on gold coated tungsten (W-Au) microelectrodes

Biosensors based on Pt or Pt/Ir based needle-type microelectrodes have been successfully employed for continuous in vivo real-time brain biomonitoring of biomarkers such as glutamate and glucose. However, when implanted, these biosensors often bend, thereby damaging its surface and degrading its bioanalytical properties. In addition, downscaling of Pt and Pt/Ir needle-type biosensors, to improve the spatial resolution and decrease tissue damage, is technically challenging. In that sense, we investigated whether the use of a material with low malleability, tungsten (W), coated with a highly conductive material, gold (Au) could be as an alternative for conventional needle-type based biosensors. Therefore, we developed implantable needle-type (50 tim 0) gold coated tungsten (W-Au) amperometric microbiosensors. First, we evaluated electrochemically, the ability of W-Au microelectrodes (50 tim 0) to continuously monitor changes in H2O2. After, we functionalized, using a layer-by-layer assembly, the surface of W-Au microelectrodes. First with permselective membrane(s) (Nafion and Nafion-PPD) and after with an enzymatic hydrogel, containing an enzyme selective for glucose (glucose oxidase). Both the enzyme loading and the applied potential were optimized and the performance of functionalized W-Au microelectrodes and fully assembled biosensors was evaluated electrochemically. Additionally, the surface of bare and functionalized microelectrodes was also characterized by imaging techniques (scanning electron microscopy). In vivo experiments revealed that, W-Au based glucose biosensors, were able to accurately monitor, in real-time, changes in brain glucose in response to relevant pharmacological challenges. (C) 2018 Elsevier B.V. All rights reserved

Cost-effectiveness analysis of a first-trimester screening test for preterm preeclampsia in the Netherlands

Objectives: The risk of preterm preeclampsia (PT PE) can significantly be reduced by starting acetylsalicylic acid ≤ 16 weeks of gestational age. First trimester predictive models based on maternal risk factors to effectively start this therapy lacked sufficient power, but recent studies showed that these models can be improved by including test results of biochemical and/or -physical markers. To investigate whether testing a biochemical marker in the first trimester is cost-effective in the Netherlands, a cost-effectiveness analysis was performed in this study. Study design: The outcome of this study was expressed as an incremental cost-effectiveness ratio (ICER) with as effect prevented PT PE cases. To evaluate the impact of each model parameter and to determine model uncertainties, both univariate and probabilistic sensitivity analyses were performed. Results: When compared to the baseline strategy, the test strategy is estimated to save almost 4 million euros per year on a national scale and at the same time this would prevent an additional 228 PT PE cases. The sensitivity analyses showed that the major drivers of the result are the costs to monitor a high-risk pregnancy and the specificity and that most of the model simulations were in the southeast quadrant: cost saving and more prevented complications. Conclusions: This study showed that a first-trimester test strategy to screen for PT PE in the first trimester is potentially cost-effective in the Dutch healthcare setting. The fact that the specificity is a major driver of the ICER indicates the importance for a (new) screening model to correctly classify low-risk pregnancies.</p

The Computation of Surface Lightness in Simple and Complex Scenes

The present thesis examined how reflectance properties and the complexity of surface mesostructure (small-scale surface relief) influence perceived lightness in centresurround displays. Chapters 2 and 3 evaluated the role of surface relief, gloss, and interreflections on lightness constancy, which was examined across changes in background albedo and illumination level. For surfaces with visible mesostructure (“rocky” surfaces), lightness constancy across changes in background albedo was better for targets embedded in glossy versus matte surfaces. However, this improved lightness constancy for gloss was not observed when illumination varied. Control experiments compared the matte and glossy rocky surrounds to two control displays, which matched either pixel histograms or a phase-scrambled power spectrum. Lightness constancy was improved for rocky glossy displays over the histogram-matched displays, but not compared to phase-scrambled variants of these images with equated power spectrums. The results were similar for surfaces rendered with 1, 2, 3 and 4 interreflections. These results suggest that lightness perception in complex centre-surround displays can be explained by the distribution of contrast across space and scale, independently of explicit information about surface shading or specularity. The results for surfaces without surface relief (“homogeneous” surfaces) differed qualitatively to rocky surfaces, exhibiting abrupt steps in perceived lightness at points at which the targets transitioned from being increments to decrements. Chapter 4 examined whether homogeneous displays evoke more complex mid-level representations similar to conditions of transparency. Matching target lightness in a homogeneous display to that in a textured or rocky display required varying both lightness and transmittance of the test patch on the textured display to obtain the most satisfactory matches. However, transmittance was only varied to match the contrast of targets against homogeneous surrounds, and not to explicitly match the amount of transparency perceived in the displays. The results suggest perceived target-surround edge contrast differs between homogeneous and textured displays. Varying the mid-level property of transparency in textured displays provides a natural means for equating both target lightness and the unique appearance of the edge contrast in homogeneous displays

The application of big data and AI in the upstream supply chain

The use of Big Data has grown in popularity in organisations to exploit the purpose of their primary data to enhance their competitiveness. In conjunction with the increased use of Big Data, there has also been a growth in the use of Artificial Intelligence (AI) to analyse the vast amounts of data generated and provide a mechanism for locating and constructing useable patterns that organisations can incorporate in their supply chain strategy programme. As these organisations embrace the use of technology and embed this in their supply chain strategy, there are questions as to how this may affect their upstream supply chains especially with regards to how SME’s may be able to cope with the potential changes. There exists the opportunity to conduct further research into this area, mainly focusing on three key industry sectors of aerospace, rail and automotive supply chains.N/

Disruption of the basal body protein POC1B results in autosomal-recessive cone-rod dystrophy

Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.G1n67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.G1n67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.G1n67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors

Sound localization with bilateral bone conduction devices

Purpose To investigate sound localization in patients bilaterally fitted with bone conduction devices (BCDs). Additionally, clinically applicable methods to improve localization accuracy were explored. Methods Fifteen adults with bilaterally fitted percutaneous BCDs were included. At baseline, sound localization, (un)aided pure-tone thresholds, device use, speech, spatial and qualities of hearing scale (SSQ) and York hearing-related quality of life (YHRQL) questionnaire were measured. Settings to optimize sound localizing were added to the BCDs. At 1 month, sound localization was assessed again and localization was practiced with a series of sounds with visual feedback. At 3 months, localization performance, device use and questionnaire scores were determined again. Results At baseline, one patient with congenital hearing loss demonstrated near excellent localization performance and four other patients (three with congenital hearing loss) localized sounds (quite) accurately. Seven patients with acquired hearing loss were able to lateralize sounds, i.e. identify whether sounds were coming from the left or right side, but could not localize sounds accurately. Three patients (one with congenital hearing loss) could not even lateralize sounds correctly. SSQ scores were significantly higher at 3 months. Localization performance, device use and YHRQL scores were not significantly different between visits. Conclusion In this study, the majority of experienced bilateral BCD users could lateralize sounds and one third was able to localize sounds (quite) accurately. The localization performance was robust and stable over time. Although SSQ scores were increased at the last visit, optimizing device settings and a short practice session did not improve sound localization

Healthy and preeclamptic pregnancies show differences in Guanylate-Binding Protein-1 plasma levels

The large interferon-inducible anti-angiogenic pro-inflammatory GTPase Guanylate Binding Protein-1 (GBP-1) is produced and secreted by activated endothelial cells and is highly induced by inflammatory cytokines and inhibited by angiogenic growth factors. During pregnancy a generalized mild inflammatory response is observed. During preeclampsia this generalized inflammatory response is even further activated and activation of the endothelium occurs. We hypothesized that GBP-1 is increased in healthy pregnancy and will be even further increased during preeclampsia. In the first experiment, plasma and placentas were collected from healthy and preeclamptic pregnancies. Plasma was also collected from non-pregnant women. For the second experiment longitudinal blood samples from women with a healthy or preeclamptic pregnancy were collected from the end of the first trimester until birth and one sample postpartum. The plasma GBP-1 levels were measured by ELISA and GBP-1 mRNA and protein levels in the placenta were tested by qPCR and immunohistochemistry. During pregnancy higher plasma concentrations of GBP-1 compared with non-pregnant women were observed. Surprisingly, during preeclampsia, plasma GBP-1 levels were lower than in control pregnancies and similar to the level of non-pregnant controls. Placental GBP-1 mRNA levels were not different between healthy and preeclamptic pregnancies and GBP-1 protein was virtually undetectable in the trophoblast by immunohistochemistry in placental tissue. Evaluation of longitudinal samples showed that plasma GBP-1 concentrations increased towards the end of pregnancy in healthy pregnancies, but not in preeclampsia. In line with our hypothesis, we found higher GBP-1 plasma levels during healthy pregnancy. However, plasma GBP-1 did not further increase during preeclampsia, but was stable. Further studies are needed to evaluate why GBP-1 does not increase during preeclampsia

Impact of Experimental Human Pneumococcal Carriage on Nasopharyngeal Bacterial Densities in Healthy Adults

Colonization of the nasopharynx by Streptococcus pneumoniae is a necessary precursor to pneumococcal diseases that result in morbidity and mortality worldwide. The nasopharynx is also host to other bacterial species, including the common pathogens Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis. To better understand how these bacteria change in relation to pneumococcal colonization, we used species-specific quantitative PCR to examine bacterial densities in 52 subjects 7 days before, and 2, 7, and 14 days after controlled inoculation of healthy human adults with S. pneumoniae serotype 6B. Overall, 33 (63%) of subjects carried S. pneumoniae post-inoculation. The baseline presence and density of S. aureus, H. influenzae, and M. catarrhalis were not statistically associated with likelihood of successful pneumococcal colonization at this study’s sample size, although a lower rate of pneumococcal colonization in the presence of S. aureus (7/14) was seen compared to that in the presence of H. influenzae (12/16). Among subjects colonized with pneumococci, the number also carrying either H. influenzae or S. aureus fell during the study and at 14 days post-inoculation, the proportion carrying S. aureus was significantly lower among those who were colonized with S. pneumoniae (p = 0.008) compared to non-colonized subjects. These data on bacterial associations are the first to be reported surrounding experimental human pneumococcal colonization and show that co-colonizing effects are likely subtle rather than absolute