On the use of marker data to determine the kinetics of the digestive behaviour of feeds

A model of the transport process that follows the progress of digesta successively through the small intestine of a monogastric is investigated. The process is multi-phase and multi-constituent, as described in detail by Bastianelli et al. [J. Anim. Sci., 74:1873–1887, 1996]. The model describes the movement of marker substances that are used to obtain data on the interactions between the intestinal sections and digesta with differing levels of soluble fibre. A multi-stage process is modelled by a set of coupled first order linear differential equations. Solutions of steady and initial value problems provide information on the transfer rates of the processes. Properties of the solutions as functions of system parameters are examined. References M. Renton, J. Hanan and K. Burrage, Using the canonical modelling approach to simplify the simulation of function in functional-structural plant models. New Phytologist, 166:845–857, 2005. doi:10.1111/j.1469-8137.2005.01330.x D. Bastianelli, D. Sauvant and A. Rerat, Mathematical modeling of digestion and nutrient absorption in pigs. J. Animal Science, 74:1873–1887, 1996. http://www.journalofanimalscience.org/content/74/8/1873.abstract R. G. Lentle and P. W. M. Janssen, Manipulating Digestion with Foods designed to Change the Physical Characteristics of digesta. Critical Reviews in Food Science and Nutrition, 50:130–145, 2010. doi:10.1080/10408390802248726 J. France, J. H. M. Thornley, M. S. Dhanoa and R. C. Siddons, On the mathematics of digesta flow kinetics. Journal of Theoretical Biology, 113:743–758, 1985. doi:10.1016/S0022-5193(85)80191-0 A. Mazanov and J. V. Nolan, Simulation of the dynamics of nitrogen metabolism in sheep. British Journal of Nutrition, 35:149–174, 1976. doi:10.1079/BJN19760017 A. Mazanov, Stability of Multi-pool Models with Lags. Journal of Theoretical Biology, 59:429–442, 1976. doi:10.1016/0022-5193(76)90181-

A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic me

Challenging local realism with human choices

A Bell test is a randomized trial that compares experimental observations against the philosophical worldview of local realism 1, in which the properties of the physical world are independent of our observation of them and no signal travels faster than light. A Bell test requires spatially distributed entanglement, fast and high-efficiency detection and unpredictable measurement settings 2,3 . Although technology can satisfy the first two of these requirements 4-7, the use of physical devices to choose settings in a Bell test involves making assumptions about the physics that one aims to test. Bell himself noted this weakness in using physical setting choices and argued that human 'free will' could be used rigorously to ensure unpredictability in Bell tests 8 . Here we report a set of local-realism tests using human choices, which avoids assumptions about predictability in physics. We recruited about 100,000 human participants to play an online video game that incentivizes fast, sustained input of unpredictable selections and illustrates Bell-test methodology 9 . The participants generated 97,347,490 binary choices, which were directed via a scalable web platform to 12 laboratories on five continents, where 13 experiments tested local realism using photons 5,6, single atoms 7, atomic ensembles 10 and superconducting devices 11 . Over a 12-hour period on 30 November 2016, participants worldwide provided a sustained data flow of over 1,000 bits per second to the experiments, which used different human-generated data to choose each measurement setting. The observed correlations strongly contradict local realism and other realistic positions in bipartite and tripartite 12 scenarios. Project outcomes include closing the 'freedom-of-choice loophole' (the possibility that the setting choices are influenced by 'hidden variables' to correlate with the particle properties 13 ), the utilization of video-game methods 14 for rapid collection of human-generated randomness, and the use of networking techniques for global participation in experimental science

Challenging local realism with human choices

A Bell test is a randomized trial that compares experimental observations against the philosophical worldview of local realism. A Bell test requires spatially distributed entanglement, fast and high-efficiency detection and unpredictable measurement settings. Although technology can satisfy the first two of these requirements, the use of physical devices to choose settings in a Bell test involves making assumptions about the physics that one aims to test. Bell himself noted this weakness in using physical setting choices and argued that human `free will' could be used rigorously to ensure unpredictability in Bell tests. Here we report a set of local-realism tests using human choices, which avoids assumptions about predictability in physics. We recruited about 100,000 human participants to play an online video game that incentivizes fast, sustained input of unpredictable selections and illustrates Bell-test methodology. The participants generated 97,347,490 binary choices, which were directed via a scalable web platform to 12 laboratories on five continents, where 13 experiments tested local realism using photons, single atoms, atomic ensembles, and superconducting devices. Over a 12-hour period on 30 November 2016, participants worldwide provided a sustained data flow of over 1,000 bits per second to the experiments, which used different human-generated data to choose each measurement setting. The observed correlations strongly contradict local realism and other realistic positions in bipartite and tripartite scenarios. Project outcomes include closing the `freedom-of-choice loophole' (the possibility that the setting choices are influenced by `hidden variables' to correlate with the particle properties), the utilization of video-game methods for rapid collection of human generated randomness, and the use of networking techniques for global participation in experimental science.Comment: This version includes minor changes resulting from reviewer and editorial input. Abstract shortened to fit within arXiv limit

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Impact of perinatal nutrition on spatial cognitive performance of pigs later in life

International audiencePerinatal nutrition can program cognitive functions in mammals. Accordingly, excessive intakeof dietary fat and/or sugar during pregnancy and/or lactation has been found to alter learningand memory of offspring in rodents. Little is known, however, on the impact of perinatalnutrition, and the most sensitive period (prenatal or postnatal) for dietary programming ofcognition in the domestic pig. We investigated the effects of prenatal vs postnatal exposureto a high-fat high-sugar (HFHS) diet on cognition of pigs. Thirty-two sows and their litterswere allocated to 1 of 4 dietary treatments in a 2×2 factorial design, with 8-week prenatal(gestation) and 8-week postnatal (lactation and post-weaning) exposure to a HFHS diet orcontrol (standard commercial) diets as factors. From weaning onwards (4 weeks of age), 3piglets per litter were selected and housed in pens of 3 littermates. Starting 3 weeks after thedietary intervention, piglets were subjected to a spatial cognitive hole-board task, in which theyhad to discriminate 4 baited buckets out of 16 in a fixed configuration. After 28 acquisitiontrials, piglets were subjected to 16 reversal trials, in which the configuration was changed.Reference memory (RM) score was calculated as the ratio between the number of visits tothe set of baited buckets and the number of visits to all buckets, and working memory (WM)score as the ratio between the number of different buckets visited and the total number of (re)visits. Data were analysed using a mixed model with pen as experimental unit. In both phasesof the task, WM and RM scores increased over trials (P<0.001). Compared to controls, pigletsexposed to the prenatal HFHS diet showed higher WM scores (0.79±0.01 vs 0.77±0.01, P=0.05)in the acquisition phase, and a trend for higher WM (0.83±0.01 vs 0.81±0.01, P=0.08) and RM(0.39±0.01 vs 0.37±0.01, P=0.06) scores in the reversal phase. In both phases, piglets exposed tothe prenatal HFHS diet made fewer visits in total (acquisition: 14.9±0.36 vs 16.1±0.31, P=0.02and reversal: 14.0±0.48 vs 15.4±0.46, P=0.04) and tended to have longer inter-visit intervalsthan controls (acquisition: 6.03±0.66 vs 4.74±0.40 sec, P=0.07 and reversal: 4.80±0.58 vs3.64±0.19 sec, P=0.05), suggesting that enhanced motivation did not explain their improvedcognitive performance. No effect of the postnatal diet or its interaction with the prenatal dietwas found. Our study highlights the key role of late prenatal, but not postnatal, nutrition forprogramming of spatial memory in pigs, which may impact their ability to cope with later lifechallenges

Reviewing the low efficiency of protein utilization in heavy preruminant calves – a reductionist approach

The efficiency of protein utilization for growth in preruminant calves is decreasing with increasing body weight. In contrast to calves weighing less than 100 kg of body weight, heavy preruminant calves do not respond in protein retention to an increased intake of indispensable amino acids in dose-response studies. The marginal efficiency of protein utilization is low compared with pigs and milk-fed lambs at a similar stage of maturity. A reductionist approach was taken to perceive the potential mechanisms for the low protein utilization in preruminant calves. Neither an imbalance in the dietary protein to energy ratio nor a single limiting indispensable amino acid was responsible for the low efficiency. Also, amino acids were not specifically used to detoxify ammonia. Alternative hypotheses to explain the low efficiency are discussed and result in (i) a reduced post-absorptive supply of amino acids: e.g. by fermentation of milk in the (premature) rumen or preferential amino acid utilization by specific tissues; or (ii) a reduced post-absorptive amino acid utilization: e.g. by decreased insulin sensitivity, utilization of amino acids for gluconeogenesis or an asynchronous nutrient supply. In conclusion, several mechanisms for the low efficiency of protein utilization in heavy preruminant calves were excluded. Other physiological processes which are potentially involved remain to be studied, because the large potential for improving protein utilization in heavy preruminant calves asks for further exploration of their amino acid metabolism