Plasma midregional proadrenomedullin (MR-proADM) concentrations and their biological determinants in a reference population

Background: Midregional proadrenomedullin (MR-proADM) is emerging as a prognostic biomarker for detecting the failure of multiple organs. Establishment of scientifically robust reference intervals facilitates interpretation of laboratory test results. The objectives of this study were (i) to establish reliable reference intervals for plasma MR-proADM using a commercially available automated fluoroimmunoassay in apparently healthy individuals, and (ii) to identify biological determinants of MR-proADM concentrations. Methods: A total of 506 questionnaire-identified apparently healthy adults were enrolled in a single-center, cross-sectional study. A final reference group (n = 172) was selected after exclusion of obese individuals, those with increased values of laboratory biomarkers indicating asymptomatic myocardial injury or dysfunction, ongoing inflammation, diabetes, dyslipidemia and renal dysfunction and outliers. Results: The 2.5th and 97.5th percentile intervals for MR-proADM values in the reference group (90% confidence interval) were 0.21 (0.19-0.23) and 0.57 (0.55-0.59) nmol/L, respectively. Although older age, higher values of HbA(1c), C-reactive protein, B-type natriuretic peptide and body mass index, together with a history of smoking and a decreased estimated glomerular filtration rate were significantly associated with increasing concentrations of MR-proADM in both univariate and multivariate analyses, magnitudes of these relationships were modest and did not substantially influence MR-proADM reference intervals. Sex-dependent difference in MR-proADM reference intervals was not detected [0.19 (0.16-0.22)-0.56 (0.54-0.60) nmol/L in females vs. 0.22 (0.20-0.25)-0.58 (0.57-0.63) nmol/L in males]. Conclusions: Our study successfully established robust reference intervals for MR-proADM concentrations in plasma. Considering the negligible influence of potential biological determinants on plasma MR-proADM, we recommend the adoption of single reference intervals for adult population as a whole

Orbit Determination with the two-body Integrals

We investigate a method to compute a finite set of preliminary orbits for solar system bodies using the first integrals of the Kepler problem. This method is thought for the applications to the modern sets of astrometric observations, where often the information contained in the observations allows only to compute, by interpolation, two angular positions of the observed body and their time derivatives at a given epoch; we call this set of data attributable. Given two attributables of the same body at two different epochs we can use the energy and angular momentum integrals of the two-body problem to write a system of polynomial equations for the topocentric distance and the radial velocity at the two epochs. We define two different algorithms for the computation of the solutions, based on different ways to perform elimination of variables and obtain a univariate polynomial. Moreover we use the redundancy of the data to test the hypothesis that two attributables belong to the same body (linkage problem). It is also possible to compute a covariance matrix, describing the uncertainty of the preliminary orbits which results from the observation error statistics. The performance of this method has been investigated by using a large set of simulated observations of the Pan-STARRS project.Comment: 23 pages, 1 figur

Montessori's mediation of meaning: a social semiotic perspective

The distinctive objects designed by Dr Maria Montessori as the centrepiece of her approach to pedagogy are the topic of this study. The Montessori approach to pedagogy, celebrating its centenary in 2007, continues to be used in classrooms throughout the world. Despite such widespread and enduring use, there has been little analysis of the Montessori objects to evaluate or understand their pedagogic impact. This study begins by outlining the provenance of the Montessori objects, reaching the conclusion that the tendency to interpret them from the perspective of the progressive education movement of the early twentieth century fails to provide insights into the developmental potential embodied in the objects. In order to appreciate that potential more fully, the study explores the design of the objects, specifically, the way in which the semiotic qualities embodied in their design orient children to the meanings of educational knowledge. A meta-analytic framework comprising three components is used to analyse the semiotic potential of the Montessori objects as educational artefacts. First, Vygotsky’s model of development is used to analyse the objects as external mediational means and to recognise the objects as complexes of signs materialising educational knowledge. In order to understand how the objects capture, in the form of concrete analogues, the linguistic meanings which construe educational knowledge, systemic functional linguistics, the second component of the framework, is used to achieve a rich and detailed social semiotic analysis of these relations, in particular, material and linguistic representations of abstract educational meanings. Finally, the pedagogic device, a central feature of Bernstein’s sociology of pedagogy, is used to analyse how the Montessori objects re-contextualise educational knowledge as developmental pedagogy. Particular attention is paid to the Montessori literacy pedagogy, in which the study of grammar plays a central role. The study reveals a central design principle which distinguishes the Montessori objects. This principle is the redundant representation of educational knowledge across multiple semiotic modes. Each representation holds constant the underlying meaning relations which construe quanta of educational knowledge, giving children the freedom to engage with this knowledge playfully, independently and successfully. The conclusion drawn from this study is that the design of the Montessori objects represents valuable educational potential which deserves continued investigation, as well as wider recognition and application. To initiate this process, the findings in this study may provide insights which can be used to develop tools for evaluating and enhancing the implementation of Montessori pedagogy in Montessori schools. The findings may also be used to adapt Montessori design principles for the benefit of educators working in non-Montessori contexts, in particular, those educators concerned with developing pedagogies which promote equitable access to educational knowledge

Assessing availability and greenhouse gas emissions of lignocellulosic biomass feedstock supply – case study for a catchment in England

© 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.Feedstocks from lignocellulosic biomass (LCB) include crop residues and dedicated per¬ennial biomass crops. The latter are often considered superior in terms of climate change mitigation potential. Uncertainty remains over their availability as feedstocks for biomass provision and the net greenhouse gas emissions (GHG) during crop production. Our objective was to assess the optimal land allocation to wheat and Miscanthus in a specific case study located in England, to increase bio¬mass availability, improve the carbon balance (and reduce the consequent GHG emissions), and mini¬mally constrain grain production losses from wheat. Using soil and climate variables for a catchment in east England, biomass yields and direct nitrogen emissions were simulated with validated process-based models. A ‘Field to up-stream factory gate’ life-cycle assessment was conducted to estimate indirect management-related GHG emissions. Results show that feedstock supply from wheat straw can be supplemented beneficially with LCB from Miscanthus grown on selected low-quality soils. In our study, 8% of the less productive arable land area was dedicated to Miscanthus, increasing total LCB provision by about 150%, with a 52% reduction in GHG emission per ton LCB delivered and only a minor effect on wheat grain production (−3%). In conclusion, even without considering the likely carbon sequestration in impoverished soils, agriculture should embrace the opportunities to provide the bioeconomy with LCB from dedicated, perennial crops.Peer reviewe

Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study

Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. Objectives: To compare different assays for prediction of events during long-term follow-up. Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator- stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA- 100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

Background: Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADPreceptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). Methods: We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. Results: A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR= 0.87, 95% CI 0.79–0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR= 0.80, 95% CI 0.74–0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR= 0.52, 95% CI 0.43–0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standarddose clopidogrel (5% vs. 4.7%, OR= 1.06 95% CI 0.96–1.17, P = 0.25). Conclusions: This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs

Risk of acquired drug resistance during short-course directly observed treatment of tuberculosis in an area with high levels of drug resistance.

BACKGROUND: Data on the performance of standardized short-course directly observed treatment (DOTS) of tuberculosis (TB) in areas with high levels of drug resistance and on the potential impact of DOTS on amplification of resistance are limited. Therefore, we analyzed treatment results from a cross-sectional sample of patients with TB enrolled in a DOTS program in an area with high levels of drug resistance in Uzbekistan and Turkmenistan in Central Asia. METHODS: Sputum samples for testing for susceptibility to 5 first-line drugs and for molecular typing were obtained from patients starting treatment in 8 districts. Patients with sputum smear results positive for TB at the end of the intensive phase of treatment and/or at 2 months into the continuation phase were tested again. RESULTS. Among 382 patients with diagnoses of TB, 62 did not respond well to treatment and were found to be infected with an identical Mycobacterium tuberculosis strain when tested again; 19 of these patients had strains that developed new or additional drug resistance. Amplification occurred in only 1.2% of patients with initially susceptible or monoresistant TB strains, but it occurred in 17% of those with polyresistant strains (but not multidrug-resistant strains, defined as strains with resistance to at least isoniazid and rifampicin) and in 7% of those with multidrug-resistant strains at diagnosis. Overall, 3.5% of the patients not initially infected with multidrug-resistant TB strains developed such strains during treatment. Amplification of resistance, however, was found only in polyresistant Beijing genotype strains. CONCLUSIONS: High levels of amplification of drug resistance demonstrated under well-established DOTS program conditions reinforce the need for implementation of DOTS-Plus for multidrug-resistant TB in areas with high levels of drug resistance. The strong association of Beijing genotype and amplification in situations of preexisting resistance is striking and may underlie the strong association between this genotype and drug resistance

Preliminary studies of sediments from the Dobczyce drinking water reservoir

The analysis of river and lake sediments indicates that the physical, chemical, biochemical and geochemical processes that influence the fate of toxic compounds and elements in sediments are numerous and complex (for example: sorption - desorption, oxidation - reduction, ion-exchange, biological activity). Due to the above-mentioned general statement, only a long term and complex research programme can lead to satisfactory answers to the questions relating to possible changes of water and environmental quality in the future. The aim of our study consisted in physical and chemical characterisation of sediments in in-depth profiles taken from the Dobczyce reservoir in southern Poland that is a main source of drinking water for the city of Kraków. Due to morphological reasons, 7 layers of sediment samples were distinguished from the ground level to about 90 cm below (total thickness of the sediments in the sampling site). Analysis of grain size distribution and application of x-ray diffraction method, enabled mineralogical description of sediments. The use of proton-induced x-ray emission (PIXE) and atomic absorption spectrometry (AAS) revealed elemental composition of the samples (Al, P, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn). Concentrations of natural 40K and artificial 137Cs radionuclides were determined by the use of gamma spectrometry. The following facts were established: 1) the oldest (deepest) and newest, recently deposited layers of sediments are similar in their physical and chemical properties. It means that the inflow of contaminants and biogenic compounds to the reservoir has changed little since it was constructed and filled with water; 2) the severe flood in 1997 changed significantly sediment composition and, in fact, led to purification of sediments in the Dobczyce reservoir