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Haemozoin is a by-product of haemoglobin digestion by intraerythrocytic malaria parasites, which induces immunologic responses on different tissues, including endothelial cells. In the present paper, the incubation of human microvascular endothelial cells with haemozoin significantly inhibited MTT reduction, a measure of cytotoxicity, without increasing the release of cytoplasmic lactate dehydrogenase. Moreover, haemozoin did not induce apoptosis or cell cycle arrest nor decreased the number of live cells, suggesting that cells viability itself was not affected and that the inhibition of MTT reduction was only apparent and probably due to accelerated MTT-formazan exocytosis. After 30 min of MTT addition, a significant increase in the % of cells exocytosing MTT formazan crystals was observed in haemozoin-treated cells compared with control cells. Such an effect was partially reversed by the addition of genistein, an inhibitor of MTT-formazan exocytosis. The rapid release of CXCL-8, a preformed chemokine contained in Weibel–Palade bodies, confirmed that haemozoin induces a perturbation of the intracellular endothelial trafficking, including the exocytosis of MTT-formazan containing vesicles. The haem moiety of haemozoin is responsible for the observed effect. Moreover, this work underlines that MTT assay should not be used to measure cytotoxicity induced by haemozoin and other methods should be preferred.
Surface abundance observations of halo stars hint at the occurrence of r-process nucleosynthesis at low metallicity ([Fe/H] < -3), possibly within the first 108 yr after the formation of the first stars. Possible loci of early-Universe r-process nucleosynthesis are the ejecta of either black hole–neutron star or neutron star–neutron star binary mergers. Here, we study the effect of the inclination–eccentricity oscillations raised by a tertiary (e.g. a star) on the coalescence time-scale of the inner compact object binaries. Our results are highly sensitive to the assumed initial distribution of the inner binary semi-major axes. Distributions with mostly wide compact object binaries are most affected by the third object, resulting in a strong increase (by more than a factor of 2) in the fraction of fast coalescences. If instead the distribution preferentially populates very close compact binaries, general relativistic precession prevents the third body from increasing the inner binary eccentricity to very high values. In this last case, the fraction of coalescing binaries is increased much less by tertiaries, but the fraction of binaries that would coalesce within 108 yr even without a third object is already high. Our results provide additional support to the compact-binary merger scenario for r-process nucleosynthesis.
The evaluation of orphan drugs raises both positive and normative issues. Due to the rarity of the disease, higher drug costs and greater uncertainty on effectiveness often result in incremental cost-effectiveness ratios (ICER) far beyond the usually accepted thresholds for reimbursement. However, decision makers may need to consider other criteria to assess the social value of orphan drugs such as equity, the rule of rescue, and the perceived need in the community. Hereditary Angioedema (HAE) is a rare congenital deficiency resulting in recurrent attacks of angioedema in affected patients. These episodes cause extreme pain and distress, and may even be fatal when air pathways are involved. In Italy, icantibant or C1-Esterase-Inhibitors (C1-INH) are the indicated treatments for acute attacks. Although more expensive, icantibant may reduce time to symptom-relief and the need for further treatments. Nonetheless, evidence on its social value is missing. The present study aims at evaluating the cost-effectiveness of icantibant and providing new insights on other potentially relevant criteria for decision making on HAE treatments.
A cost-effectiveness model of icantibant versus C1-INH (Berinert) was developed. Using a two-part bayesian model, costs were estimated from real-world data of an unpublished national registry. Efficacy data were synthesized from both the registry and an indirect comparison of existing trials, whereas utilities were derived from the literature.
In our Italian registry, respectively 98 percent and 60 percent of patients self-administered icatibant or Berinert at home in absence of medical personnel. On average, per treatment costs were 60 percent higher and attack duration 25 percent shorter with icantibant compared to Berinert. The resulting ICER greatly exceeded the considered threshold of EUR30,000.
On cost-effectiveness grounds icantibant did not demonstrate good value for money compared to Berinert. However, further considerations are needed on whether standard health-related quality of life measures are able to truly reflect societal preferences for HAE treatments.The use of real-world data for the economic evaluation of orphan drugs can support decision making when evidence from clinical studies is too sparse.
Thailand is among the first non-OECD countries to have introduced a form of Universal Health Coverage (UHC). This policy represents a natural experiment to evaluate the effects of public health insurance on health behaviours. In this paper, we examine the impact of Thailand’s UHC programme on preventive activities, unhealthy or risky behaviours and health care consumption using data from the Thai Health and Welfare Survey. We use doubly robust estimators that combine propensity scores and linear regressions to estimate differences-in-differences (DD) and differences-in-DD models. Our results offer important insights. First, UHC increases individuals’ likelihood of having an annual check-up, especially among women. Regarding health care consumption, we observe that UHC increases hospital admissions by over 2% and increases outpatient visits by 13%. However, there is no evidence that UHC leads to an increase in unhealthy behaviours or a reduction of preventive efforts. In other words, we find no evidence of ex ante moral hazard. Overall, these findings suggest positive health impacts among the Thai population covered by UHC.
The propagation of the action potential in the heart chambers is accurately described by
the Bidomain model, which is commonly accepted and used in the specialistic literature.
However, its mathematical structure of a degenerate parabolic system entails high
computational costs in the numerical solution of the associated linear system. Domain
decomposition methods are a natural way to reduce computational costs, and Optimized
Schwarz Methods have proven in the recent years their effectiveness in accelerating the
convergence of such algorithms. The latter are based on interface matching conditions more
efficient than the classical Dirichlet or Neumann ones. In this paper we analyze an
Optimized Schwarz approach for the numerical solution of the Bidomain problem. We assess
the convergence of the iterative method by means of Fourier analysis, and we investigate
the parameter optimization in the interface conditions. Numerical results in 2D and 3D are
given to show the effectiveness of the method.
A multicenter survey of 11 cancer centers was performed to determine the rate of hospital-onset Clostridium difficile infection (HO-CDI) and surveillance practices. Pooled rates of HO-CDI in patients with cancer were twice the rates reported for all US patients (15.8 vs 7.4 per 10,000 patient-days). Rates were elevated regardless of diagnostic test used.
In the light of the literature describing oral language difficulties in developmental dyslexia (DD), event-related potentials were used in order to compare morphosyntactic processing in 16 adults with DD (aged 20–28 years) and unimpaired controls. Sentences including subject–verb agreement violations were presented auditorily, with grammaticality and subject number as main factors. Electrophysiological data revealed differences between groups concerning both the latency of the P600 component and the additional presence in the DD group of a negativity broadly diffused all over the scalp. Moreover, these electrophysiological anomalies increased when plural sentences were processed. On the whole, the results support the hypothesis of a linguistic deficit and of different language processing modalities in DD participants.
Higher-order models represent a computationally less expensive alternative to the Stokes model for ice-sheet modeling. In this work, we develop linear and quadratic finite-element methods, implemented on parallel architectures, for the three-dimensional first-order model of Dukowicz and others (2010) that is based on the Blatter-Pattyn model, and for the depth-integrated model of Schoof and Hindmarsh (2010). We then apply our computational models to three of the ISMIP-HOM benchmark test cases (Pattyn and others, 2008). We compare results obtained from our models with those obtained using a reliable Stokes computational model, showing that our first-order model implementation produces reliable and accurate solutions for almost all characteristic length scales of the test geometries considered. Good agreement with the reference Stokes solution is also obtained by our depth-integrated model implementation in fast-sliding regimes and for medium to large length scales. We also provide a comprehensive comparison between results obtained from our first-order model implementation and implementations developed by ISMIP-HOM participants; this study shows that our implementation is at least as good as the previous ones. Finally, a comparison between linear and quadratic finite- element approximations is carried out, showing, as expected, the better accuracy of the quadratic finite-element method.
A reliable evaluation of crop nutritional status is crucial for supporting fertilization aiming at maximizing qualitative and quantitative aspects of production and reducing the environmental impact of cropping systems. Most of the available simulation models evaluate crop nutritional status according to the nitrogen (N) dilution law, which derives critical N concentration as a function of above-ground biomass. An alternative approach, developed during a project carried out with students of the Cropping Systems Masters course at the University of Milan, was tested and compared with existing models (N dilution law and approaches implemented in EPIC and DAISY models). The new model (MAZINGA) reproduces the effect of leaf self-shading in lowering plant N concentration (PNC) through an inverse of the fraction of radiation intercepted by the canopy. The models were tested using data collected in four rice (Oryza sativa L.) experiments carried out in Northern Italy under potential and N-limited conditions. MAZINGA was the most accurate in identifying the critical N concentration, and therefore in discriminating PNC of plants growing under N-limited and non-limited conditions, respectively. In addition, the present work proved the effectiveness of crop models when used as tools for supporting education.
The Bidomain model is nowadays one of the most accurate mathematical descriptions of the action potential propagation in the heart.
However, its numerical approximation is in general fairly expensive as a consequence of the mathematical features
of this system. For this reason, a simplification of this model, called Monodomain problem is quite often
adopted in order to reduce computational costs. Reliability of this model is however questionable, in particular in
the presence of applied currents and in the regions where the upstroke or the late recovery of the action potential is occurring.
In this paper we investigate a domain decomposition approach for this problem, where the entire computational
domain is suitably split and the two models are solved in different subdomains. Since the mathematical features of the two problems are rather
different, the heterogeneous coupling is non trivial. Here we investigate appropriate interface matching conditions
for the coupling on non overlapping domains. Moreover, we pursue an Optimized Schwarz approach for the numerical solution of the heterogeneous problem. Convergence of the iterative method is analyzed by means of a Fourier analysis. We investigate the parameters to be selected in the matching radiation-type conditions to accelerate the convergence. Numerical results both in two and three dimensions illustrate the effectiveness of the coupling strategy.
To assess rubella and measles susceptibility among women of childbearing age we conducted a cross-sectional seroprevalence study in four cities and one rural area in Argentina. A convenience sample of women aged 15–49 years seeking care in public health-care institutions was selected (n=2804). Serum specimens were tested for rubella and measles IgG antibody titres. The overall susceptibility to rubella and measles was 8·8 and 12·5% respectively. Seroprevalence differences were found for both rubella (P<0·001) and measles (P=0·002) across sites. Rubella seroprevalence was higher in women aged [ges ]40 years than in younger women (P=0·04). Measles seroprevalence tended to increase with age (P<0·001). Approximately 15% of women aged 15–29 years were not immune to measles. No risk factors were associated with rubella seronegativity; however, age (P<0·001) and having less than four pregnancies (P<0·001) were factors associated with measles seronegativity. Our findings support the introduction of supplemental immunization activities targeting adolescents and young adults to prevent congenital rubella syndrome and measles outbreaks over time.
To determine the impact of stool surveillance cultures of critically ill patients on controlling vancomycin-resistant enterococci (VRE) outbreak bacteremia.
Stool surveillance cultures were performed on patients who had hematologic malignancy or were critically ill at the time of hospital admission to identify those colonized with VRE. Hence, contact isolation was initiated.
A tertiary-care cancer center with a high prevalence of VRE.
All patients with hematologic malignancy who were admitted to the hospital as well as all of those admitted to the intensive care unit were eligible.
Active stool surveillance cultures performed between 1997 and 2001 decreased the incidence density of VRE bacteremias eightfold while vancomycin use remained constant. In fiscal year (FY) 1997 and FY 1998, there were five and three VRE outbreak bacteremias, respectively. The outbreak clones were responsible for infection in 69% of those patients with VRE bacteremia. However, the stool surveillance program resulted in the complete control of VRE bacteremia by FY 1999 until the end of the study.
Despite the steady use of vancomycin, the active surveillance program among high-risk patients with hematologic malignancy and those who were critically ill resulted in the complete control of VRE outbreak bacteremia at our institution.
In silicon nanocrystal (nc) based metal-oxide-semiconductor (MOS) memory structures a fine control of the Si nc location in the gate oxide is required for the pinpointing of optimal device architectures. In this work, we show how to manipulate and control the depth-position, size and surface density of two dimensional (2D) arrays of Si ncs embedded in thin (<10 nm) SiO2 layers, fabricated by ultra-low-energy (typically 1 keV) ion implantation and subsequent annealing. Particular emphasis is placed upon the influence of implantation, annealing conditions and oxide thickness on the nanocrystal characteristics (e.g. size, density) and the charge storage properties of associated MOS structures. Structural investigation is performed by using specific characterization methods including Fresnel imaging for the measurement of the injection distance between the substrate and the nc band, as well as spatially resolved Electron Energy Loss Spectroscopy using the spectrum-imaging mode of a Scanning Transmission Electron Microscope to evaluate the size distribution and density of the ncs.
In this retrospective evaluation of the 4-year clinical use of minocycline and rifampin-impregnated catheters in bone marrow transplantation (BMT) patients, we report low risk of development of staphylococcal resistance to the antibiotics coating the catheters and efficacy in preventing primary staphylococcal bloodstream infections.
Ligand binding is an essential step in many biological and biochemical processes, notably protein activation. In many cases, the binding rates are determined by competition: blockers competing with ligands or decoys competing with receptors. Often, the diffusivities of the various species also play a key role. The usual modelling of these processes, however, either involves well-mixed systems, for which spatial variations are neglected, or steady-state situations for which all time evolution has ceased. The model presented here can instead account for the spatial variations that originate as a consequence of inhomogeneous initial conditions and localized binding sites. It describes their evolution in time due to a combination of mechanisms of diffusion, competition and reaction. The model, which is formulated in terms of a coupled system of equations for the probability densities of the various populations, is easy to adapt to different specific conditions and is particularly well suited for numerical calculations, e.g., on a parallel computer. Since it yields concrete predictions, it can be readily used to predict the concentrations and distributions of the various species that are needed to obtain prescribed responses.
The chorion is the acellular envelope surrounding mature eggs of teleostean fish. The macromolecular composition of the zebrafish (Danio rerio) egg chorion, organised as a three-layered structure, has been analysed. SDS-PAGE analysis, under reducing conditions, of isolated and purified chorions revealed a reproducible pattern of four major polypeptides (116, 97, 50 and 43kDa) and several minor bands. Lectin binding assays showed that both the 116 kDa and 50kDa proteins were recognised by concanavalin agglutinin (Con A), Galanthus nivalis agglutinin (GNA), Sambucus nigra bark agglutinin (SNA) and Ricinus communis agglutinin (RCA 120), suggesting that these polypeptides are N-linked glycoproteins. By contrast, neither the 97 kDa nor the 43 kDa polypeptides were stained by these lectins, indicating that these polypeptides are not glycosylated. Amino acid analysis also showed significant differences in the average content of some amino acids, for example serine and proline, when compared with previous reports.
Structural studies have been carried out on SnO2 multilayer thin film grown by the Rheotaxial Growth and Thermal Oxidation method on A120 3 substrates. A preliminary analysis of the X-ray diffraction patterns shows that, in addition to the Sn0 2 cassiterite phase, a strong contribution from an orthorhombic Sn02 phase is present.
In the case of the 3-layer film, the orthorhombic phase is structurally and microstructurally stable after an annealing up to 32 h at 400 'C. The cation coordination is similar to that found in cassiterite, but the chains of edge-sharing [SnO6]8- octahedra run in a zig-zag fashion along the  direction, each straight unit containing four octahedra. The relationship between the two phases is discussed on the basis of structural simulations including twinning planes in the crystal structure.