Variation in target attainment of β-lactam antibiotic dosing between international pediatric formularies

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. β-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dose recommendations from the major paediatric reference sources and tries to answer the question: does β-lactam dose heterogeneity matter? Does it impact on pharmacodynamic (PD) target attainment? For three important severe clinical infections - pneumonia, sepsis and meningitis - pharmacokinetic (PK) models were identified for common β-lactam antibiotics. Real-world demographics were derived from three multi-center point prevalence surveys. Simulation results were compared with minimum inhibitory concentration (MIC) distributions, to inform appropriateness of recommended doses in targeted and empiric treatment. Whilst cephalosporin dose regimens are largely adequate for target attainment, they also pose most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin and meropenem doses as potentially requiring review/optimisation in order to preserve the use of these agents in future

Prompt interval temporal logic

Interval temporal logics are expressive formalisms for temporal representation and reasoning, which use time intervals as primitive temporal entities. They have been extensively studied for the past two decades and successfully applied in AI and computer science. Unfortunately, they lack the ability of expressing promptness conditions, as it happens with the commonly-used temporal logics, e.g., LTL: whenever we deal with a liveness request, such as \u201csomething good eventually happens\u201d, there is no way to impose a bound on the delay with which it is fulfilled. In the last years, such an issue has been addressed in automata theory, game theory, and temporal logic. In this paper, we approach it in the interval temporal logic setting. First, we introduce PROMPT-PNL, a prompt extension of the well-studied interval temporal logic PNL, and we prove the undecidability of its satisfiability problem; then, we show how to recover decidability (NEXPTIME-completeness) by imposing a natural syntactic restriction on it

Compact High-Velocity Clouds at High Resolution

Six examples of the compact, isolated high-velocity clouds catalogued by Braun & Burton (1999) and identified with a dynamically cold ensemble of primitive objects falling towards the barycenter of the Local Group have been imaged with the Westerbork Synthesis Radio Telescope; an additional ten have been imaged with the Arecibo telescope. The imaging reveals a characteristic core/halo morphology: one or several cores of cool, relatively high-column-density material, are embedded in an extended halo of warmer, lower-density material. Several of the cores show kinematic gradients consistent with rotation; these CHVCs are evidently rotationally supported and dark-matter dominated. The imaging data allows several independent estimates of the distances to these objects, which lie in the range 0.3 to 1.0 Mpc. The CHVC properties resemble what might be expected from very dark dwarf irregular galaxies.Comment: 12 pages, 7 figures, to appear in "The Chemical Evolution of the Milky Way: Stars versus Clusters", eds. F. Matteuchi and F. Giovannelli, Kluwer Academic Publisher

Resource dedication problem in a multi-project environment

There can be different approaches to the management of resources within the context of multi-project scheduling problems. In general, approaches to multiproject scheduling problems consider the resources as a pool shared by all projects. On the other hand, when projects are distributed geographically or sharing resources between projects is not preferred, then this resource sharing policy may not be feasible. In such cases, the resources must be dedicated to individual projects throughout the project durations. This multi-project problem environment is defined here as the resource dedication problem (RDP). RDP is defined as the optimal dedication of resource capacities to different projects within the overall limits of the resources and with the objective of minimizing a predetermined objective function. The projects involved are multi-mode resource constrained project scheduling problems with finish to start zero time lag and non-preemptive activities and limited renewable and nonrenewable resources. Here, the characterization of RDP, its mathematical formulation and two different solution methodologies are presented. The first solution approach is a genetic algorithm employing a new improvement move called combinatorial auction for RDP, which is based on preferences of projects for resources. Two different methods for calculating the projects’ preferences based on linear and Lagrangian relaxation are proposed. The second solution approach is a Lagrangian relaxation based heuristic employing subgradient optimization. Numerical studies demonstrate that the proposed approaches are powerful methods for solving this problem

Inside-Out Evacuation of Transitional Protoplanetary Disks by the Magneto-Rotational Instability

How do T Tauri disks accrete? The magneto-rotational instability (MRI) supplies one means, but protoplanetary disk gas is typically too poorly ionized to be magnetically active. Here we show that the MRI can, in fact, explain observed accretion rates for the sub-class of T Tauri disks known as transitional systems. Transitional disks are swept clean of dust inside rim radii of ~10 AU. Stellar coronal X-rays ionize material in the disk rim, activating the MRI there. Gas flows from the rim to the star, at a rate limited by the depth to which X-rays ionize the rim wall. The wider the rim, the larger the surface area that the rim wall exposes to X-rays, and the greater the accretion rate. Interior to the rim, the MRI continues to transport gas; the MRI is sustained even at the disk midplane by super-keV X-rays that Compton scatter down from the disk surface. Accretion is therefore steady inside the rim. Blown out by radiation pressure, dust largely fails to accrete with gas. Contrary to what is usually assumed, ambipolar diffusion, not Ohmic dissipation, limits how much gas is MRI-active. We infer values for the transport parameter alpha on the order of 0.01 for GM Aur, TW Hyd, and DM Tau. Because the MRI can only afflict a finite radial column of gas at the rim, disk properties inside the rim are insensitive to those outside. Thus our picture provides one robust setting for planet-disk interaction: a protoplanet interior to the rim will interact with gas whose density, temperature, and transport properties are definite and decoupled from uncertain initial conditions. Our study also supplies half the answer to how disks dissipate: the inner disk drains from the inside out by the MRI, while the outer disk photoevaporates by stellar ultraviolet radiation.Comment: Accepted to Nature Physics June 7, 2007. The manuscript for publication is embargoed per Nature policy. This arxiv.org version contains more technical details and discussion, and is distributed with permission from the editors. 10 pages, 4 figure

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Interval temporal logic model checking: The border between good and bad HS fragments

The model checking problem has thoroughly been explored in the context of standard point-based temporal logics, such as LTL, CTL, and CTL 17, whereas model checking for interval temporal logics has been brought to the attention only very recently. In this paper, we prove that the model checking problem for the logic of Allen\u2019s relations started-by and finished-by is highly intractable, as it can be proved to be EXPSPACE-hard. Such a lower bound immediately propagates to the full Halpern and Shoham\u2019s modal logic of time intervals (HS). In contrast, we show that other noteworthy HS fragments, namely, Propositional Neighbourhood Logic extended with modalities for the Allen relation starts (resp., finishes) and its inverse started-by (resp., finished-by), turn out to have\u2014maybe unexpectedly\u2014the same complexity as LTL (i.e., they are PSPACE-complete), thus joining the group of other already studied, well-behaved albeit less expressive, HS fragments

Impacts of organic and conventional crop management on diversity and activity of free-living nitrogen fixing bacteria and total bacteria are subsidiary to temporal effects

A three year field study (2007-2009) of the diversity and numbers of the total and metabolically active free-living diazotophic bacteria and total bacterial communities in organic and conventionally managed agricultural soil was conducted at the Nafferton Factorial Systems Comparison (NFSC) study, in northeast England. The result demonstrated that there was no consistent effect of either organic or conventional soil management across the three years on the diversity or quantity of either diazotrophic or total bacterial communities. However, ordination analyses carried out on data from each individual year showed that factors associated with the different fertility management measures including availability of nitrogen species, organic carbon and pH, did exert significant effects on the structure of both diazotrophic and total bacterial communities. It appeared that the dominant drivers of qualitative and quantitative changes in both communities were annual and seasonal effects. Moreover, regression analyses showed activity of both communities was significantly affected by soil temperature and climatic conditions. The diazotrophic community showed no significant change in diversity across the three years, however, the total bacterial community significantly increased in diversity year on year. Diversity was always greatest during March for both diazotrophic and total bacterial communities. Quantitative analyses using qPCR of each community indicated that metabolically active diazotrophs were highest in year 1 but the population significantly declined in year 2 before recovering somewhat in the final year. The total bacterial population in contrast increased significantly each year. Seasonal effects were less consistent in this quantitative study