Novel Insights in the faecal egg count reduction test for monitoring drug efficacy against gastrointestinal nematodes of veterinary importance

The faecal egg count reduction test (FECRT) is the method of choice to monitor anthelmintic efficacy against gastro-intestinal nematodes in livestock. Guidelines on how to conduct a FECRT are made available by the World Association for the Advancement of Veterinary Parasitology (WAAVP). Since the publication of these guidelines in the early 1990s, some limitations have been noted, including (i) the ignorance of host-parasite interactions that depend on animal and parasite species, (ii) their feasibility under field conditions, (iii) appropriateness of study design, and (iv) the low analytic sensitivity of the recommended faecal egg count (FEC) method. Therefore, the objective of the present study was to empirically assess the impact of the level of excretion and aggregation of FEC, sample size and detection limit of the FEC method on the sensitivity and specificity of the FECRT to detect reduced efficacy (<90% or <95%) and to develop recommendations for surveys on anthelmintic resistance. A simulation study was performed in which the FECRT (based on the arithmetic mean of grouped FEC of the same animals before and after drug administration) was conducted under varying conditions of mean FEC, aggregation of FEC (inversely correlated with k), sample size, detection limit and ‘true’ drug efficacies. Classification trees were built to explore the impact of the above factors on the sensitivity and specificity of detecting a truly reduced efficacy. For a reduced-efficacy threshold of 90%, most combinations resulted in a reliable detection of reduced and normal efficacy. For the reduced-efficacy threshold of 95% however, unreliable FECRT results were found when sample sizes <15 were combined with highly aggregated FEC (k = 0.25) and detection limits ≥5 EPG or when combined with detection limits ≥15 EPG. Overall, an increase in sample size and mean preDA FEC, and a decrease in detection limit improved the diagnostic accuracy. FECRT remained inconclusive under any evaluated condition for drug efficacies ranging from 87.5% to 92.5% for a reduced-efficacy-threshold of 90% and from 92.5% to 97.5% for a threshold of 95%. The results highlight that (i) the interpretation of this FECRT is affected by a complex interplay of factors, including the level of excretion and aggregation of FEC and (ii) the diagnostic value of FECRT to detect small reductions in efficacy is limited. This study, therefore, provides a framework allowing researchers to adapt their study design according to a wide range of field conditions, while ensuring a good diagnostic performance of the FECRT

Images, structural properties and metal abundances of galaxy clusters observed with Chandra ACIS-I at 0.1<z<1.3

We have assembled a sample of 115 galaxy clusters at 0.1<z<1.3 with archived Chandra ACIS-I observations. We present X-ray images of the clusters and make available region files containing contours of the smoothed X-ray emission. The structural properties of the clusters were investigated and we found a significant absence of relaxed clusters (as determined by centroid shift measurements) at z>0.5. The slope of the surface brightness profiles at large radii were steeper on average by 15% than the slope obtained by fitting a simple beta-model to the emission. This slope was also found to be correlated with cluster temperature, with some indication that the correlation is weaker for the clusters at z>0.5. We measured the mean metal abundance of the cluster gas as a function of redshift and found significant evolution, with the abundances dropping by 50% between z=0.1 and z~1. This evolution was still present (although less significant) when the cluster cores were excluded from the abundance measurements, indicating that the evolution is not solely due to the disappearance of relaxed, cool core clusters (which are known to have enhanced core metal abundances) from the population at z>0.5.Comment: 23 pages, 12 figures. Accepted for publication in ApJS. Updated to match published version. Redshifts of two clusters (RXJ1701 and CL0848) corrected and two observations of MACSJ0744.8 have been combined into one. Conclusions unchanged. A version with images of all of the clusters is available at http://hea-www.harvard.edu/~bmaughan/clusters.htm

Foot-and-mouth disease in Tanzania from 2001 to 2006.

Foot-and-mouth disease (FMD) is endemic in Tanzania, with outbreaks occurring almost each year in different parts of the country. There is now a strong political desire to control animal diseases as part of national poverty alleviation strategies. However, FMD control requires improving the current knowledge on the disease dynamics and factors related to FMD occurrence so control measures can be implemented more efficiently. The objectives of this study were to describe the FMD dynamics in Tanzania from 2001 to 2006 and investigate the spatiotemporal patterns of transmission. Extraction maps, the space-time K-function and space-time permutation models based on scan statistics were calculated for each year to evaluate the spatial distribution, the spatiotemporal interaction and the spatiotemporal clustering of FMD-affected villages. From 2001 to 2006, 878 FMD outbreaks were reported in 605 different villages of 5815 populated places included in the database. The spatial distribution of FMD outbreaks was concentrated along the Tanzania-Kenya, Tanzania-Zambia borders, and the Kagera basin bordering Uganda, Rwanda and Tanzania. The spatiotemporal interaction among FMD-affected villages was statistically significant (P≤0.01) and 12 local spatiotemporal clusters were detected; however, the extent and intensity varied across the study period. Dividing the country in zones according to their epidemiological status will allow improving the control of FMD and delimiting potential FMD-free areas

Efficient construction of free energy profiles of breathing metal–organic frameworks using advanced molecular dynamics simulations

In order to reliably predict and understand the breathing behavior of highly flexible metal–organic frameworks from thermodynamic considerations, an accurate estimation of the free energy difference between their different metastable states is a prerequisite. Herein, a variety of free energy estimation methods are thoroughly tested for their ability to construct the free energy profile as a function of the unit cell volume of MIL-53(Al). The methods comprise free energy perturbation, thermodynamic integration, umbrella sampling, metadynamics, and variationally enhanced sampling. A series of molecular dynamics simulations have been performed in the frame of each of the five methods to describe structural transformations in flexible materials with the volume as the collective variable, which offers a unique opportunity to assess their computational efficiency. Subsequently, the most efficient method, umbrella sampling, is used to construct an accurate free energy profile at different temperatures for MIL-53(Al) from first principles at the PBE+D3(BJ) level of theory. This study yields insight into the importance of the different aspects such as entropy contributions and anharmonic contributions on the resulting free energy profile. As such, this thorough study provides unparalleled insight in the thermodynamics of the large structural deformations of flexible materials

Minimal Basis Iterative Stockholder: Atoms in Molecules for Force-Field Development

Atomic partial charges appear in the Coulomb term of many force-field models and can be derived from electronic structure calculations with a myriad of atoms-in-molecules (AIM) methods. More advanced models have also been proposed, using the distributed nature of the electron cloud and atomic multipoles. In this work, an electrostatic force field is defined through a concise approximation of the electron density, for which the Coulomb interaction is trivially evaluated. This approximate "pro-density" is expanded in a minimal basis of atom-centered s-type Slater density functions, whose parameters are optimized by minimizing the Kullback-Leibler divergence of the pro-density from a reference electron density, e.g. obtained from an electronic structure calculation. The proposed method, Minimal Basis Iterative Stockholder (MBIS), is a variant of the Hirshfeld AIM method but it can also be used as a density-fitting technique. An iterative algorithm to refine the pro-density is easily implemented with a linear-scaling computational cost, enabling applications to supramolecular systems. The benefits of the MBIS method are demonstrated with systematic applications to molecular databases and extended models of condensed phases. A comparison to 14 other AIM methods shows its effectiveness when modeling electrostatic interactions. MBIS is also suitable for rescaling atomic polarizabilities in the Tkatchenko-Sheffler scheme for dispersion interactions.Comment: 61 pages, 12 figures, 2 table

Novel Insights in the Fecal Egg Count Reduction Test for Monitoring Drug Efficacy against Soil-Transmitted Helminths in Large-Scale Treatment Programs

The reduction in number of eggs excreted in stools after drug administration is a primary parameter to monitor the efficacy of drugs against parasitic worms. Guidelines on how to perform such a fecal egg count reduction test (FECRT) are provided by the World Health Organization. However, it remains unclear to which extent these guidelines are cost-effective. We, therefore, performed a simulation study in which the FECRT was performed under varying conditions to determine the critical values for sample size, the detection limit of the fecal egg count (FEC) method, mean baseline FEC, and variation of FEC across host population that allow for conclusive FECRT results. The results revealed that a reliable monitoring system demands a sample size of 200 subjects and that in some cases FECRT results may be thwarted by low mean baseline FEC. For this sample size, the detection of the FEC method or the variation of FEC across the host population did not affect the FECRT results. Our findings underscore that the current guidelines are not cost-effective, demanding too much financial and technical resources. We, therefore, propose novel guidelines to support future monitoring programs