Minimum target prices for production of direct acting antivirals and associated diagnostics to combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182

Space Motions of the Dwarf Spheroidal Galaxies Draco and Sculptor based on HST Proper Motions with ~10-year Time Baseline

We present new proper motion (PM) measurements of the dwarf spheroidal galaxies (dSphs) Draco and Sculptor using multi-epoch images obtained with the Hubble Space Telescope ACS/WFC. Our PM results have uncertainties far lower than previous measurements, even made with the same instrument. The PM results for Draco and Sculptor are (mu_W,mu_N)_Dra = (-0.0562+/-0.0099,-0.1765+/-0.0100) mas/yr and (mu_W,mu_N)_Scl = (-0.0296+/-0.0209,-0.1358 +/-0.0214) mas/yr. The implied Galactocentric velocity vectors for Draco and Sculptor have radial and tangential components: (V_rad,V_tan)_Dra = (-88.6,161.4) +/- (4.4,5.6) km/s; and (V_rad,V_tan)_Scl = (72.6,200.2) +/- (1.3,10.8) km/s. We study the detailed orbital history of both Draco and Sculptor via numerical orbit integrations. Orbital periods of Draco and Sculptor are found to be 1-2 and 2-5 Gyrs, respectively, accounting for uncertainties in the MW mass. We also study the influence of the Large Magellanic Cloud (LMC) on the orbits of Draco and Sculptor. Overall, the inclusion of the LMC increases the scatter in the orbital results. Based on our calculations, Draco shows a rather wide range of orbital parameters depending on the MW mass and inclusion/exclusion of the LMC, but Sculptor's orbit is very well constrained with its most recent pericentric approach to the MW being 0.3-0.4 Gyr ago. Our new PMs imply that the orbital trajectories of both Draco and Sculptor are confined within the Disk of Satellites (DoS), better so than implied by earlier PM measurements, and likely rule out the possibility that these two galaxies were accreted together as part of a tightly bound group.Comment: 17 pages, 8 figures, 6 tables. Accepted for publication in Ap

Coral reef potential connectivity in the southwest Indian Ocean

The tropical southwest Indian Ocean is a coral biodiversity hotspot, with remote reefs physically connected by larval dispersal through eddies and a complex set of equatorial and boundary currents. Based on multidecadal, 2 km resolution hydrodynamic and larval dispersal models that incorporate temporal variability in dispersal, we find that powerful zonal currents, current bifurcations, and geographic isolation act as leaky dispersal barriers, partitioning the southwest Indian Ocean into clusters of reefs that tend to consistently retain larvae, and therefore gene flow, over many generations. Whilst exceptionally remote, the Chagos Archipelago can broadcast (and receive) considerable numbers of larvae to (and from) reefs across the wider southwest Indian Ocean, most significantly exchanging larvae with the Inner Islands of Seychelles, but also the Mozambique Channel region. Considering multi-generational dispersal indicates that most coral populations in the southwest Indian Ocean are physically connected within a few hundred steps of dispersal. These results suggest that regional biogeography and population structure can be largely attributed to geologically recent patterns of larval dispersal, although some notable discrepancies indicate that palaeogeography and environmental suitability also play an important role. The model output and connectivity matrices are available in full and will provide useful physical context to regional biogeography and connectivity studies, as well as supporting marine spatial planning efforts