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

Evidence and clinical relevance of maternal-fetal cardiac coupling:A scoping review

BACKGROUND: Researchers have long suspected a mutual interaction between maternal and fetal heart rhythms, referred to as maternal-fetal cardiac coupling (MFCC). While several studies have been published on this phenomenon, they vary in terms of methodologies, populations assessed, and definitions of coupling. Moreover, a clear discussion of the potential clinical implications is often lacking. Subsequently, we perform a scoping review to map the current state of the research in this field and, by doing so, form a foundation for future clinically oriented research on this topic.METHODS: A literature search was performed in PubMed, Embase, and Cochrane. Filters were only set for language (English, Dutch, and German literature were included) and not for year of publication. After screening for the title and the abstract, a full-text evaluation of eligibility followed. All studies on MFCC were included which described coupling between heart rate measurements in both the mother and fetus, regardless of the coupling method used, gestational age, or the maternal or fetal health condition.RESULTS: 23 studies remained after a systematic evaluation of 6,672 studies. Of these, 21 studies found at least occasional instances of MFCC. Methods used to capture MFCC are synchrograms and corresponding phase coherence indices, cross-correlation, joint symbolic dynamics, transfer entropy, bivariate phase rectified signal averaging, and deep coherence. Physiological pathways regulating MFCC are suggested to exist either via the autonomic nervous system or due to the vibroacoustic effect, though neither of these suggested pathways has been verified. The strength and direction of MFCC are found to change with gestational age and with the rate of maternal breathing, while also being further altered in fetuses with cardiac abnormalities and during labor.CONCLUSION: From the synthesis of the available literature on MFCC presented in this scoping review, it seems evident that MFCC does indeed exist and may have clinical relevance in tracking fetal well-being and development during pregnancy.</p