Modeling HIV/AIDS Drug Price Determinants in Brazil: Is Generic Competition a Myth?

Brazil became the first developing country to guarantee free and universal access to HIV/AIDS treatment, with antiretroviral drugs (ARVs) being delivered to nearly 190,000 patients. The analysis of ARV price evolution and market dynamics in Brazil can help anticipate issues soon to afflict other developing countries, as the 2010 revision of the World Health Organization guidelines shifts demand towards more expensive treatments, and, at the same time, current evolution of international legislation and trade agreements on intellectual property rights may reduce availability of generic drugs for HIV care.Our analyses are based on effective prices paid for ARV procurement in Brazil between 1996 and 2009. Data panel structure was exploited to gather ex-ante and ex-post information and address various sources of statistical bias. In-difference estimation offered in-depth information on ARV market characteristics which significantly influence prices. Although overall ARV prices follow a declining trend, changing characteristics in the generic segment help explain recent increase in generic ARV prices. Our results show that generic suppliers are more likely to respond to factors influencing demand size and market competition, while originator suppliers tend to set prices strategically to offset compulsory licensing threats and generic competition.In order to guarantee the long term sustainability of access to antiretroviral treatment, our findings highlight the importance of preserving and stimulating generic market dynamics to sustain developing countries' bargaining power in price negotiations undertaken with originator companies

Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkins disease

BACKGROUND: Faced with unsatisfactory results of treatment for advanced Hodgkin's disease, we investigated three combinations of chemotherapy. METHODS: From 1993 to 1998, 1201 eligible patients 15 to 65 years of age who had newly diagnosed Hodgkin's disease in unfavorable stage IIB or IIIA or stage IIIB or IV were randomly assigned to receive eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); or increased-dose BEACOPP, each followed by local radiotherapy when indicated. Enrollment in the COPP-ABVD group was stopped in 1996 owing to inferior results. RESULTS: For the final analysis, 1195 of 1201 patients could be evaluated: 260 in the COPP-ABVD group, 469 in the BEACOPP group, and 466 in the increased-dose BEACOPP group; the median follow-up was 72, 54, and 51 months, respectively. The rate of freedom from treatment failure at five years was 69 percent in the COPP-ABVD group, 76 percent in the BEACOPP group, and 87 percent in the increased-dose BEACOPP group (P=0.04 for the comparison of the COPP-ABVD group with the BEACOPP group and P<0.001 for the comparison of the increased-dose BEACOPP group with the COPP-ABVD group and with the BEACOPP group), and the five-year rates of overall survival were 83 percent, 88 percent, and 91 percent, respectively (P=0.16 for the comparison of the COPP-ABVD group with the BEACOPP group, P=0.06 for the comparison of the BEACOPP group with the increased-dose BEACOPP group, and P=0.002 for the comparison of the COPP-ABVD group with the increased-dose BEACOPP group). Rates of early progression were significantly lower with increased-dose BEACOPP than with COPP-ABVD or standard BEACOPP. CONCLUSIONS: Increased-dose BEACOPP resulted in better tumor control and overall survival than did COPP-ABVD

Impact of permeability evolution in igneous sills on hydrothermal flow and hydrocarbon transport in volcanic sedimentary basins

Sills emplaced in organic-rich sedimentary rocks trigger the generation and migration of hydrocarbons in volcanic sedimentary basins. Based on seismic and geological observations, numerical modeling studies of hydrothermal flow around sills show that thermogenic methane is channeled below the intrusion towards its tip, where hydrothermal vents nucleate and transport methane to the surface. However, these models typically assume impermeable sills and ignore potential effects of permeability evolution in cooling sills, e.g., due to fracturing. Here, we combine a geological field study of a volcanic basin (Neuquén Basin, Argentina) with a hybrid finite-element–finite-volume method (FEM–FVM) of numerical modeling of hydrothermal flow around a sill, including hydrocarbon generation and transport. Our field observations show widespread veins within sills composed of graphitized bitumen and cooling joints filled with solid bitumen or fluidized shale. Raman spectroscopy indicates graphitization at temperatures between 350 and 500 ∘C, suggesting fluid flow within the intrusions during cooling. This finding motivates our modeling setup, which investigates flow patterns around and through intrusions that become porous and permeable upon solidification. The results show three flow phases affecting the transport of hydrocarbons generated in the contact aureole: (1) contact-parallel flow toward the sill tip prior to solidification, (2) upon complete solidification, sudden vertical “flushing” of overpressured hydrocarbon-rich fluids from the lower contact aureole towards and into the hot sill along its entire length, and (3) stabilization of hydrocarbon distribution and fading hydrothermal flow. In low-permeability host rocks, hydraulic fracturing facilitates flow and hydrocarbon migration toward the sill by temporarily elevating porosity and permeability. Up to 7.5 % of the generated methane is exposed to temperatures &gt;400 ∘C in the simulations and may thus be permanently stored as graphite in or near the sill. Porosity and permeability creation within cooling sills may impact hydrothermal flow, hydrocarbon transport, and venting in volcanic basins, as it considerably alters the fluid pressure configuration, provides vertical flow paths, and helps to dissipate overpressure below the sills.</p

Finite temperature density matrix and two-point correlations in the antiferromagnetic XXZ chain

We derive finite temperature versions of integral formulae for the two-point correlation functions in the antiferromagnetic XXZ chain. The derivation is based on the summation of density matrix elements characterizing a finite chain segment of length $m$. On this occasion we also supply a proof of the basic integral formula for the density matrix presented in an earlier publication.Comment: 35 page

Distinct degassing pulses during magma invasion in the stratified Karoo Basin – New insights from hydrothermal fluid flow modelling

Magma emplacement in organic‐rich sedimentary basins is a main driver of past environmental crises. Using a 2D numerical model, we investigate the process of thermal cracking in contact aureoles of cooling sills and subsequent transport and emission of thermogenic methane by hydrothermal fluids. Our model includes a Mohr‐Coulomb failure criterion to initiate hydrofracturing and a dynamic porosity/permeability. We investigate the Karoo Basin, taking into account host‐rock material properties from borehole data, realistic total organic carbon content, and different sill geometries. Consistent with geological observations, we find that thermal plumes quickly rise at the edges of saucer‐shaped sills, guided along vertically fractured high permeability pathways. Contrastingly, less focused and slower plumes rise from the edges and the central part of flat‐lying sills. Using a novel upscaling method based on sill‐to‐sediment ratio we find that degassing of the Karoo Basin occurred in two distinct phases during magma invasion. Rapid degassing triggered by sills emplaced within the top 1.5 km emitted ~1.6·103 Gt of thermogenic methane, while thermal plumes originating from deeper sills, carrying a 12‐times greater mass of methane, may not reach the surface. We suggest that these large quantities of methane could be re‐mobilized by the heat provided by neighboring sills. We conclude that the Karoo LIP may have emitted as much as ~22.3·103 Gt of thermogenic methane in the half million years of magmatic activity, with emissions up to 3 Gt/year. This quantity of methane and the emission rates can explain the negative δ13C excursion of the Toarcian environmental crisis. Key Points Sill geometry and emplacement depth as well as intruded host rock type are the main factors controlling methane mobilization and degassing Dehydration‐related porosity increase and pore‐pressure‐induced hydrofracturing are important mechanisms for a quick transport of methane from sill to the surface The Karoo Basin may have degassed ~22.3·103 Gt of thermogenic methane in the half million years of magmatic activit