Diego Miralles

1. Am J Med. 1992 Sep;93(3):352-3. Not everything that glitters is Lyme disease. Miralles D, Hartman B, Brause B, Fisher L, Murray HW. Cornell University Medical College, New York, New York. PMID: 1524093 [PubMed - indexed for MEDLINE]. Publication Types: ...

In the TORO, RESIST and POWER trials, the HIV-RNA < 50 copy endpoint showed the strongest durability over time, whereas HIV-RNA reductions of more than 1 log10 or below 400 copies/ml were less sustained during 48 weeks of treatment. Clinical trials of new antiretroviral drugs in highly experienced patients also show high rates of HIV-RNA suppression below 50 copies/ml. HIV-RNA suppression below 50 copies/ml should now become the standard efficacy endpoint across trials of both naive and experienced patients.

Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent. To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus. HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28. Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113 cells/microl (range, 41-268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor. This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions.

Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC(50) of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily [DOSAGE ERROR CORRECTED] were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.

A process-based methodology is applied to estimate land-surface evaporation from multi-satellite information. GLEAM (Global Land-surface Evaporation: the Amsterdam Methodology) combines a wide range of remotely-sensed observations to derive daily actual evaporation and its different components. Soil water stress conditions are defined from a root-zone profile of soil moisture and used to estimate transpiration based on a Priestley and Taylor equation. The methodology also derives evaporationfrom bare soil and snow sublimation. Tall vegetation rainfall interception is independently estimated by means of the Gash analytical model. Here, GLEAM is applied daily, at global scale and a quarter degree resolution. Triple collocation is used to calculate the error structure of the evaporation estimates and test the relative merits of two different precipitation inputs. The spatial distribution of evaporation - and its different components - is analysed to understand the relative importance of each component over different ecosystems. Annual land evaporation is estimated as 67.9 × 103 km3, 80% corresponding to transpiration, 11% to interception loss, 7% to bare soil evaporation and 2% snow sublimation. Results show that rainfall interception plays an important role in the partition of precipitation into evaporation and water available for runoff at a continental scale. This study gives insights into the relative importance of precipitation and net radiation in driving evaporation, and how the seasonal influence of these controls varies over different regions. Precipitation is recognised as an important factor driving evaporation, not only in areas that have limited soil water availability, but also in areas of high rainfall interception and low available energy.

A new methodology for estimating forest rainfall interception from multisatellite observations is presented. The Climate Prediction Center morphing technique (CMORPH) precipitation product is used as driving data and is applied to Gash's analytical model to derive daily interception rates at global scale. Results compare well with field observations of rainfall interception (R = 0.86, n = 42). Global estimates are presented and spatial differences in the distribution of interception over different ecosystems analyzed. According to our findings, interception loss is responsible for the evaporation of approximately 13% of the total incoming rainfall over broadleaf evergreen forests, 19% in broadleaf deciduous forests, and 22% in needleleaf forests. The product is sensitive to the volume of rainfall, rain intensity, and forest cover. In combination with separate estimates of transpiration it offers the potential to study the impact of climate change and deforestation on the dynamics of the global hydrological cycle.

This paper outlines a new strategy to derive evaporation from satellite observations. The approach uses a variety of satellite-sensor products to estimate daily evaporation at a global scale and 0.25 degree spatial resolution. Central to this methodology is the use of the Priestley and Taylor (PT) evaporation model. The minimalistic PT equation combines a small number of inputs, the majority of which can be detected from space. This reduces the number of variables that need to be modelled. Key distinguishing features of the approach are the use of microwave-derived soil moisture, land surface temperature and vegetation density, as well as the detailed estimation of rainfall interception loss. The modelled evaporation is validated against one year of eddy covariance measurements from 43 stations. The estimated annual totals correlate well with the stations' annual cumulative evaporation (R=0.80, N=43) and present a low average bias (-5%). The validation of the daily time series at each individual station shows good model performance in all vegetation types and climate conditions with an average correlation coefficient of <span style="text-decoration: overline">R</span>=0.83, still lower than the <span style="text-decoration: overline">R</span>=0.90 found in the validation of the monthly time series. The first global map of annual evaporation developed through this methodology is also presented.

A new methodology for estimating forest rainfall interception from multisatellite observations is presented. The Climate Prediction Center morphing technique (CMORPH) precipitation product is used as driving data and is applied to Gash&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s analytical model to derive daily interception rates at global scale. Results compare well with field observations of rainfall interception (R = 0.86, n = 42). Global estimates are

A new methodology for estimating forest rainfall interception from multisatellite observations is presented. The Climate Prediction Center morphing technique (CMORPH) precipitation product is used as driving data and is applied to Gash&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s analytical model to derive daily interception rates at global scale. Results compare well with field observations of rainfall interception (R = 0.86, n = 42). Global estimates are

This paper outlines a new methodology to derive evaporation from satellite observations. The approach uses a variety of satellite-sensor products to estimate daily evaporation at a global scale, with a 0.25 degree spatial resolution. Central to this approach is the use of the Priestley and Taylor (PT) evaporation model. Because the PT equation is driven by net radiation, this strategy avoids the need to specify surface fields of variables, such as the surface conductance, which cannot be detected directly from space. Key distinguishing features are the use of microwave-derived soil moisture, land surface temperature and vegetation density, as well as the use of a detailed rainfall interception module. The modelled evaporation is validated against one year of eddy covariance measurements from 43 stations. The estimated annual totals correlate well with the stations' annual cumulative evaporation (R = 0.84, N = 43) and show a negligible bias (-1.5%). The validation of the daily time series at each individual station shows good model performance in all vegetation types and climate conditions with an average correlation coefficient of <span style="border-top: 1px solid #000; color: #000;">R</span> = 0.84, still lower than the <span style="border-top: 1px solid #000; color: #000;">R</span> = 0.91 found in the validation of the monthly time series. The first global map of annual evaporation developed through this methodology is also presented.