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Energy and technology review
The state of the laboratory address by LLNL Director Roger Batzel is summarized, and a breakdown of the laboratory funding is given. The Livermore defense-related committment is described, including the design and development of advanced nuclear weapons as well as research in inertial confinement fusion, nonnuclear ordnance, and particle beam technology. LLNL is also applying its scientific and engineering resources to the dual challenge of meeting future energy needs without degrading the quality of the biosphere. Some representative examples are given of the supporting groups vital for providing the specialized expertise and new technologies required by the laboratory's major research programs. (GHT
Antiviral Resistance and Correlates of Virologic Failure in the first Cohort of HIV-Infected Children Gaining Access to Structured Antiretroviral Therapy in Lima, Peru: A Cross-Sectional Analysis
Background: The impact of extended use of ART in developing countries has been enormous. A thorough
understanding of all factors contributing to the success of antiretroviral therapy is required. The current study aims to
investigate the value of cross-sectional drug resistance monitoring using DNA and RNA oligonucleotide ligation assays
(OLA) in treatment cohorts in low-resource settings. The study was conducted in the first cohort of children gaining
access to structured ART in Peru.
Methods: Between 2002–5, 46 eligible children started the standard regimen of AZT, 3TC and NFV Patients had a
median age of 5.6 years (range: 0.7-14y), a median viral load of 1.7·105 RNA/ml (range: 2.1·103 – 1.2·106), and a median
CD4-count of 232 cells/μL (range: 1–1591). Of these, 20 patients were classified as CDC clinical category C and 31/46 as
CDC immune category 3. At the time of cross-sectional analysis in 2005, adherence questionnaires were administered.
DNA OLAs and RNA OLAs were performed from frozen PBMC and plasma, RNA genotyping from dried blood spots.
Results: During the first year of ART, 44% of children experienced virologic failure, with an additional 9% failing by the
end of the second year. Virologic failure was significantly associated with the number of resistance mutations detected by
DNA-OLA (p < 0.001) during cross-sectional analysis, but also with low immunologic CDC-scores at baseline (p < 0.001).
Children who had been exposed to unsupervised short-term antiretrovirals before starting structured ART showed
significantly higher numbers of resistance mutations by DNA-OLA (p = 0.01). Detection of M184V (3TC resistance) by
RNA-OLA and DNA-OLA demonstrated a sensitivity of 0.93 and 0.86 and specificity of 0.67 and 0.7, respectively, for the
identification of virologic failure. The RT mutations N88D and L90M (NFV resistance) detected by DNA-OLA correlated
with virologic failure, whereas mutations at RT position 215 (AZT resistance) were not associated with virologic failure.
Conclusions: Advanced immunosuppression at baseline and previous exposures to unsupervised brief cycles of ART
significantly impaired treatment outcomes at a time when structured ART was finally introduced in his cohort. Brief
maternal exposures to with AZT +/− NVP for the prevention of mother-to-child transmission did not affect treatment
outcomes in this group of children. DNA-OLA from frozen PBMC provided a highly specific tool to detect archived drug
resistance. RNA consensus genotyping from dried blood spots and RNA-OLA fromplasma consistently detected drug
resistance mutations, but merely in association with virologic failur
Updated tests of scaling and universality for the spin-spin correlations in the 2D and 3D spin-S Ising models using high-temperature expansions
We have extended, from order 12 through order 25, the high-temperature series
expansions (in zero magnetic field) for the spin-spin correlations of the
spin-S Ising models on the square, simple-cubic and body-centered-cubic
lattices. On the basis of this large set of data, we confirm accurately the
validity of the scaling and universality hypotheses by resuming several tests
which involve the correlation function, its moments and the exponential or the
second-moment correlation-lengths.Comment: 21 pages, 8 figure
A comparison of 3 regimens to prevent nevirapine resistance mutations in hiv-infected pregnant women receiving a single intrapartum dose of nevirapine
Background. Intrapartum single-dose (SD) nevirapine (NVP) reduces perinatal transmission of human immunodeficiency virus (HIV) infection but selects for NVP-resistant virus, which compromises subsequent NVP-based therapy. A 1-week "tail" of lamivudine and zidovudine after SD-NVP decreases the risk of resistance. We hypothesized that increasing the duration or potency of the tail would further reduce this risk to 250 cells/mu L, most receiving zidovudine, were randomized at 28-38 weeks gestation to receive 1 of 3 intrapartum and postpartum regimens: (A) zidovudine plus enteric-coated didanosine plus lopinavir and ritonavir for 7 days, (B) zidovudine plus enteric-coated didanosine for 30 days, or (C) regimen 1 for 30 days. The incidence of NVP resistance mutations at day 10 or week 6 post partum in each arm was compared with that of a historical comparison group who received prenatal zidovudine and SD-NVP. NVP resistance was identified by consensus sequencing and a sensitive oligonucleotide ligation assay (OLA). Results. At entry, the 169 participants had a median CD4 cell count of 456 cells/mu L and an HIV load of 3.49 log(10) copies/mL. The incidence of mutations in each of the 3 P1032 arms was 0% by sequencing and 1.8%, 7.1%, and 5.3% by OLA in arms A, B, and C, respectively, compared with 13.4% by sequencing and 29.4% by OLA in the comparison group (P < .001 for each study arm vs comparison group). Grade 4 anemia developed in 1 woman. Conclusions. A 7-day tail of highly active combination therapy or 1 month of dual therapy after SD-NVP prevents most NVP resistance to minimal toxicity. Clinical Trials Registration. The IMPAACT P1032 Clinical Trial is NCT00109590, and the PHPT-2 Clinical Trial is NCT00398684
Indinavir-Loaded pH-Sensitive Microparticles for Taste Masking: Toward Extemporaneous Pediatric Anti-HIV/AIDS Liquid Formulations with Improved Patient Compliance
The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads ∼15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7–1.5 g)