HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention

The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections.     

Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.     

Polymerase chain reaction-restriction fragment-length polymorphism method to distinguish Liriomyza huidobrensis from L. Langei (Diptera: Agromyzidae) applied to three recent leafminer invasions.

A molecular method is presented for differentiating the morphologically cryptic leafminers Liriomyza langei Frick and L. huidobrensis (Blanchard). This method requires polymerase chain reaction (PCR) amplification of a 1031-bp region of mitochondrial cytochrome oxidase DNA followed by restriction fragment analysis using the restriction enzymes SpeI and EcoRV. Spel cuts the mitochondrial fragment of L. langei into two fragments, but does not cut the L. huidobrensis fragment. EcoRV cuts the L. huidobrensis fragment into two fragments, but does not cut the L. langei fragment. This PCR-restriction fragment-length polymorphism (RFLP) method is faster and less costly than DNA sequencing,which is currently the only other way to differentiate these two species. We apply the method to samples from recently introduced leafminer populations in Sri Lanka, Canada, and South Africa and find that the invasive leafminer in all three locations is L. huidobrensis.     

A quasi-elastic light scattering and cinematographic investigation of motile Chlamydomonas reinhardtii.

Quasi-elastic light scattering and cinematographical techniques were used to investigate the motility of Chlamydomonas reinhardtii (wild type). It was found that quantitative information on the trajectory of motion was required for a meaningful interpretation of the autocorrelation functions. Two models for describing the oscillatory motion of the cell were developed; one based on the instantaneous forward-and-backward motion of the cell, and the other based on a sinusoidal perturbation to the average forward motion. Both models gave satisfactory agreement with the shape of the experimentally measured autocorrelation function, thus making it possible to use this measurement to determine mean progressive swimming velocities in a population of greater than 200 cells.     

Teratogenicity of three substituted 4-biphenyls in the rat as a result of the chemical breakdown and possible metabolism of a thromboxane A2-receptor blocker

AH23848 is a potent thromboxane A2-receptor blocker inhibiting platelet aggregation in vitro and in vivo. Oral administration to pregnant rats during days 7-16 of pregnancy, at doses of 0, 10, 45, or 200 mg/kg twice daily, resulted in dose-related maternal, embryonic, and fetal toxicity. The most notable observation was herniation of the diaphragm occurring in 1.5 and 100.0% of fetuses at the 45 and 200 mg/kg doses, respectively, when examined at term. A further study at 150 mg/kg twice daily during days 7-16, 7-11, or 12-16 of pregnancy revealed incidences of diaphragmatic hernia up to 42%. Herniation varied from small areas of eventration of membranous diaphragm to fetuses with apparent total absence of the diaphragm. The positions of the hernias in the diaphragm, following dosing over varying periods of organogenesis, reflected the chronology of diaphragm formation in the rat. The teratology of AH23848 was unrelated to its thromboxane A2-receptor blocker properties but was related to a chemical breakdown product, 4-biphenylmethanol. Some substituted biphenyl compounds appear to be specific teratogens in the rat, with their effects targeted at the developing diaphragm. A possible mechanism of herniation is the interference with muscularisation of the membranous diaphragm, resulting in weakness and perforation.     

Interaction between contrasting rice genotypes and soil physical conditions induced by hydraulic stresses typical of alternate wetting and drying irrigation of soil

Background and aims

Drought events, agricultural practices and plant communities influence microbial and soil abiotic parameters which can feedback to fodder production. This study aimed to determine which soil legacies influence plant biomass production and nutritional quality, and its resistance and recovery to extreme weather events.

Methods

In a greenhouse experiment, soil legacy effects on Lolium perenne were examined, first under optimal conditions, and subsequently during and after drought. We used subalpine grassland soils previously cultivated for two years with grass communities of distinct functional composition, and subjected to combinations of climatic stress and simulated management.

Results

The soil legacy of climatic stress increased biomass production of Lolium perenne and its resistance and recovery to a new drought. This beneficial effect resulted from higher nutrient availability in soils previously exposed to climatic stresses due to lower competitive abilities and resistance of microbial communities to a new drought. This negative effect on microbial communities was strongest in soils from previously cut and fertilized grasslands or dominated by conservative grasses.

Conclusion

In subalpine grasslands more frequent climatic stresses could benefit fodder production in the short term, but threaten ecosystem functioning and the maintenance of traditional agricultural practices in the long term.

     

The SER Standards: a globally relevant and inclusive tool for improving restoration practice—a reply to Higgs et al.

In response to a critique by Higgs et al., this article clarifies the content and intent of the Society for Ecological Restoration's (SER) International Standards for the Practice of Ecological Restoration. Higgs et al. expressed concern that the SER Standards are not sufficiently underpinned by principles and risk disenfranchising some practitioners by narrowing what qualifies as ecological restoration. To demonstrate that these concerns are unfounded, we discuss the policy context and principles on which the Standards are based, its organizational structure, the innovative and inclusive approach used for development, and highlight significant errata by Higgs et al.