Should expectations about the rate of new antiretroviral drug development impact the timing of HIV treatment initiation and expectations about treatment benefits?

Background: Many analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART). Objectives: To determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS. Methods: We enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982-2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm 3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE). Results: In base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mm 3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%. Conclusions: The future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients. © 2014 Khademi et al

A global analysis of the comparability of winter chill models for fruit and nut trees

Many fruit and nut trees must fulfill a chilling requirement to break their winter dormancy and resume normal growth in spring. Several models exist for quantifying winter chill, and growers and researchers often tacitly assume that the choice of model is not important and estimates of species chilling requirements are valid across growing regions. To test this assumption, Safe Winter Chill (the amount of winter chill that is exceeded in 90% of years) was calculated for 5,078 weather stations around the world, using the Dynamic Model [in Chill Portions (CP)], the Chilling Hours (CH) Model and the Utah Model [Utah Chill Units (UCU)]. Distributions of the ratios between different winter chill metrics were mapped on a global scale. These ratios should be constant if the models were strictly proportional. Ratios between winter chill metrics varied substantially, with the CH/CP ratio ranging between 0 and 34, the UCU/CP ratio between −155 and +20 and the UCU/CH ratio between −10 and +5. The models are thus not proportional, and chilling requirements determined in a given location may not be valid elsewhere. The Utah Model produced negative winter chill totals in many Subtropical regions, where it does not seem to be useful. Mean annual temperature and daily temperature range influenced all winter chill ratios, but explained only between 12 and 27% of the variation. Data on chilling requirements should always be amended with information on the location and experimental conditions of the study in which they were determined, ideally including site-specific conversion factors between winter chill models. This would greatly facilitate the transfer of such information across growing regions, and help prepare growers for the impact of climate change

Bumble Bees (Bombus spp) along a Gradient of Increasing Urbanization

BACKGROUND: Bumble bees and other wild bees are important pollinators of wild flowers and several cultivated crop plants, and have declined in diversity and abundance during the last decades. The main cause of the decline is believed to be habitat destruction and fragmentation associated with urbanization and agricultural intensification. Urbanization is a process that involves dramatic and persistent changes of the landscape, increasing the amount of built-up areas while decreasing the amount of green areas. However, urban green areas can also provide suitable alternative habitats for wild bees. METHODOLOGY/PRINCIPAL FINDINGS: We studied bumble bees in allotment gardens, i.e. intensively managed flower rich green areas, along a gradient of urbanization from the inner city of Stockholm towards more rural (periurban) areas. Keeping habitat quality similar along the urbanization gradient allowed us to separate the effect of landscape change (e.g. proportion impervious surface) from variation in habitat quality. Bumble bee diversity (after rarefaction to 25 individuals) decreased with increasing urbanization, from around eight species on sites in more rural areas to between five and six species in urban allotment gardens. Bumble bee abundance and species composition were most affected by qualities related to the management of the allotment areas, such as local flower abundance. The variability in bumble bee visits between allotment gardens was higher in an urban than in a periurban context, particularly among small and long-tongued bumble bee species. CONCLUSIONS/SIGNIFICANCE: Our results suggest that allotment gardens and other urban green areas can serve as important alternatives to natural habitats for many bumble bee species, but that the surrounding urban landscape influences how many species that will be present. The higher variability in abundance of certain species in the most urban areas may indicate a weaker reliability of the ecosystem service pollination in areas strongly influenced by human activity

Country-specific effects of neonicotinoid pesticides on honey bees and wild bees

Neonicotinoid seed dressings have caused concern world-wide. We use large field experiments to assess the effects of neonicotinoid-treated crops on three bee species across three countries (Hungary, Germany, and the United Kingdom). Winter-sown oilseed rape was grown commercially with either seed coatings containing neonicotinoids (clothianidin or thiamethoxam) or no seed treatment (control). For honey bees, we found both negative (Hungary and United Kingdom) and positive (Germany) effects during crop flowering. In Hungary, negative effects on honey bees (associated with clothianidin) persisted over winter and resulted in smaller colonies in the following spring (24% declines). In wild bees (Bombus terrestris and Osmia bicornis), reproduction was negatively correlated with neonicotinoid residues. These findings point to neonicotinoids causing a reduced capacity of bee species to establish new populations in the year following exposure

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials

Oxidative discolouration in whole-head and cut lettuce: biochemical and environmental influences on a complex phenotype and potential breeding strategies to improve shelf-life

Lettuce discolouration is a key post-harvest trait. The major enzyme controlling oxidative discolouration has long been considered to be polyphenol oxidase (PPO) however, levels of PPO and subsequent development of discolouration symptoms have not always correlated. The predominance of a latent state of the enzyme in plant tissues combined with substrate activation and contemporaneous suicide inactivation mechanisms are considered as potential explanations for this phenomenon. Leaf tissue physical properties have been associated with subsequent discolouration and these may be influenced by variation in nutrient availability, especially excess nitrogen and head maturity at harvest. Mild calcium and irrigation stress has also been associated with a reduction in subsequent discolouration, although excess irrigation has been linked to increased discolouration potentially through leaf physical properties. These environmental factors, including high temperature and UV light intensities, often have impacts on levels of phenolic compounds linking the environmental responses to the biochemistry of the PPO pathway. Breeding strategies targeting the PALand PPOpathway biochemistry and environmental response genes are discussed as a more cost-effective method of mitigating oxidative discolouration then either modified atmosphere packaging or post-harvest treatments, although current understanding of the biochemistry means that such programs are likely to be limited in nature and it is likely that they will need to be deployed alongside other methods for the foreseeable future