Opportunities for improving the efficiency of paediatric HIV treatment programmes

Objectives: To conduct two economic analyses addressing whether to: routinely monitor HIV-infected children on antiretroviral therapy (ART) clinically or with laboratory tests; continue or stop cotrimoxazole prophylaxis when children become stabilized on ART. Design and methods: The ARROW randomized trial investigated alternative strategies to deliver paediatric ART and cotrimoxazole prophylaxis in 1206 Ugandan/Zimbabwean children. Incremental cost-effectiveness and value of implementation analyses were undertaken. Scenario analyses investigated whether laboratory monitoring (CD4 tests for efficacy monitoring; haematology/biochemistry for toxicity) could be tailored and targeted to be delivered cost-effectively. Cotrimoxazole use was examined in malaria-endemic and non-endemic settings. Results: Using all trial data, clinical monitoring delivered similar health outcomes to routine laboratory monitoring, but at a reduced cost, so was cost-effective. Continuing cotrimoxazole improved health outcomes at reduced costs. Restricting routine CD4+ monitoring to after 52 weeks following ART initiation and removing toxicity testing was associated with an incremental cost-effectiveness ratio of $6084 per quality-adjusted life-year (QALY) across all age groups, but was much lower for older children (12+ years at initiation; incremental cost-effectiveness ratio =$769/QALY). Committing resources to improve cotrimoxazole implementation appears cost-effective. A healthcare system that could pay $600/QALY should be willing to spend up to$12.0 per patient-year to ensure continued provision of cotrimoxazole. Conclusion: Clinically driven monitoring of ART is cost-effective in most circumstances. Routine laboratory monitoring is generally not cost-effective at current prices, except possibly CD4 testing amongst adolescents initiating ART. Committing resources to ensure continued provision of cotrimoxazole in health facilities is more likely to represent an efficient use of resources

Multiple viral infections in Agaricus bisporus - characterisation of 18 unique RNA viruses and 8 ORFans identified by deep sequencing

Thirty unique non-host RNAs were sequenced in the cultivated fungus, Agaricus bisporus, comprising 18 viruses each encoding an RdRp domain with an additional 8 ORFans (non-host RNAs with no similarity to known sequences). Two viruses were multipartite with component RNAs showing correlative abundances and common 3′ motifs. The viruses, all positive sense single-stranded, were classified into diverse orders/families. Multiple infections of Agaricus may represent a diverse, dynamic and interactive viral ecosystem with sequence variability ranging over 2 orders of magnitude and evidence of recombination, horizontal gene transfer and variable fragment numbers. Large numbers of viral RNAs were detected in multiple Agaricus samples; up to 24 in samples symptomatic for disease and 8–17 in asymptomatic samples, suggesting adaptive strategies for co-existence. The viral composition of growing cultures was dynamic, with evidence of gains and losses depending on the environment and included new hypothetical viruses when compared with the current transcriptome and EST databases. As the non-cellular transmission of mycoviruses is rare, the founding infections may be ancient, preserved in wild Agaricus populations, which act as reservoirs for subsequent cell-to-cell infection when host populations are expanded massively through fungiculture

Leaderless genes in bacteria: clue to the evolution of translation initiation mechanisms in prokaryotes

<p>Abstract</p> <p>Background</p> <p>Shine-Dalgarno (SD) signal has long been viewed as the dominant translation initiation signal in prokaryotes. Recently, leaderless genes, which lack 5'-untranslated regions (5'-UTR) on their mRNAs, have been shown abundant in archaea. However, current large-scale <it>in silico </it>analyses on initiation mechanisms in bacteria are mainly based on the SD-led initiation way, other than the leaderless one. The study of leaderless genes in bacteria remains open, which causes uncertain understanding of translation initiation mechanisms for prokaryotes.</p> <p>Results</p> <p>Here, we study signals in translation initiation regions of all genes over 953 bacterial and 72 archaeal genomes, then make an effort to construct an evolutionary scenario in view of leaderless genes in bacteria. With an algorithm designed to identify multi-signal in upstream regions of genes for a genome, we classify all genes into SD-led, TA-led and atypical genes according to the category of the most probable signal in their upstream sequences. Particularly, occurrence of TA-like signals about 10 bp upstream to translation initiation site (TIS) in bacteria most probably means leaderless genes.</p> <p>Conclusions</p> <p>Our analysis reveals that leaderless genes are totally widespread, although not dominant, in a variety of bacteria. Especially for <it>Actinobacteria </it>and <it>Deinococcus-Thermus</it>, more than twenty percent of genes are leaderless. Analyzed in closely related bacterial genomes, our results imply that the change of translation initiation mechanisms, which happens between the genes deriving from a common ancestor, is linearly dependent on the phylogenetic relationship. Analysis on the macroevolution of leaderless genes further shows that the proportion of leaderless genes in bacteria has a decreasing trend in evolution.</p

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

Effects of acute and chronic temperature changes on the functional responses of the dogfish Scyliorhinus canicula (Linnaeus, 1758) towards amphipod prey Echinogammarus marinus (Leach, 1815)

Predation is a strong driver of population dynamics and community structure and it is essential to reliably quantify and predict predation impacts on prey populations in a changing thermal landscape. Here, we used comparative functional response analyses to assess how predator-prey interactions between dogfish and invertebrate prey change under different warming scenarios. The Functional Response Type, attack rate, handling time and maximum feeding rate estimates were calculated for Scyliorhinus canicula preying upon Echinogammarus marinus under temperatures of 11.3 °C and 16.3 °C, which represent both the potential daily variation and predicted higher summer temperatures within Strangford Lough, N. Ireland. A two x two design of “Predator Acclimated”, “Prey Acclimated”, “Both Acclimated”, and “Both Unacclimated” was implemented to test functional responses to temperature rise. Attack rate was higher at 11.3 °C than at 16.3 °C, but handling time was lower and maximum feeding rates were higher at 16.3 °C. Non-acclimated predators had similar maximum feeding rate towards non-acclimated and acclimated prey, whereas acclimated predators had significantly higher maximum feeding rates towards acclimated prey as compared to non-acclimated prey. Results suggests that the predator attack rate is decreased by increasing temperature but when both predator and prey are acclimated the shorter handling times considerably increase predator impact. The functional response of the fish changed from Type II to Type III with an increase in temperature, except when only the prey were acclimated. This change from population destabilizing Type II to more stabilizing Type III could confer protection to prey at low densities but increase the maximum feeding rate by Scyliorhinus canicula in the future. However, predator movement between different thermal regimes may maintain a Type II response, albeit with a lower maximum feeding rate. This has implications for the way the increasing population Scyliorhinus canicula in the Irish Sea may exploit valuable fisheries stocks in the future

Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences

Hepatitis B virus (HBV) is a diverse, partially double-stranded DNA virus, with 9 genotypes (A-I), and a putative 10th genotype (J), characterized thus far. Given the broadening interest in HBV sequencing, there is an increasing requirement for a consistent, unified approach to HBV genotype and subgenotype classification. We set out to generate an updated resource of reference sequences using the diversity of all genomic-length HBV sequences available in public databases. We collated and aligned genomic-length HBV sequences from public databases and used maximum-likelihood phylogenetic analysis to identify genotype clusters. Within each genotype, we examined the phylogenetic support for currently defined subgenotypes, as well as identifying well-supported clades and deriving reference sequences for them. Based on the phylogenies generated, we present a comprehensive set of HBV reference sequences at the genotype and subgenotype level. All of the generated data, including the alignments, phylogenies and chosen reference sequences, are available online (https://doi.org/10.6084/m9.figshare.8851946) as a simple open-access resource

Vertical migration of the toxic dinoflagellate Gymnodinium catenatum under different concentrations of nutrients and humic substances in culture

Vertical migration behaviour by the chainforming dinoflagellate Gymnodinium catenatum Graham was investigated using vertically-stratified laboratory columns. Under surface nutrient-deplete conditions, with nutrients added only at depth, 100% of cells underwent vertical migration (VM), starting downwards migration 3 h before the end of the light period and beginning upwards migration 3 h before the start of the light period. Cells in nutrient-replete columns showed no VM, but they were more dispersed in the upper layer during the dark compared to the light period. When surface layers (S) were nitrate-deplete (-N) and enriched with humic substances (H) contained in Huon River water and bottom waters (B) were nutrient replete (R) (SH-NBR), the pattern of VM was altered-50% of cells underwent migration and 50% remained at the pycnocline. In columns with nitrate-replete and humic-enriched surface layers (SHRBR), most cells underwent VM, while 30% remained at the surface. Cells in SH-NBR columns showed increased N quotas and intra-cellular nitrate concentrations after 4 days, indicating nitrate uptake by G. catenatum in bottom layers. The concomitant increase in particulate organic nitrogen (PON) with the decrease in external nitrate concentrations in bottom layers provide convincing evidence that VM by G. catenatum facilitates nutrient retrieval at depth. However, addition of humic substances (a potential source of organic nitrogen) to surface layers did not ameliorate G. catenatum N depletion sufficiently to preclude the need for NO3- uptake at depth. Furthermore, there was no detectable pattern of increasing carbon (C) quota during the day (photosynthate accumulation) or increasing N quota during the night (nitrate assimilation). Toxic dinoflagellate G. catenatum blooms are commonly associated with nitrate depletion in surface waters in south-east Tasmanian waters (Australia). Therefore, vertical migration, facilitating N uptake at depth, could play an important role in this organism's ecological strategy, enabling it to exploit environments where light and nutrients are vertically separated. © 2006 Elsevier B.V. All rights reserved