High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Building capacity for clinical research in developing countries: the INDOX cancer research network experience

Transnational Organisations increasingly prioritise the need to support local research capacity in low and middle income countries in order that local priorities are addressed with due consideration of contextual issues. There remains limited evidence on the best way in which this should be done or the ways in which external agencies can support this process

Termite environmental tolerances are more linked to desiccation than temperature in modified tropical forests

Termites are vital members of old-growth tropical forests, being perhaps the main decomposers of dead plant material at all stages of humification (decay). Termite abundance and diversity drop in selectively logged forest, and it has been hypothesised that this drop is due to a low tolerance to changing micro-climatic conditions. Specifically, the thermal adaptation hypothesis suggests that tropical species are operating at, or close to, their thermal optimum, and therefore, small temperature increases can have drastic effects on abundance, however, other climatic variables such as humidity might also cause termite abundance to drop. We tested termite tolerance to these two climatic variables (temperature and humidity). We found that termites had a higher CTmax than expected, and that three traits, feeding group, body sclerotisation, and nesting type, were significantly correlated with CTmax. We found that termite desiccation tolerance was low, however, and that all termite genera lost significantly more water in a desiccated environment than in a control. Body sclerotisation, the only trait that was tested, was surprisingly not significantly correlated with desiccation tolerance. Our results suggest that desiccation, rather than ambient temperature, may be the determining factor in dictating termite distributions in modified forests. Should climate change lead to reduced humidity within tropical rainforests, termite abundances and the rates of the functions they perform could be severely reduced

Summer temperature—but not growing season length—influences radial growth of Salix arctica in coastal Arctic tundra

Arctic climate change is leading to an advance of plant phenology (the timing of life history events) with uncertain impacts on tundra ecosystems. Although the lengthening of the growing season is thought to lead to increased plant growth, we have few studies of how plant phenology change is altering tundra plant productivity. Here, we test the correspondence between 14 years of Salix arctica phenology data and radial growth on Qikiqtaruk–Herschel Island, Yukon Territory, Canada. We analysed stems from 28 individuals using dendroecology and linear mixed-effect models to test the statistical power of growing season length and climate variables to individually predict radial growth. We found that summer temperature best explained annual variation in radial growth. We found no strong evidence that leaf emergence date, earlier leaf senescence date, or total growing season length had any direct or lagged effects on radial growth. Radial growth was also not explained by interannual variation in precipitation, MODIS surface greenness (NDVI), or sea ice concentration. Our results demonstrate that at this site, for the widely distributed species S. arctica, temperature—but not growing season length—influences radial growth. These findings challenge the assumption that advancing phenology and longer growing seasons will increase the productivity of all plant species in Arctic tundra ecosystems

Attitudes towards vaccines and intention to vaccinate against COVID-19: a cross-sectional analysis-implications for public health communications in Australia

Objective: To examine SARS-CoV-2 vaccine confidence, attitudes and intentions in Australian adults as part of the iCARE Study. Design and setting: Cross-sectional online survey conducted when free COVID-19 vaccinations first became available in Australia in February 2021. Participants: Total of 1166 Australians from general population aged 18-90 years (mean 52, SD of 19). Main outcome measures: Primary outcome: responses to question 'If a vaccine for COVID-19 were available today, what is the likelihood that you would get vaccinated?'.Secondary outcome: analyses of putative drivers of uptake, including vaccine confidence, socioeconomic status and sources of trust, derived from multiple survey questions. Results: Seventy-eight per cent reported being likely to receive a SARS-CoV-2 vaccine. Higher SARS-CoV-2 vaccine intentions were associated with: increasing age (OR: 2.01 (95% CI 1.77 to 2.77)), being male (1.37 (95% CI 1.08 to 1.72)), residing in least disadvantaged area quintile (2.27 (95% CI 1.53 to 3.37)) and a self-perceived high risk of getting COVID-19 (1.52 (95% CI 1.08 to 2.14)). However, 72% did not believe they were at a high risk of getting COVID-19. Findings regarding vaccines in general were similar except there were no sex differences. For both the SARS-CoV-2 vaccine and vaccines in general, there were no differences in intentions to vaccinate as a function of education level, perceived income level and rurality. Knowing that the vaccine is safe and effective and that getting vaccinated will protect others, trusting the company that made it and vaccination recommended by a doctor were reported to influence a large proportion of the study cohort to uptake the SARS-CoV-2 vaccine. Seventy-eight per cent reported the intent to continue engaging in virus-protecting behaviours (mask wearing, social distancing, etc) postvaccine. Conclusions: Most Australians are likely to receive a SARS-CoV-2 vaccine. Key influencing factors identified (eg, knowing vaccine is safe and effective, and doctor's recommendation to get vaccinated) can inform public health messaging to enhance vaccination rate

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Multiparticle azimuthal correlations for extracting event-by-event elliptic and triangular flow in Au + Au collisions at sNN =200 GeV

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1<|η|<3 in Au + Au collisions at sNN=200 GeV, as a function of centrality. The multiparticle cumulant technique is used to obtain the elliptic flow coefficients v2{2},v2{4},v2{6}, and v2{8}, and triangular flow coefficients v3{2} and v3{4}. Using the small-variance limit, we estimate the mean and variance of the event-by-event v2 distribution from v2{2} and v2{4}. In a complementary analysis, we also use a folding procedure to study the distributions of v2 and v3 directly, extracting both the mean and variance. Implications for initial geometrical fluctuations and their translation into the final-state momentum distributions are discussed