Natural selection on individual variation in tolerance of gastrointestinal nematode infection

This is the final version of the article. Available from the publisher via the DOI in this record.Hosts may mitigate the impact of parasites by two broad strategies: resistance, which limits parasite burden, and tolerance, which limits the fitness or health cost of increasing parasite burden. The degree and causes of variation in both resistance and tolerance are expected to influence host-parasite evolutionary and epidemiological dynamics and inform disease management, yet very little empirical work has addressed tolerance in wild vertebrates. Here, we applied random regression models to longitudinal data from an unmanaged population of Soay sheep to estimate individual tolerance, defined as the rate of decline in body weight with increasing burden of highly prevalent gastrointestinal nematode parasites. On average, individuals lost weight as parasite burden increased, but whereas some lost weight slowly as burden increased (exhibiting high tolerance), other individuals lost weight significantly more rapidly (exhibiting low tolerance). We then investigated associations between tolerance and fitness using selection gradients that accounted for selection on correlated traits, including body weight. We found evidence for positive phenotypic selection on tolerance: on average, individuals who lost weight more slowly with increasing parasite burden had higher lifetime breeding success. This variation did not have an additive genetic basis. These results reveal that selection on tolerance operates under natural conditions. They also support theoretical predictions for the erosion of additive genetic variance of traits under strong directional selection and fixation of genes conferring tolerance. Our findings provide the first evidence of selection on individual tolerance of infection in animals and suggest practical applications in animal and human disease management in the face of highly prevalent parasites.This study was funded by Natural Environment Research Council (http://www.nerc.ac.uk/) Standard Grant no. NE/G004854/1 and European Research Council (http://erc.europa.eu/) Large Grant no. 250098 to JMP. ADH is supported by European Research Council grant no. R/120448-11-1 to V. Lummaa; DHN is supported by Biotechnology and Biological Sciences Research Council (http://www.bbsrc.ac.uk/) David Phillips Fellowship no. BB/H021686/1; AJW is supported by BBSRC David Phillips Fellowship no. BB/G022976/1; ALG is supported by Princeton University and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers

Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure

Background: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. / Methods: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. / Results: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). / Conclusions: Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure

Heavy Flavour Production at Tevatron and Parton Shower Effects

We present hadron-level predictions from the Monte Carlo generator Cascade and numerical calculations of charm and beauty production at the Fermilab Tevatron within the framework of the $k_T$-factorization QCD approach. Our consideration is based on the CCFM-evolved unintegrated gluon densities in a proton. The performed analysis covers the total and differential cross sections of open charm and beauty quarks, $B$ and $D$ mesons (or rather muons from their semileptonic decays) and the total and differential cross sections of $b \bar b$ di-jet hadroproduction. We study the theoretical uncertainties of our calculations and investigate the effects coming from parton showers in initial and final states. Our predictions are compared with the recent experimental data taken by the D0 and CDF collaborations. Special attention is put on the specific angular correlations between the final-state particles. We demonstrate that the final state parton shower plays a crucial role in the description of such observables. The decorrelated part of angular separations can be fully described, if the process $gg^*\rightarrow gg$ is included.Comment: Fig 8,9 10 replaced, small corrections in text A discussion of the delta phi results is adde

Maternally derived anti-helminth antibodies predict offspring survival in a wild mammal

The transfer of antibodies from mother to offspring provides crucial protection against infection to offspring during early life in humans and domestic and laboratory animals. However, few studies have tested the consequences of variation in maternal antibody transfer for offspring fitness in the wild. Further, separating the immunoprotective effects of antibodies from their association with nutritional resources provided by mothers is difficult. Here, we measured plasma levels of total and parasite-specific antibodies in neonatal (less than 10 days old) wild Soay sheep over 25 years to quantify variation in maternal antibody transfer and test its association with offspring survival. Maternal antibody transfer was predicted by maternal age and previous antibody responses, and was consistent within mothers across years. Neonatal total IgG antibody levels were positively related to early growth, suggesting they reflected nutritional transfer. Neonatal parasite-specific IgG levels positively predicted first-year survival, independent of lamb weight, total IgG levels and subsequent lamb parasite-specific antibody levels. This relationship was partly mediated via an indirect negative association with parasite burden. We show that among-female variation in maternal antibody transfer can have long-term effects on offspring growth, parasite burden and fitness in the wild, and is likely to impact naturally occurring host–parasite dynamics

PDF dependence of Higgs cross sections at the Tevatron and LHC: response to recent criticism

We respond to some criticism questioning the validity of the current Standard Model Higgs exclusion limits at the Tevatron, due to the significant dependence of the dominant production cross section from gluon-gluon fusion on the choice of parton distribution functions (PDFs) and the strong coupling (alpha_S). We demonstrate the ability of the Tevatron jet data to discriminate between different high-x gluon distributions, performing a detailed quantitative comparison to show that fits not explicitly including these data fail to give a good description. In this context we emphasise the importance of the consistent treatment of luminosity uncertainties. We comment on the values of alpha_S obtained from fitting deep-inelastic scattering data, particularly the fixed-target NMC data, and we show that jet data are needed for stability. We conclude that the Higgs cross-section uncertainties due to PDFs and alpha_S currently used by the Tevatron and LHC experiments are not significantly underestimated, contrary to some recent claims.Comment: 44 pages, 19 figures. v2: version published in JHEP (paragraph added at bottom of p.15

The impact of electronic records on patient safety : a qualitative study

BACKGROUND: Our aim was to explore NHS staff perceptions and experiences of the impact on patient safety of introducing a maternity system. METHODS: Qualitative semi-structured interviews were conducted with 19 members of NHS staff who represented a variety of staff groups (doctors, midwives, health care assistants), staff grades (consultant and midwife grades) and wards within a maternity unit. Participants represented a single maternity unit at a NHS teaching hospital in the North of England. Interviews were conducted during the first 12 months of the system being implemented and were analysed thematically. RESULTS: Participants perceived there to be an elevated risk to patient safety during the system's implementation. The perceived risks were attributed to a range of social and technical factors. For example, poor system design and human error which resulted in an increased potential for missing information and inputting error. CONCLUSIONS: The first 12 months of introducing the maternity system was perceived to and in some cases had already caused actual risk to patient safety. Trusts throughout the NHS are facing increasing pressure to become paperless and should be aware of the potential adverse impacts on patient safety that can occur when introducing electronic systems. Given the potential for increased risk identified, recommendations for further research and for NHS trusts introducing electronic systems are proposed

A comparison of photographic, replication and direct clinical examination methods for detecting developmental defects of enamel

Different methods have been used for detecting developmental defects of enamel (DDE). This study aimed to compare photographic and replication methods with the direct clinical examination method for detecting DDE in children's permanent incisors

Translating research into practice in Leeds and Bradford (TRiPLaB): a protocol for a programme of research

Background The National Institute for Health Research (NIHR) has funded nine Collaborations for Leadership in Applied Health Research and Care (CLAHRCs). Each CLAHRC is a partnership between higher education institutions (HEIs) and the NHS in nine UK regional health economies. The CLAHRC for Leeds, York, and Bradford comprises two 'research themes' and three 'implementation themes.' One of these implementation themes is Translating Research into Practice in Leeds and Bradford (TRiPLaB). TRiPLaB aims to develop, implement, and evaluate methods for inducing and sustaining the uptake of research knowledge into practice in order to improve the quality of health services for the people of Leeds and Bradford. Methods TRiPLaB is built around a three-stage, sequential, approach using separate, longitudinal case studies conducted with collaborating NHS organisations, TRiPLaB will select robust innovations to implement, conduct a theory-informed exploration of the local context using a variety of data collection and analytic methods, and synthesise the information collected to identify the key factors influencing the uptake and adoption of targeted innovations. This synthesis will inform the development of tailored, multifaceted, interventions designed to increase the translation of research findings into practice. Mixed research methods, including time series analysis, quasi-experimental comparison, and qualitative process evaluation, will be used to evaluate the impact of the implementation strategies deployed. Conclusion TRiPLaB is a theory-informed, systematic, mixed methods approach to developing and evaluating tailored implementation strategies aimed at increasing the translation of research-based findings into practice in one UK health economy. Through active collaboration with its local NHS, TRiPLaB aims to improve the quality of health services for the people of Leeds and Bradford and to contribute to research knowledge regarding the interaction between context and adoption behaviour in health services