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1.  Health effects of adopting low greenhouse gas emission diets in the UK 
BMJ Open  2015;5(4):e007364.
Dietary changes which improve health are also likely to be beneficial for the environment by reducing emissions of greenhouse gases (GHG). However, previous analyses have not accounted for the potential acceptability of low GHG diets to the general public. This study attempted to quantify the health effects associated with adopting low GHG emission diets in the UK.
Epidemiological modelling study.
UK population.
Adoption of diets optimised to achieve the WHO nutritional recommendations and reduce GHG emissions while remaining as close as possible to existing dietary patterns.
Main outcome
Changes in years of life lost due to coronary heart disease, stroke, several cancers and type II diabetes, quantified using life tables.
If the average UK dietary intake were optimised to comply with the WHO recommendations, we estimate an incidental reduction of 17% in GHG emissions. Such a dietary pattern would be broadly similar to the current UK average. Our model suggests that it would save almost 7 million years of life lost prematurely in the UK over the next 30 years and increase average life expectancy by over 8 months. Diets that result in additional GHG emission reductions could achieve further net health benefits. For emission reductions greater than 40%, improvements in some health outcomes may decrease and acceptability will diminish.
There are large potential benefits to health from adopting diets with lower associated GHG emissions in the UK. Most of these benefits can be achieved without drastic changes to existing dietary patterns. However, to reduce emissions by more than 40%, major dietary changes that limit both acceptability and the benefits to health are required.
PMCID: PMC4420981  PMID: 25929258
2.  Health effects of home energy efficiency interventions in England: a modelling study 
BMJ Open  2015;5(4):e007298.
To assess potential public health impacts of changes to indoor air quality and temperature due to energy efficiency retrofits in English dwellings to meet 2030 carbon reduction targets.
Health impact modelling study.
English household population.
Three retrofit scenarios were modelled: (1) fabric and ventilation retrofits installed assuming building regulations are met; (2) as with scenario (1) but with additional ventilation for homes at risk of poor ventilation; (3) as with scenario (1) but with no additional ventilation to illustrate the potential risk of weak regulations and non-compliance.
Main outcome
Primary outcomes were changes in quality adjusted life years (QALYs) over 50 years from cardiorespiratory diseases, lung cancer, asthma and common mental disorders due to changes in indoor air pollutants, including secondhand tobacco smoke, PM2.5 from indoor and outdoor sources, radon, mould, and indoor winter temperatures.
The modelling study estimates showed that scenario (1) resulted in positive effects on net mortality and morbidity of 2241 (95% credible intervals (CI) 2085 to 2397) QALYs per 10 000 persons over 50 years follow-up due to improved temperatures and reduced exposure to indoor pollutants, despite an increase in exposure to outdoor-generated particulate matter with a diameter of 2.5 μm or less (PM2.5). Scenario (2) resulted in a negative impact of −728 (95% CI −864 to −592) QALYs per 10 000 persons over 50 years due to an overall increase in indoor pollutant exposures. Scenario (3) resulted in −539 (95% CI −678 to -399) QALYs per 10 000 persons over 50 years follow-up due to an increase in indoor exposures despite the targeting of pollutants.
If properly implemented alongside ventilation, energy efficiency retrofits in housing can improve health by reducing exposure to cold and air pollutants. Maximising the health benefits requires careful understanding of the balance of changes in pollutant exposures, highlighting the importance of ventilation to mitigate the risk of poor indoor air quality.
PMCID: PMC4420956  PMID: 25916488
3.  Clarifying life lost due to cold and heat: a new approach using annual time series 
BMJ Open  2015;5(4):e005640.
To clarify whether deaths associated with hot and cold days are among the frail who would have died anyway in the next few weeks or months.
Time series regression analysis of annual deaths in relation to annual summaries of cold and heat.
London, UK.
3 530 280 deaths from all natural causes among London residents between October 1949 and September 2006.
Main outcome measures
Change in annual risk of death (all natural cause, cardiovascular and respiratory) associated with each additional 1°C of average cold (or heat) below (above) the threshold (18°C) across each year.
Cold years were associated with increased deaths from all causes. For each additional 1° of cold across the year, all-cause mortality increased by 2.3% (95% CI 0.7% to 3.8%), after adjustment for influenza and secular trends. The estimated association between hot years and all-cause mortality was very imprecise and thus inconclusive (effect estimate 1.7%, −2.9% to 6.5%). These estimates were broadly robust to changes in the way temperature and trend were modelled. Estimated risk increments using weekly data but otherwise comparable were cold: 2.0% (2.0% to 2.1%) and heat: 3.9% (3.4% to 3.8%).
In this London annual series, we saw an association of cold with mortality which was broadly similar in magnitude to that found in published daily studies and our own weekly analysis, suggesting that most deaths due to cold were among individuals who would not have died in the next 6 months. The estimated association with heat was imprecise, with the CI including magnitudes found in daily studies but also including zero.
PMCID: PMC4401844  PMID: 25877269
Aged; Climate Change; Humans; London; Mortality; Temperature
4.  Promoting Health and Advancing Development through Improved Housing in Low-Income Settings 
There is major untapped potential to improve health in low-income communities through improved housing design, fittings, materials and construction. Adverse effects on health from inadequate housing can occur through a range of mechanisms, both direct and indirect, including as a result of extreme weather, household air pollution, injuries or burns, the ingress of disease vectors and lack of clean water and sanitation. Collaborative action between public health professionals and those involved in developing formal and informal housing could advance both health and development by addressing risk factors for a range of adverse health outcomes. Potential trade-offs between design features which may reduce the risk of some adverse outcomes whilst increasing the risk of others must be explicitly considered.
PMCID: PMC3795192  PMID: 23271143
Housing; Household energy; Sanitation; Development; Health
5.  Short-term effects of air pollution on a range of cardiovascular events in England and Wales: case-crossover analysis of the MINAP database, hospital admissions and mortality 
Heart  2014;100(14):1093-1098.
To inform potential pathophysiological mechanisms of air pollution effects on cardiovascular disease (CVD), we investigated short-term associations between ambient air pollution and a range of cardiovascular events from three national databases in England and Wales.
Using a time-stratified case-crossover design, over 400 000 myocardial infarction (MI) events from the Myocardial Ischaemia National Audit Project (MINAP) database, over 2 million CVD emergency hospital admissions and over 600 000 CVD deaths were linked with daily mean concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter less than 10 μm in aerodynamic diameter (PM10), particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5) and sulfur dioxide (SO2), and daily maximum of 8-hourly running mean of O3 measured at the nearest air pollution monitoring site to the place of residence. Pollutant effects were modelled using lags up to 4 days and adjusted for ambient temperature and day of week.
For mortality, no CVD outcome analysed was clearly associated with any pollutant, except for PM2.5 with arrhythmias, atrial fibrillation and pulmonary embolism. With hospital admissions, only NO2 was associated with a raised risk: CVD 1.7% (95% CI 0.9 to 2.6), non-MI CVD 2.0% (1.1 to 2.9), arrhythmias 2.9% (0.6 to 5.2), atrial fibrillation 2.8% (0.3 to 5.4) and heart failure 4.4% (2.0 to 6.8) for a 10th–90th centile increase. With MINAP, only NO2 was associated with an increased risk of MI, which was specific to non-ST-elevation myocardial infarction (non-STEMIs): 3.6% (95% CI 0.4 to 6.9).
This study found no clear evidence for pollution effects on STEMIs and stroke, which ultimately represent thrombogenic processes, though it did for pulmonary embolism. The strongest associations with air pollution were observed with selected non-MI outcomes.
PMCID: PMC4078678  PMID: 24952943
6.  Estimating the Health Effects of Greenhouse Gas Mitigation Strategies: Addressing Parametric, Model, and Valuation Challenges 
Environmental Health Perspectives  2014;122(5):447-455.
Background: Policy decisions regarding climate change mitigation are increasingly incorporating the beneficial and adverse health impacts of greenhouse gas emission reduction strategies. Studies of such co-benefits and co-harms involve modeling approaches requiring a range of analytic decisions that affect the model output.
Objective: Our objective was to assess analytic decisions regarding model framework, structure, choice of parameters, and handling of uncertainty when modeling health co-benefits, and to make recommendations for improvements that could increase policy uptake.
Methods: We describe the assumptions and analytic decisions underlying models of mitigation co-benefits, examining their effects on modeling outputs, and consider tools for quantifying uncertainty.
Discussion: There is considerable variation in approaches to valuation metrics, discounting methods, uncertainty characterization and propagation, and assessment of low-probability/high-impact events. There is also variable inclusion of adverse impacts of mitigation policies, and limited extension of modeling domains to include implementation considerations. Going forward, co-benefits modeling efforts should be carried out in collaboration with policy makers; these efforts should include the full range of positive and negative impacts and critical uncertainties, as well as a range of discount rates, and should explicitly characterize uncertainty. We make recommendations to improve the rigor and consistency of modeling of health co-benefits.
Conclusion: Modeling health co-benefits requires systematic consideration of the suitability of model assumptions, of what should be included and excluded from the model framework, and how uncertainty should be treated. Increased attention to these and other analytic decisions has the potential to increase the policy relevance and application of co-benefits modeling studies, potentially helping policy makers to maximize mitigation potential while simultaneously improving health.
Citation: Remais JV, Hess JJ, Ebi KL, Markandya A, Balbus JM, Wilkinson P, Haines A, Chalabi Z. 2014. Estimating the health effects of greenhouse gas mitigation strategies: addressing parametric, model, and valuation challenges. Environ Health Perspect 122:447–455;
PMCID: PMC4014758  PMID: 24583270
7.  The role of gene–environment correlations and interactions in middle childhood depressive symptoms 
Development and psychopathology  2013;25(1):10.1017/S0954579412000922.
Depression is known to be associated with a wide array of environmental factors. Such associations are due at least in part to genetic influences on both. This issue has been little explored with preadolescent children. Measures of family chaos and parenting style at age 9 and child depressive symptoms at age 12 were completed by 3,258 twin pairs from the Twins Early Development Study and their parents. Quantitative genetic modeling was used to explore common and unique genetic and environmental influences on both family environment and later depressive symptoms. Depressive symptoms at age 12 were significantly heritable. Moderate genetic effects influenced parenting style and family chaos at the age of 9, indicating gene–environment correlation. There were significant genetic correlations between family environment and depressive symptoms. There was some evidence of a Gene×Environment interaction, with stronger genetic effects on depressive symptoms for children with more suboptimal family environment. There was an Environment×Environment interaction, with effects of nonshared environment on depressive symptoms stronger for twins with more adverse parenting experiences. There is some evidence for gene–environment correlation between aspects of family environment in middle childhood and subsequent depressive symptoms. This suggests that one of the mechanisms by which genes lead to depressive symptoms may be by themselves influencing depressogenic environments.
PMCID: PMC3819563  PMID: 23398755
8.  Measurement error in time-series analysis: a simulation study comparing modelled and monitored data 
Assessing health effects from background exposure to air pollution is often hampered by the sparseness of pollution monitoring networks. However, regional atmospheric chemistry-transport models (CTMs) can provide pollution data with national coverage at fine geographical and temporal resolution. We used statistical simulation to compare the impact on epidemiological time-series analysis of additive measurement error in sparse monitor data as opposed to geographically and temporally complete model data.
Statistical simulations were based on a theoretical area of 4 regions each consisting of twenty-five 5 km × 5 km grid-squares. In the context of a 3-year Poisson regression time-series analysis of the association between mortality and a single pollutant, we compared the error impact of using daily grid-specific model data as opposed to daily regional average monitor data. We investigated how this comparison was affected if we changed the number of grids per region containing a monitor. To inform simulations, estimates (e.g. of pollutant means) were obtained from observed monitor data for 2003–2006 for national network sites across the UK and corresponding model data that were generated by the EMEP-WRF CTM. Average within-site correlations between observed monitor and model data were 0.73 and 0.76 for rural and urban daily maximum 8-hour ozone respectively, and 0.67 and 0.61 for rural and urban loge(daily 1-hour maximum NO2).
When regional averages were based on 5 or 10 monitors per region, health effect estimates exhibited little bias. However, with only 1 monitor per region, the regression coefficient in our time-series analysis was attenuated by an estimated 6% for urban background ozone, 13% for rural ozone, 29% for urban background loge(NO2) and 38% for rural loge(NO2). For grid-specific model data the corresponding figures were 19%, 22%, 54% and 44% respectively, i.e. similar for rural loge(NO2) but more marked for urban loge(NO2).
Even if correlations between model and monitor data appear reasonably strong, additive classical measurement error in model data may lead to appreciable bias in health effect estimates. As process-based air pollution models become more widely used in epidemiological time-series analysis, assessments of error impact that include statistical simulation may be useful.
PMCID: PMC3871053  PMID: 24219031
Measurement error; Epidemiology; Time-series; Mortality; Nitrogen dioxide; Ozone
9.  Rumination, anxiety, depressive symptoms and subsequent depression in adolescents at risk for psychopathology: a longitudinal cohort study 
BMC Psychiatry  2013;13:250.
A ruminative style of responding to low mood is associated with subsequent high depressive symptoms and depressive disorder in children, adolescents and adults. Scores on self-report rumination scales correlate strongly with scores on anxiety and depression symptom scales. This may confound any associations between rumination and subsequent depression.
Our sample comprised 658 healthy adolescents at elevated risk for psychopathology. This study applied ordinal item (non-linear) factor analysis to pooled items from three self-report questionnaires to explore whether there were separate, but correlated, constructs of rumination, depression and anxiety. It then tested whether rumination independently predicted depressive disorder and depressive symptoms over the subsequent 12 months, after adjusting for confounding variables.
We identified a single rumination factor, which was correlated with factors representing cognitive symptoms of depression, somatic symptoms of depression and anxiety symptoms; and one factor representing adaptive responses to low mood. Elevated rumination scores predicted onset of depressive disorders over the subsequent year (p = 0.035), and levels of depressive symptoms 12 months later (p < 0.0005), after adjustment for prior levels of depressive and anxiety symptoms.
High rumination predicts onset of depressive disorder in healthy adolescents. Therapy that reduces rumination and increases distraction/problem-solving may reduce onset and relapse rates of depression.
PMCID: PMC3851454  PMID: 24103296
Depression; Anxiety; Rumination; Factor analysis; Adolescence; Psychometrics
10.  Magnetic resonance imaging of a randomized controlled trial investigating predictors of recovery following psychological treatment in adolescents with moderate to severe unipolar depression: study protocol for Magnetic Resonance-Improving Mood with Psychoanalytic and Cognitive Therapies (MR-IMPACT) 
BMC Psychiatry  2013;13:247.
Major depressive disorders (MDD) are a debilitating and pervasive group of mental illnesses afflicting many millions of people resulting in the loss of 110 million working days and more than 2,500 suicides per annum. Adolescent MDD patients attending NHS clinics show high rates of recurrence into adult life. A meta-analysis of recent research shows that psychological treatments are not as efficacious as previously thought. Modest treatment outcomes of approximately 65% of cases responding suggest that aetiological and clinical heterogeneity may hamper the better use of existing therapies and discovery of more effective treatments. Information with respect to optimal treatment choice for individuals is lacking, with no validated biomarkers to aid therapeutic decision-making.
Magnetic resonance-Improving Mood with Psychoanalytic and Cognitive Therapies, the MR-IMPACT study, plans to identify brain regions implicated in the pathophysiology of depressions and examine whether there are specific behavioural or neural markers predicting remission and/or subsequent relapse in a subsample of depressed adolescents recruited to the IMPACT randomised controlled trial (Registration # ISRCTN83033550).
MR-IMPACT is an investigative biomarker component of the IMPACT pragmatic effectiveness trial. The aim of this investigation is to identify neural markers and regional indicators of the pathophysiology of and treatment response for MDD in adolescents. We anticipate that these data may enable more targeted treatment delivery by identifying those patients who may be optimal candidates for therapeutic response.
Trial registration
Adjunctive study to IMPACT trial (Current Controlled Trials: ISRCTN83033550).
PMCID: PMC3851239  PMID: 24094274
11.  Four issues in undernutrition-related health impact modeling 
Undernutrition modeling makes it possible to evaluate the potential impact of such events as a food-price shock or harvest failure on the prevalence and severity of undernutrition. There are, however, uncertainties in such modeling. In this paper we discuss four methodological issues pertinent to impact estimation: (1) the conventional emphasis on energy intake rather than dietary quality; (2) the importance of the distribution of nutrient intakes; (3) the timing of both the ‘food shock’ and when the response is assessed; and (4) catch-up growth and risk accumulation.
PMCID: PMC3852289  PMID: 24073617
Nutrition; Malnutrition; Epidemiology; Health impact; Food prices; Modeling
12.  The importance of health co-benefits in macroeconomic assessments of UK Greenhouse Gas emission reduction strategies 
Climatic Change  2013;121(2):223-237.
We employ a single-country dynamically-recursive Computable General Equilibrium model to make health-focussed macroeconomic assessments of three contingent UK Greenhouse Gas (GHG) mitigation strategies, designed to achieve 2030 emission targets as suggested by the UK Committee on Climate Change. In contrast to previous assessment studies, our main focus is on health co-benefits additional to those from reduced local air pollution. We employ a conservative cost-effectiveness methodology with a zero net cost threshold. Our urban transport strategy (with cleaner vehicles and increased active travel) brings important health co-benefits and is likely to be strongly cost-effective; our food and agriculture strategy (based on abatement technologies and reduction in livestock production) brings worthwhile health co-benefits, but is unlikely to eliminate net costs unless new technological measures are included; our household energy efficiency strategy is likely to breakeven only over the long term after the investment programme has ceased (beyond our 20 year time horizon). We conclude that UK policy makers will, most likely, have to adopt elements which involve initial net societal costs in order to achieve future emission targets and longer-term benefits from GHG reduction. Cost-effectiveness of GHG strategies is likely to require technological mitigation interventions and/or demand-constraining interventions with important health co-benefits and other efficiency-enhancing policies that promote internalization of externalities. Health co-benefits can play a crucial role in bringing down net costs, but our results also suggest the need for adopting holistic assessment methodologies which give proper consideration to welfare-improving health co-benefits with potentially negative economic repercussions (such as increased longevity).
Electronic supplementary material
The online version of this article (doi:10.1007/s10584-013-0881-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4372778  PMID: 25834297
13.  Developing and testing a street audit tool using Google Street View to measure environmental supportiveness for physical activity 
Walking for physical activity is associated with substantial health benefits for adults. Increasingly research has focused on associations between walking behaviours and neighbourhood environments including street characteristics such as pavement availability and aesthetics. Nevertheless, objective assessment of street-level data is challenging. This research investigates the reliability of a new street characteristic audit tool designed for use with Google Street View, and assesses levels of agreement between computer-based and on-site auditing.
The Forty Area STudy street VIEW (FASTVIEW) tool, a Google Street View based audit tool, was developed incorporating nine categories of street characteristics. Using the tool, desk-based audits were conducted by trained researchers across one large UK town during 2011. Both inter and intra-rater reliability were assessed. On-site street audits were also completed to test the criterion validity of the method. All reliability scores were assessed by percentage agreement and the kappa statistic.
Within-rater agreement was high for each category of street characteristic (range: 66.7%-90.0%) and good to high between raters (range: 51.3%-89.1%). A high level of agreement was found between the Google Street View audits and those conducted in-person across the nine categories examined (range: 75.0%-96.7%).
The audit tool was found to provide a reliable and valid measure of street characteristics. The use of Google Street View to capture street characteristic data is recommended as an efficient method that could substantially increase potential for large-scale objective data collection.
PMCID: PMC3765385  PMID: 23972205
Physical activity; Walking; Environment; Street audit
14.  Chromosomal rearrangements maintain a polymorphic supergene controlling butterfly mimicry 
Nature  2011;477(7363):203-206.
Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes1. Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for ‘pin’ and ‘thrum’ floral types in Primula1 and Fagopyrum2, but classic examples are also found in insect mimicry3–5 and snail morphology6. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge7–10. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species9–11, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the Plocus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow.
PMCID: PMC3717454  PMID: 21841803
15.  Microsatellites for the Marsh Fritillary Butterfly: De Novo Transcriptome Sequencing, and a Comparison with Amplified Fragment Length Polymorphism (AFLP) Markers 
PLoS ONE  2013;8(1):e54721.
Until recently the isolation of microsatellite markers from Lepidoptera has proved troublesome, expensive and time-consuming. Following on from a previous study of Edith's checkerspot butterfly, Euphydryas editha, we developed novel microsatellite markers for the vulnerable marsh fritillary butterfly, E. aurinia. Our goal was to optimize the process in order to reduce both time and cost relative to prevailing techniques. This was accomplished by using a combination of previously developed techniques: in silico mining of a de novo assembled transcriptome sequence, and genotyping the microsatellites found there using an economic method of fluorescently labelling primers.
Principal Findings
In total, we screened nine polymorphic microsatellite markers, two of which were previously published, and seven that were isolated de novo. These markers were able to amplify across geographically isolated populations throughout Continental Europe and the UK. Significant deviations from Hardy-Weinberg equilibrium were evident in some populations, most likely due to the presence of null alleles. However, we used an Fst outlier approach to show that these markers are likely selectively neutral. Furthermore, using a set of 128 individuals from 11 populations, we demonstrate consistency in population differentiation estimates with previously developed amplified fragment length polymorphism (AFLP) markers (r = 0.68, p<0.001).
Rapid development of microsatellite markers for difficult taxa such as Lepidoptera, and concordant results with other putatively neutral molecular markers, demonstrate the potential of de novo transcriptional sequencing for future studies of population structure and gene flow that are desperately needed for declining species across fragmented landscapes.
PMCID: PMC3549983  PMID: 23349956
16.  Butterfly genome reveals promiscuous exchange of mimicry adaptations among species 
Dasmahapatra, Kanchon K | Walters, James R. | Briscoe, Adriana D. | Davey, John W. | Whibley, Annabel | Nadeau, Nicola J. | Zimin, Aleksey V. | Hughes, Daniel S. T. | Ferguson, Laura C. | Martin, Simon H. | Salazar, Camilo | Lewis, James J. | Adler, Sebastian | Ahn, Seung-Joon | Baker, Dean A. | Baxter, Simon W. | Chamberlain, Nicola L. | Chauhan, Ritika | Counterman, Brian A. | Dalmay, Tamas | Gilbert, Lawrence E. | Gordon, Karl | Heckel, David G. | Hines, Heather M. | Hoff, Katharina J. | Holland, Peter W.H. | Jacquin-Joly, Emmanuelle | Jiggins, Francis M. | Jones, Robert T. | Kapan, Durrell D. | Kersey, Paul | Lamas, Gerardo | Lawson, Daniel | Mapleson, Daniel | Maroja, Luana S. | Martin, Arnaud | Moxon, Simon | Palmer, William J. | Papa, Riccardo | Papanicolaou, Alexie | Pauchet, Yannick | Ray, David A. | Rosser, Neil | Salzberg, Steven L. | Supple, Megan A. | Surridge, Alison | Tenger-Trolander, Ayse | Vogel, Heiko | Wilkinson, Paul A. | Wilson, Derek | Yorke, James A. | Yuan, Furong | Balmuth, Alexi L. | Eland, Cathlene | Gharbi, Karim | Thomson, Marian | Gibbs, Richard A. | Han, Yi | Jayaseelan, Joy C. | Kovar, Christie | Mathew, Tittu | Muzny, Donna M. | Ongeri, Fiona | Pu, Ling-Ling | Qu, Jiaxin | Thornton, Rebecca L. | Worley, Kim C. | Wu, Yuan-Qing | Linares, Mauricio | Blaxter, Mark L. | Constant, Richard H. ffrench | Joron, Mathieu | Kronforst, Marcus R. | Mullen, Sean P. | Reed, Robert D. | Scherer, Steven E. | Richards, Stephen | Mallet, James | McMillan, W. Owen | Jiggins, Chris D.
Nature  2012;487(7405):94-98.
The evolutionary importance of hybridization and introgression has long been debated1. We used genomic tools to investigate introgression in Heliconius, a rapidly radiating genus of neotropical butterflies widely used in studies of ecology, behaviour, mimicry and speciation2-5 . We sequenced the genome of Heliconius melpomene and compared it with other taxa to investigate chromosomal evolution in Lepidoptera and gene flow among multiple Heliconius species and races. Among 12,657 predicted genes for Heliconius, biologically important expansions of families of chemosensory and Hox genes are particularly noteworthy. Chromosomal organisation has remained broadly conserved since the Cretaceous, when butterflies split from the silkmoth lineage. Using genomic resequencing, we show hybrid exchange of genes between three co-mimics, H. melpomene, H. timareta, and H. elevatus, especially at two genomic regions that control mimicry pattern. Closely related Heliconius species clearly exchange protective colour pattern genes promiscuously, implying a major role for hybridization in adaptive radiation.
PMCID: PMC3398145  PMID: 22722851
17.  5-HTTLPR and Early Childhood Adversities Moderate Cognitive and Emotional Processing in Adolescence 
PLoS ONE  2012;7(11):e48482.
Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) and exposure to early childhood adversities (CA) are independently associated with individual differences in cognitive and emotional processing. Whether these two factors interact to influence cognitive and emotional processing is not known.
Methodology and Principal Findings
We used a sample of 238 adolescents from a community study characterised by the presence of the short allele of 5-HTTLPR (LL, LS, SS) and the presence or absence of exposure to CA before 6 years of age. We measured cognitive and emotional processing using a set of neuropsychological tasks selected predominantly from the CANTAB® battery. We found that adolescents homozygous for the short allele (SS) of 5-HTTLPR and exposed to CA were worse at classifying negative and neutral stimuli and made more errors in response to ambiguous negative feedback. In addition, cognitive and emotional processing deficits were associated with diagnoses of anxiety and/or depressions.
Conclusion and Significance
Cognitive and emotional processing deficits may act as a transdiagnostic intermediate marker for anxiety and depressive disorders in genetically susceptible individuals exposed to CA.
PMCID: PMC3509124  PMID: 23209555
18.  Concentration–Response Function for Ozone and Daily Mortality: Results from Five Urban and Five Rural U.K. Populations 
Environmental Health Perspectives  2012;120(10):1411-1417.
Background: Short-term exposure to ozone has been associated with increased daily mortality. The shape of the concentration–response relationship—and, in particular, if there is a threshold—is critical for estimating public health impacts.
Objective: We investigated the concentration–response relationship between daily ozone and mortality in five urban and five rural areas in the United Kingdom from 1993 to 2006.
Methods: We used Poisson regression, controlling for seasonality, temperature, and influenza, to investigate associations between daily maximum 8-hr ozone and daily all-cause mortality, assuming linear, linear-threshold, and spline models for all-year and season-specific periods. We examined sensitivity to adjustment for particles (urban areas only) and alternative temperature metrics.
Results: In all-year analyses, we found clear evidence for a threshold in the concentration–response relationship between ozone and all-cause mortality in London at 65 µg/m3 [95% confidence interval (CI): 58, 83] but little evidence of a threshold in other urban or rural areas. Combined linear effect estimates for all-cause mortality were comparable for urban and rural areas: 0.48% (95% CI: 0.35, 0.60) and 0.58% (95% CI: 0.36, 0.81) per 10-µg/m3 increase in ozone concentrations, respectively. Seasonal analyses suggested thresholds in both urban and rural areas for effects of ozone during summer months.
Conclusions: Our results suggest that health impacts should be estimated across the whole ambient range of ozone using both threshold and nonthreshold models, and models stratified by season. Evidence of a threshold effect in London but not in other study areas requires further investigation. The public health impacts of exposure to ozone in rural areas should not be overlooked.
PMCID: PMC3491921  PMID: 22814173
concentration–response function; daily mortality; ozone; U.K. population
19.  CerealsDB 2.0: an integrated resource for plant breeders and scientists 
BMC Bioinformatics  2012;13:219.
Food security is an issue that has come under renewed scrutiny amidst concerns that substantial yield increases in cereal crops are required to feed the world’s booming population. Wheat is of fundamental importance in this regard being one of the three most important crops for both human consumption and livestock feed; however, increase in crop yields have not kept pace with the demands of a growing world population. In order to address this issue, plant breeders require new molecular tools to help them identify genes for important agronomic traits that can be introduced into elite varieties. Studies of the genome using next-generation sequencing enable the identification of molecular markers such as single nucleotide polymorphisms that may be used by breeders to identify and follow genes when breeding new varieties. The development and application of next-generation sequencing technologies has made the characterisation of SNP markers in wheat relatively cheap and straightforward. There is a growing need for the widespread dissemination of this information to plant breeders.
CerealsDB is an online resource containing a range of genomic datasets for wheat (Triticum aestivum) that will assist plant breeders and scientists to select the most appropriate markers for marker assisted selection. CerealsDB includes a database which currently contains in excess of 100,000 putative varietal SNPs, of which several thousand have been experimentally validated. In addition, CerealsDB contains databases for DArT markers and EST sequences, and links to a draft genome sequence for the wheat variety Chinese Spring.
CerealsDB is an open access website that is rapidly becoming an invaluable resource within the wheat research and plant breeding communities.
PMCID: PMC3447715  PMID: 22943283
Wheat; Single nucleotide polymorphisms; SNPs; Database
21.  Pdl1 Is a Putative Lipase that Enhances Photorhabdus Toxin Complex Secretion 
PLoS Pathogens  2012;8(5):e1002692.
The Toxin Complex (TC) is a large multi-subunit toxin first characterized in the insect pathogens Photorhabdus and Xenorhabdus, but now seen in a range of pathogens, including those of humans. These complexes comprise three protein subunits, A, B and C which in the Xenorhabdus toxin are found in a 4∶1∶1 stoichiometry. Some TCs have been demonstrated to exhibit oral toxicity to insects and have the potential to be developed as a pest control technology. The lack of recognisable signal sequences in the three large component proteins hinders an understanding of their mode of secretion. Nevertheless, we have shown the Photorhabdus luminescens (Pl) Tcd complex has been shown to associate with the bacteria's surface, although some strains can also release it into the surrounding milieu. The large number of tc gene homologues in Pl make study of the export process difficult and as such we have developed and validated a heterologous Escherichia coli expression model to study the release of these important toxins. In addition to this model, we have used comparative genomics between a strain that releases high levels of Tcd into the supernatant and one that retains the toxin on its surface, to identify a protein responsible for enhancing secretion and release of these toxins. This protein is a putative lipase (Pdl1) which is regulated by a small tightly linked antagonist protein (Orf53). The identification of homologues of these in other bacteria, linked to other virulence factor operons, such as type VI secretion systems, suggests that these genes represent a general and widespread mechanism for enhancing toxin release in Gram negative pathogens.
Author Summary
Bacterial pathogens of insects deploy a range of toxins to combat the innate immune system and kill the host. There is significant interest in developing these toxins as candidates for crop protection strategies. To date, transgenic crops expressing Bacillus thuringiensis Cry toxins have been used to resist predation by pests. In order to minimize the risk of insect resistance development, current research in crop biotechnology comprises the design of new transgenic plants expressing toxins with different modes of action. The Toxin Complex (TC) gene family first identified in the insect pathogen Photorhabdus has received interest as an alternative. It remains obscure how Photorhabdus regulates, assembles, and secretes such a large toxin complex. We have identified a small lipase protein, Pdl1, which enhances secretion and leads to the release of the Toxin complex off the bacterial surface. This is of wider significance because TC toxin homologues are also found in a range of human pathogens, such as Yersinia in which they have been implicated in human virulence. Furthermore homologues of pdl are also seen tightly linked to other virulence loci such as the type VI systems of Vibrio. We speculate that this Pdl mediated secretion enhancement system is a widespread and important mechanism used by Gram negative bacterial pathogens.
PMCID: PMC3355079  PMID: 22615559
22.  The Buncefield Oil Depot Fire of 2005: Potential Air-Pollution Health Impacts Under Alternative Meteorological Scenarios 
PLoS Currents  2012;4:RRN1300.
Objective: To model the possible air pollution-related health impact of the 2005 oil depot fire at Buncefield, near London, UK, under alternative meteorological conditions to those experienced at the time.
Design: Atmospheric dispersion modelling of the smoke plume was conducted under the range of meteorological conditions occurring throughout 2005 assuming constant particle emission rates. Population exposure to particle concentrations (PM10) was calculated by linking the atmospheric dispersion modelling data (2 km resolution) and postcode population data. Health impacts were estimated using time-series-based exposure-response relationships for PM10 available from the epidemiological literature.
Main outcomes: Estimates of pollution-related deaths brought forward, emergency hospital admissions from respiratory problems and emergency hospital admissions from cardiovascular disease.
Findings: The highest four-day population exposure to PM10 for meteorological data from 2005 was predicted to occur between 5 and 8 August 2005, when northerly winds would have carried the plume towards London and surrounding areas of high population density. On these days, we estimated the additional PM10 exposure would have resulted in around 12 extra deaths brought forward, and around 13 additional emergency hospital admissions and a similar additional number of emergency admissions for cardiovascular disease. These numbers are slightly greater than estimated deaths and emergency admissions attributable to regular anthropogenic PM10 concentrations in south east England over the same four day period.
Conclusions: Although the particle pollution-related health impacts of the Buncefield fire could have been higher under different meteorological conditions, it is unlikely that the impacts would be substantially greater than those attributable to regular anthropogenic particle pollution over the similar period.
Keywords: oil depot fire; health impact; epidemiology; air pollution; explosion; atmospheric dispersion modelling; exposure
PMCID: PMC3271948  PMID: 22453896
23.  The Buncefield Oil Depot Fire of 2005: Potential Air-Pollution Health Impacts Under Alternative Meteorological Scenarios 
PLoS Currents  2012;4:RRN1300.
Objective: To model the possible air pollution-related health impact of the 2005 oil depot fire at Buncefield, near London, UK, under alternative meteorological conditions to those experienced at the time.
Design: Atmospheric dispersion modelling of the smoke plume was conducted under the range of meteorological conditions occurring throughout 2005 assuming constant particle emission rates. Population exposure to particle concentrations (PM10) was calculated by linking the atmospheric dispersion modelling data (2 km resolution) and postcode population data. Health impacts were estimated using time-series-based exposure-response relationships for PM10 available from the epidemiological literature.
Main outcomes: Estimates of pollution-related deaths brought forward, emergency hospital admissions from respiratory problems and emergency hospital admissions from cardiovascular disease.
Findings: The highest four-day population exposure to PM10 for meteorological data from 2005 was predicted to occur between 5 and 8 August 2005, when northerly winds would have carried the plume towards London and surrounding areas of high population density. On these days, we estimated the additional PM10 exposure would have resulted in around 12 extra deaths brought forward, and around 13 additional emergency hospital admissions and a similar additional number of emergency admissions for cardiovascular disease. These numbers are slightly greater than estimated deaths and emergency admissions attributable to regular anthropogenic PM10 concentrations in south east England over the same four day period.
Conclusions: Although the particle pollution-related health impacts of the Buncefield fire could have been higher under different meteorological conditions, it is unlikely that the impacts would be substantially greater than those attributable to regular anthropogenic particle pollution over the similar period.
Keywords: oil depot fire; health impact; epidemiology; air pollution; explosion; atmospheric dispersion modelling; exposure
PMCID: PMC3271948  PMID: 22453896
24.  Improving mood with psychoanalytic and cognitive therapies (IMPACT): a pragmatic effectiveness superiority trial to investigate whether specialised psychological treatment reduces the risk for relapse in adolescents with moderate to severe unipolar depression: study protocol for a randomised controlled trial 
Trials  2011;12:175.
Up to 70% of adolescents with moderate to severe unipolar major depression respond to psychological treatment plus Fluoxetine (20-50 mg) with symptom reduction and improved social function reported by 24 weeks after beginning treatment. Around 20% of non responders appear treatment resistant and 30% of responders relapse within 2 years. The specific efficacy of different psychological therapies and the moderators and mediators that influence risk for relapse are unclear. The cost-effectiveness and safety of psychological treatments remain poorly evaluated.
Improving Mood with Psychoanalytic and Cognitive Therapies, the IMPACT Study, will determine whether Cognitive Behavioural Therapy or Short Term Psychoanalytic Therapy is superior in reducing relapse compared with Specialist Clinical Care. The study is a multicentre pragmatic effectiveness superiority randomised clinical trial: Cognitive Behavioural Therapy consists of 20 sessions over 30 weeks, Short Term Psychoanalytic Psychotherapy 30 sessions over 30 weeks and Specialist Clinical Care 12 sessions over 20 weeks. We will recruit 540 patients with 180 randomised to each arm. Patients will be reassessed at 6, 12, 36, 52 and 86 weeks. Methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, research assessors independent of treatment team and blind to randomization, analysis by intention to treat, data management using remote data entry, measures of quality assurance, advanced statistical analysis, manualised treatment protocols, checks of adherence and competence of therapists and assessment of cost-effectiveness. We will also determine whether time to recovery and/or relapse are moderated by variations in brain structure and function and selected genetic and hormone biomarkers taken at entry.
The objective of this clinical trial is to determine whether there are specific effects of specialist psychotherapy that reduce relapse in unipolar major depression in adolescents and thereby costs of treatment to society. We also anticipate being able to utilise psychotherapy experience, neuroimaging, genetic and hormone measures to reveal what techniques and their protocols may work best for which patients.
Trial Registration
Current Controlled Trials ISRCTN83033550
PMCID: PMC3148993  PMID: 21752257
25.  Profiles of family-focused adverse experiences through childhood and early adolescence: The ROOTS project a community investigation of adolescent mental health 
BMC Psychiatry  2011;11:109.
Adverse family experiences in early life are associated with subsequent psychopathology. This study adds to the growing body of work exploring the nature and associations between adverse experiences over the childhood years.
Primary carers of 1143 randomly recruited 14-year olds in Cambridgeshire and Suffolk, UK were interviewed using the Cambridge Early Experiences Interview (CAMEEI) to assess family-focused adversities. Adversities were recorded retrospectively in three time periods (early and later childhood and early adolescence). Latent Class Analysis (LCA) grouped individuals into adversity classes for each time period and longitudinally. Adolescents were interviewed to generate lifetime DSM-IV diagnoses using the K-SADS-PL. The associations between adversity class and diagnoses were explored.
LCA generated a 4-class model for each time period and longitudinally. In early childhood 69% were allocated to a low adversity class; a moderate adversity class (19%) showed elevated rates of family loss, mild or moderate family discord, financial difficulties, maternal psychiatric illness and higher risk for paternal atypical parenting; a severe class (6%) experienced higher rates on all indicators and almost exclusively accounted for incidents of child abuse; a fourth class, characterised by atypical parenting from both parents, accounted for the remaining 7%. Class membership was fairly stable (~ 55%) over time with escape from any adversity by 14 years being uncommon. Compared to those in the low class, the odds ratio for reported psychopathology in adolescents in the severe class ranged from 8 for disruptive behaviour disorders through to 4.8 for depressions and 2.0 for anxiety disorders. Only in the low adversity class did significantly more females than males report psychopathology.
Family adversities in the early years occur as multiple rather than single experiences. Although some children escape adversity, for many this negative family environment persists over the first 15 years of life. Different profiles of family risk may be associated with specific mental disorders in young people. Sex differences in psychopathologies may be most pronounced in those exposed to low levels of family adversities.
PMCID: PMC3199756  PMID: 21736727

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