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1.  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.
doi:10.1007/s11524-012-9773-8
PMCID: PMC3795192  PMID: 23271143
Housing; Household energy; Sanitation; Development; Health
2.  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; http://dx.doi.org/10.1289/ehp.1306744
doi:10.1289/ehp.1306744
PMCID: PMC4014758  PMID: 24583270
3.  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.
doi:10.1017/S0954579412000922
PMCID: PMC3819563  PMID: 23398755
4.  Measurement error in time-series analysis: a simulation study comparing modelled and monitored data 
Background
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.
Methods
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).
Results
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).
Conclusion
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.
doi:10.1186/1471-2288-13-136
PMCID: PMC3871053  PMID: 24219031
Measurement error; Epidemiology; Time-series; Mortality; Nitrogen dioxide; Ozone
5.  Rumination, anxiety, depressive symptoms and subsequent depression in adolescents at risk for psychopathology: a longitudinal cohort study 
BMC Psychiatry  2013;13:250.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-244X-13-250
PMCID: PMC3851454  PMID: 24103296
Depression; Anxiety; Rumination; Factor analysis; Adolescence; Psychometrics
6.  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.
Background
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.
Methods/Design
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).
Discussion
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).
doi:10.1186/1471-244X-13-247
PMCID: PMC3851239  PMID: 24094274
7.  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.
doi:10.1186/1742-7622-10-9
PMCID: PMC3852289  PMID: 24073617
Nutrition; Malnutrition; Epidemiology; Health impact; Food prices; Modeling
8.  Developing and testing a street audit tool using Google Street View to measure environmental supportiveness for physical activity 
Background
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.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.1186/1479-5868-10-103
PMCID: PMC3765385  PMID: 23972205
Physical activity; Walking; Environment; Street audit
9.  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.
doi:10.1038/nature10341
PMCID: PMC3717454  PMID: 21841803
10.  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.
Background
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).
Significance
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.
doi:10.1371/journal.pone.0054721
PMCID: PMC3549983  PMID: 23349956
11.  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.
doi:10.1038/nature11041
PMCID: PMC3398145  PMID: 22722851
12.  5-HTTLPR and Early Childhood Adversities Moderate Cognitive and Emotional Processing in Adolescence 
PLoS ONE  2012;7(11):e48482.
Background
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.
doi:10.1371/journal.pone.0048482
PMCID: PMC3509124  PMID: 23209555
13.  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.
doi:10.1289/ehp.1104108
PMCID: PMC3491921  PMID: 22814173
concentration–response function; daily mortality; ozone; U.K. population
14.  CerealsDB 2.0: an integrated resource for plant breeders and scientists 
BMC Bioinformatics  2012;13:219.
Background
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.
Description
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.
Conclusion
CerealsDB is an open access website that is rapidly becoming an invaluable resource within the wheat research and plant breeding communities.
doi:10.1186/1471-2105-13-219
PMCID: PMC3447715  PMID: 22943283
Wheat; Single nucleotide polymorphisms; SNPs; Database
16.  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.
doi:10.1371/journal.ppat.1002692
PMCID: PMC3355079  PMID: 22615559
17.  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
doi:10.1371/currents.RRN1300
PMCID: PMC3271948  PMID: 22453896
18.  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
doi:10.1371/currents.RRN1300
PMCID: PMC3271948  PMID: 22453896
19.  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.
Background
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.
Methods/Design
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.
Discussion
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
doi:10.1186/1745-6215-12-175
PMCID: PMC3148993  PMID: 21752257
20.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-244X-11-109
PMCID: PMC3199756  PMID: 21736727
21.  Long-term effects of flooding on mortality in England and Wales, 1994-2005: controlled interrupted time-series analysis 
Environmental Health  2011;10:11.
Background
Limited evidence suggests that being flooded may increase mortality and morbidity among affected householders not just at the time of the flood but for months afterwards. The objective of this study is to explore the methods for quantifying such long-term health effects of flooding by analysis of routine mortality registrations in England and Wales.
Methods
Mortality data, geo-referenced by postcode of residence, were linked to a national database of flood events for 1994 to 2005. The ratio of mortality in the post-flood year to that in the pre-flood year within flooded postcodes was compared with that in non-flooded boundary areas (within 5 km of a flood). Further analyses compared the observed number of flood-area deaths in the year after flooding with the number expected from analysis of mortality trends stratified by region, age-group, sex, deprivation group and urban-rural status.
Results
Among the 319 recorded floods, there were 771 deaths in the year before flooding and 693 deaths in the year after (post-/pre-flood ratio of 0.90, 95% CI 0.82, 1.00). This ratio did not vary substantially by age, sex, population density or deprivation. A similar post-flood 'deficit' of deaths was suggested by the analyses based on observed/expected deaths.
Conclusions
The observed post-flood 'deficit' of deaths is counter-intuitive and difficult to interpret because of the possible influence of population displacement caused by flooding. The bias that might arise from such displacement remains unquantified but has important implications for future studies that use place of residence as a marker of exposure.
doi:10.1186/1476-069X-10-11
PMCID: PMC3042000  PMID: 21288358
22.  Pyrosequencing the transcriptome of the greenhouse whitefly, Trialeurodes vaporariorum reveals multiple transcripts encoding insecticide targets and detoxifying enzymes 
BMC Genomics  2011;12:56.
Background
The whitefly Trialeurodes vaporariorum is an economically important crop pest in temperate regions that has developed resistance to most classes of insecticides. However, the molecular mechanisms underlying resistance have not been characterised and, to date, progress has been hampered by a lack of nucleotide sequence data for this species. Here, we use pyrosequencing on the Roche 454-FLX platform to produce a substantial and annotated EST dataset. This 'unigene set' will form a critical reference point for quantitation of over-expressed messages via digital transcriptomics.
Results
Pyrosequencing produced around a million sequencing reads that assembled into 54,748 contigs, with an average length of 965 bp, representing a dramatic expansion of existing cDNA sequences available for T. vaporariorum (only 43 entries in GenBank at the time of this publication). BLAST searching of non-redundant databases returned 20,333 significant matches and those gene families potentially encoding gene products involved in insecticide resistance were manually curated and annotated. These include, enzymes potentially involved in the detoxification of xenobiotics and those encoding the targets of the major chemical classes of insecticides. A total of 57 P450s, 17 GSTs and 27 CCEs were identified along with 30 contigs encoding the target proteins of six different insecticide classes.
Conclusion
Here, we have developed new transcriptomic resources for T. vaporariorum. These include a substantial and annotated EST dataset that will serve the community studying this important crop pest and will elucidate further the molecular mechanisms underlying insecticide resistance.
doi:10.1186/1471-2164-12-56
PMCID: PMC3036619  PMID: 21261962
23.  Genome-Wide Analysis Reveals Loci Encoding Anti-Macrophage Factors in the Human Pathogen Burkholderia pseudomallei K96243 
PLoS ONE  2010;5(12):e15693.
Burkholderia pseudomallei is an important human pathogen whose infection biology is still poorly understood. The bacterium is endemic to tropical regions, including South East Asia and Northern Australia, where it causes melioidosis, a serious disease associated with both high mortality and antibiotic resistance. B. pseudomallei is a Gram-negative facultative intracellular pathogen that is able to replicate in macrophages. However despite the critical nature of its interaction with macrophages, few anti-macrophage factors have been characterized to date. Here we perform a genome-wide gain of function screen of B. pseudomallei strain K96243 to identify loci encoding factors with anti-macrophage activity. We identify a total of 113 such loci scattered across both chromosomes, with positive gene clusters encoding transporters and secretion systems, enzymes/toxins, secondary metabolite, biofilm, adhesion and signal response related factors. Further phenotypic analysis of four of these regions shows that the encoded factors cause striking cellular phenotypes relevant to infection biology, including apoptosis, formation of actin ‘tails’ and multi-nucleation within treated macrophages. The detailed analysis of the remaining host of loci will facilitate genetic dissection of the interaction of this important pathogen with host macrophages and thus further elucidate this critical part of its infection cycle.
doi:10.1371/journal.pone.0015693
PMCID: PMC3008741  PMID: 21203527
24.  Diversity of Beetle Genes Encoding Novel Plant Cell Wall Degrading Enzymes 
PLoS ONE  2010;5(12):e15635.
Plant cell walls are a heterogeneous mixture of polysaccharides and proteins that require a range of different enzymes to degrade them. Plant cell walls are also the primary source of cellulose, the most abundant and useful biopolymer on the planet. Plant cell wall degrading enzymes (PCWDEs) are therefore important in a wide range of biotechnological processes from the production of biofuels and food to waste processing. However, despite the fact that the last common ancestor of all deuterostomes was inferred to be able to digest, or even synthesize, cellulose using endogenous genes, all model insects whose complete genomes have been sequenced lack genes encoding such enzymes. To establish if the apparent “disappearance” of PCWDEs from insects is simply a sampling problem, we used 454 mediated pyrosequencing to scan the gut transcriptomes of beetles that feed on a variety of plant derived diets. By sequencing the transcriptome of five beetles, and surveying publicly available ESTs, we describe 167 new beetle PCWDEs belonging to eight different enzyme families. This survey proves that these enzymes are not only present in non-model insects but that the multigene families that encode them are apparently undergoing complex birth-death dynamics. This reinforces the observation that insects themselves, and not just their microbial symbionts, are a rich source of PCWDEs. Further it emphasises that the apparent absence of genes encoding PCWDEs from model organisms is indeed simply a sampling artefact. Given the huge diversity of beetles alive today, and the diversity of their lifestyles and diets, we predict that beetle guts will emerge as an important new source of enzymes for use in biotechnology.
doi:10.1371/journal.pone.0015635
PMCID: PMC3003705  PMID: 21179425
25.  Short term effects of temperature on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial Ischaemia National Audit Project (MINAP) registry 
Objective To examine the short term relation between ambient temperature and risk of myocardial infarction.
Design Daily time series regression analysis.
Setting 15 conurbations in England and Wales.
Participants 84 010 hospital admissions for myocardial infarction recorded in the Myocardial Ischaemia National Audit Project during 2003-6 (median 57 events a day).
Main outcome measures Change in risk of myocardial infarction associated with a 1°C difference in temperature, including effects delayed by up to 28 days.
Results Smoothed graphs revealed a broadly linear relation between temperature and myocardial infarction, which was well characterised by log-linear models without a temperature threshold: each 1°C reduction in daily mean temperature was associated with a 2.0% (95% confidence interval 1.1% to 2.9%) cumulative increase in risk of myocardial infarction over the current and following 28 days, the strongest effects being estimated at intermediate lags of 2-7 and 8-14 days: increase per 1°C reduction 0.6% (95% confidence interval 0.2% to 1.1%) and 0.7% (0.3% to 1.1%), respectively. Heat had no detrimental effect. Adults aged 75-84 and those with previous coronary heart disease seemed more vulnerable to the effects of cold than other age groups (P for interaction 0.001 or less in each case), whereas those taking aspirin were less vulnerable (P for interaction 0.007).
Conclusions Increases in risk of myocardial infarction at colder ambient temperatures may be one driver of cold related increases in overall mortality, but an increased risk of myocardial infarction at higher temperatures was not detected. The risk of myocardial infarction in vulnerable people might be reduced by the provision of targeted advice or other interventions, triggered by forecasts of lower temperature.
doi:10.1136/bmj.c3823
PMCID: PMC2919679  PMID: 20699305

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