The number of publicly available parasitic worm genome sequences has increased dramatically in the past three years, and research interest in helminth functional genomics is now quickly gathering ...pace in response to the foundation that has been laid by these collective efforts. A systematic approach to the organisation, curation, analysis and presentation of these data is clearly vital for maximising the utility of these data to researchers. We have developed a portal called WormBase ParaSite (http://parasite.wormbase.org) for interrogating helminth genomes on a large scale. Data from over 100 nematode and platyhelminth species are integrated, adding value by way of systematic and consistent functional annotation (e.g. protein domains and Gene Ontology terms), gene expression analysis (e.g. alignment of life-stage specific transcriptome data sets), and comparative analysis (e.g. orthologues and paralogues). We provide several ways of exploring the data, including genome browsers, genome and gene summary pages, text search, sequence search, a query wizard, bulk downloads, and programmatic interfaces. In this review, we provide an overview of the back-end infrastructure and analysis behind WormBase ParaSite, and the displays and tools available to users for interrogating helminth genomic data.
The overall 5‐year relative survival rate for all cancers combined is now 68%, and there are over 16.9 million survivors in the United States. Evidence from laboratory and observational studies ...suggests that factors such as diet, physical activity, and obesity may affect risk for recurrence and overall survival after a cancer diagnosis. The purpose of this American Cancer Society guideline is to provide evidence‐based, cancer‐specific recommendations for anthropometric parameters, physical activity, diet, and alcohol intake for reducing recurrence and cancer‐specific and overall mortality. The audiences for this guideline are health care providers caring for cancer survivors as well as cancer survivors and their families. The guideline is intended to serve as a resource for informing American Cancer Society programs, health policy, and the media. Sources of evidence that form the basis of this guideline are systematic literature reviews, meta‐analyses, pooled analyses of cohort studies, and large randomized clinical trials published since 2012. Recommendations for nutrition and physical activity during cancer treatment, informed by current practice, large cancer care organizations, and reviews of other expert bodies, are also presented. To provide additional context for the guidelines, the authors also include information on the relationship between health‐related behaviors and comorbidities, long‐term sequelae and patient‐reported outcomes, and health disparities, with attention to enabling survivors' ability to adhere to recommendations. Approaches to meet survivors' needs are addressed as well as clinical care coordination and resources for nutrition and physical activity counseling after a cancer diagnosis.
Atherosclerosis, the chronic accumulation of cholesterol-rich plaque within arteries, is associated with a broad spectrum of cardiovascular diseases including myocardial infarction, aortic aneurysm, ...peripheral vascular disease, and stroke. Atherosclerotic cardiovascular disease remains a leading cause of mortality in high-income countries and recent years have witnessed a notable increase in prevalence within low- and middle-income regions of the world. Considering this prominent and evolving global burden, there is a need to identify the cellular mechanisms that underlie the pathogenesis of atherosclerosis to discover novel therapeutic targets for preventing or mitigating its clinical sequelae. Despite decades of research, we still do not fully understand the complex cell-cell interactions that drive atherosclerosis, but new investigative approaches are rapidly shedding light on these essential mechanisms. The vascular endothelium resides at the interface of systemic circulation and the underlying vessel wall and plays an essential role in governing pathophysiological processes during atherogenesis. In this review, we present emerging evidence that implicates the activated endothelium as a driver of atherosclerosis by directing site-specificity of plaque formation and by promoting plaque development through intracellular processes, which regulate endothelial cell proliferation and turnover, metabolism, permeability, and plasticity. Moreover, we highlight novel mechanisms of intercellular communication by which endothelial cells modulate the activity of key vascular cell populations involved in atherogenesis, and discuss how endothelial cells contribute to resolution biology - a process that is dysregulated in advanced plaques. Finally, we describe important future directions for preclinical atherosclerosis research, including epigenetic and targeted therapies, to limit the progression of atherosclerosis in at-risk or affected patients.
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic ...heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
A common approach to improving probabilistic forecasts is to identify and leverage the forecasts from experts in the crowd based on forecasters' performance on prior questions with known outcomes. ...However, such information is often unavailable to decision-makers on many forecasting problems, and thus it can be difficult to identify and leverage expertise. In the current paper, we propose a novel algorithm for aggregating probabilistic forecasts using forecasters' meta-predictions about what other forecasters will predict. We test the performance of an extremised version of our algorithm against current forecasting approaches in the literature and show that our algorithm significantly outperforms all other approaches on a large collection of 500 binary decision problems varying in five levels of difficulty. The success of our algorithm demonstrates the potential of using meta-predictions to leverage latent expertise in environments where forecasters' expertise cannot otherwise be easily identified.
In this article, the American Cancer Society (ACS) provides estimates of new breast cancer cases and deaths in 2006 and describes trends in incidence, mortality, and survival for female breast cancer ...in the United States. These estimates are based on incidence data from the National Cancer Institute (NCI) and the North American Association of Central Cancer Registries, which includes state data from NCI and the National Program of Cancer Registries of the Centers for Disease Control and Prevention and mortality data from the National Center for Health Statistics for the most recent years available (1975 to 2002). This article also shows trends in screening mammography. Approximately 212,920 new cases of invasive breast cancer, 61,980 in situ cases, and 40,970 deaths are expected to occur among US women in 2006. As previously reported, breast cancer incidence rates increased rapidly among women of all races from 1980 to 1987, a period when there was increasing uptake of mammography by a growing proportion of US women, and then continued to increase, but at a much slower rate, from 1987 to 2002. Trends in incidence vary by age, race, socioeconomic status, and stage. The continuing increase in incidence (all stages combined) is limited to White women age 50 and older; recent trends are stable for African American women age 50 and older and White women under age 50 years and are decreasing for African American women under age 50 years. Although incidence rates (all races combined) are substantially higher for women age 50 and older (375.0 per 100,000 females) compared with women younger than 50 years (42.5 per 100,000 females), approximately 23% of breast cancers are diagnosed in women younger than 50 years because those women represent 73% of the female population. For women age 35 and younger, age‐specific incidence rates are slightly higher among African Americans compared with Whites but then cross over so that Whites have substantially higher incidence at all later ages. Among women of all races and ages, breast cancer mortality rates declined at an average rate of 2.3% per year between 1990 and 2002, a trend that reflects progress in both early detection and treatment. However, death rates in African American women remain 37% higher than in Whites, despite lower incidence rates. Although, in national surveys, approximately 70% of women age 40 years and older report having had a mammogram in the past 2 years, rates vary by race/ethnicity and are markedly lower among women with lower levels of education, without health insurance, and in recent immigrants. Furthermore, a recent study suggests that the true percentage of women having regular mammography is lower than reported in survey data. Encouraging patients age 40 years and older to have annual mammography and clinical breast exam is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate referrals and treatment. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high‐quality screening, diagnosis, and treatment to all segments of the population.
Building on previous research on the use of macroeconomic factors for conflict prediction and using data on political instability provided by the Political Instability Task Force, this article ...proposes two minimal forecasting models of political instability optimised to have the greatest possible predictive power for one-year and two-year event horizons, while still making predictions that are fully explainable. Both models employ logistic regression and use just three predictors: polity code (a measure of government type), infant mortality, and years of stability (i.e., years since the last instability event). These models make predictions for 176 countries on a country-year basis and achieve AUPRC's of 0.108 and 0.115 for the one-year and two-year models respectively. They use public data with ongoing availability so are readily reproducible. They use Monte Carlo simulations to construct confidence intervals for their predictions and are validated by testing their predictions for a set of reference years separate from the set of reference years used to train them. This validation shows that the models are not overfitted but suggests that some of the previous models in the literature may have been. The models developed in this article are able to explain their predictions by showing, for a given prediction, which predictors were the most influential and by using counterfactuals to show how the predictions would have been altered had these predictors taken different values. These models are compared to models created by lasso regression and it is shown that they have at least as good predictive power but that their predictions can be more readily explained. Because policy makers are more likely to be influenced by models whose predictions can explained, the more interpretable a model is the more likely it is to influence policy.
Specific dietary risk factors for excess adiposity in young people are poorly understood. However, studies in adults suggest dietary energy density, fat and fibre are critical dietary factors.
To ...examine longitudinal relationships between a dietary pattern (DP) characterised by dietary energy density, % total energy from fat and fibre density and fat mass (FM) in children from 7 to 15 years of age.
Subjects were 6772 children from the UK Avon Longitudinal Study of Parents and Children. Dietary intake was assessed using a 3-day food diary at 7, 10 and 13 years of age. An energy-dense, high-fat, low-fibre DP was identified using reduced rank regression and subjects scored for the DP at each age. FM was measured at 11, 13 and 15 years and FM index (FMI) calculated as FM/height((x)). Longitudinal models were adjusted for dietary misreporting, physical activity and maternal factors.
DP z-scores at all ages were positively associated with later FMI. A 1 s.d. unit increase in DP z-score was longitudinally associated with an average increase in FMI z-score of 0.04 s.d. units (95% confidence interval (CI), 0.01-0.07). For each 1 s.d. unit increase in DP z-score, the odds of being in the highest quintile for FMI (as a marker of excess adiposity) increased by 13% (95% CI, 1-27%).
Dietary habits during childhood are associated with increased adiposity in adolescence, with specific implications for dietary energy density, fat and fibre intake. Improving diet quality may reduce the risk of obesity in young people.
Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. ...We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk ERR per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative absolute risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10 000 head CT scans is estimated to occur. Nevertheless, although clinical benefits should outweigh the small absolute risks, radiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate. Funding US National Cancer Institute and UK Department of Health.
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