Evidence of widespread selection on standing variation in Europe at height-associated SNPs.

Strong signatures of positive selection at newly arising genetic variants are well documented in humans(1-8), but this form of selection may not be widespread in recent human evolution(9). Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation(10-12). By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P < 4.3 × 10(-4)). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ∼10(-3)-10(-5) per allele) rather than genetic drift alone (P < 10(-15))

Identification of MEN1 gene mutations in families with MEN 1 and related disorders

Following identification of the MEN1 gene, we analysed patients from 12 MEN 1 families, 8 sporadic cases of MEN 1, and 13 patients with MEN 1-like symptoms (e.g. cases of familial isolated hyperparathyroidism (FIHPT), familial acromegaly, or atypical MEN 1 cases) for the presence of germline MEN1 mutations. The entire coding region of the MEN1 gene was sequenced, and mutations were detected in 11 MEN 1 families; one sporadic MEN 1 patient, one case of FIHPT and one MEN 1-like case. Constitutional DNA samples from individuals without MEN1 mutations were digested with several restriction enzymes, Southern blotted and probed with MEN1 cDNA to analyse for the presence of larger deletions of the MEN1 gene unable to be detected by PCR. One MEN 1 patient was found to carry such a deletion. This patient was heterozygous for the D418D polymorphism, however sequence analysis of RT-PCR products showed that only the variant allele was transcribed, thus confirming the result obtained by Southern analysis, which indicated loss of a region containing the initiation codon of one allele. © 2000 Cancer Research Campaig

Changes in HPV prevalence following a national bivalent HPV vaccination programme in Scotland: a 7-year cross-sectional study

Background: On Sept 1, 2008, Scotland launched routine vaccination for human papillomavirus (HPV) types 16 and 18, targeted at 12–13-year-old girls, of whom 92·4% were fully vaccinated in 2008–09. In this study, we report on vaccine effectiveness of the bivalent vaccine in these vaccinated women who attended for routine cervical screening at age 20–21 years. Methods: In this 7-year cross-sectional study (covering birth cohorts 1988–1995), we sampled approximately 1000 samples per year from those attending cervical screening at age 20–21 years and tested each for HPV. By linkage to vaccination records we ascertained prevalence by birth cohort and vaccination status. Estimates of vaccine effectiveness for HPV types 16 and 18, HPV types 31, 33, and 45, other high-risk types, and any HPV were calculated using logistic regression. Findings: In total, 8584 samples were HPV genotyped. Prevalence of HPV types 16 and 18 reduced substantially from 30·0% (95% CI 26·9–33·1) in the 1988 cohort to 4·5% (3·5–5·7) in the 1995 cohort, giving a vaccine effectiveness of 89·1% (85·1–92·3) for those vaccinated at age 12–13 years. All cross-protective types showed significant vaccine effectiveness (HPV type 31, 93·8% [95% CI 83·8–98·5]; HPV type 33, 79·1% [64·2–89·0]; HPV type 45, 82·6% [61·5–93·9]). Unvaccinated individuals born in 1995 had a reduced odds of HPV types 16 and 18 infection compared with those born in 1988 (adjusted odds ratio 0·13 [95% CI 0·06–0·28]) and reduced odds of HPV types 31, 33, and 45 (odds ratio 0·45 [0·23–0·89]). Interpretation: Bivalent vaccination has led to a startling reduction in vaccine and cross-protective HPV types 7 years after vaccination. There is also evidence of herd protection against the vaccine-specific and cross-protective types in unvaccinated individuals born in 1995. These findings should be considered in cost-effectiveness models informing vaccine choice and models to shape the future of cervical screening programmes

Determinants of adults' intention to vaccinate against pandemic swine flu

This article has been made available through the Brunel Open Access Publishing Fund.This article has been made available through the Brunel Open Access Publishing Fund.Background: Vaccination is one of the cornerstones of controlling an influenza pandemic. To optimise vaccination rates in the general population, ways of identifying determinants that influence decisions to have or not to have a vaccination need to be understood. Therefore, this study aimed to predict intention to have a swine influenza vaccination in an adult population in the UK. An extension of the Theory of Planned Behaviour provided the theoretical framework for the study. Methods: Three hundred and sixty two adults from the UK, who were not in vaccination priority groups, completed either an online (n = 306) or pen and paper (n = 56) questionnaire. Data were collected from 30th October 2009, just after swine flu vaccination became available in the UK, and concluded on 31st December 2009. The main outcome of interest was future swine flu vaccination intentions. Results: The extended Theory of Planned Behaviour predicted 60% of adults’ intention to have a swine flu vaccination with attitude, subjective norm, perceived control, anticipating feelings of regret (the impact of missing a vaccination opportunity), intention to have a seasonal vaccine this year, one perceived barrier: “I cannot be bothered to get a swine flu vaccination” and two perceived benefits: “vaccination decreases my chance of getting swine flu or its complications” and “if I get vaccinated for swine flu, I will decrease the frequency of having to consult my doctor,” being significant predictors of intention. Black British were less likely to intend to have a vaccination compared to Asian or White respondents. Conclusions: Theoretical frameworks which identify determinants that influence decisions to have a pandemic influenza vaccination are useful. The implications of this research are discussed with a view to maximising any future pandemic influenza vaccination uptake using theoretically-driven applications.This article is available through the Brunel Open Access Publishing Fund

Liquid Biopsies: The Future of Cancer Early Detection

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics

Liquid biopsies : the future of cancer early detection

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits

PMCID: PMC3410907This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Developing infrared spectroscopic detection for stratifying brain tumour patients: glioblastoma multiforme vs. lymphoma

Over a third of brain tumour patients visit their general practitioner more than five times prior to diagnosis in the UK, leading to 62% of patients being diagnosed as emergency presentations. Unfortunately, symptoms are non-specific to brain tumours, and the majority of these patients complain of headaches on multiple occasions before being referred to a neurologist. As there are currently no methods in place for the early detection of brain cancer, the affected patients’ average life expectancy is reduced by 20 years. These statistics indicate that the current pathway is ineffective, and there is a vast need for a rapid diagnostic test. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is sensitive to the hallmarks of cancer, as it analyses the full range of macromolecular classes. The combination of serum spectroscopy and advanced data analysis has previously been shown to rapidly and objectively distinguish brain tumour severity. Recently, a novel high-throughput ATR accessory has been developed, which could be cost-effective to the National Health Service in the UK, and valuable for clinical translation. In this study, 765 blood serum samples have been collected from healthy controls and patients diagnosed with various types of brain cancer, contributing to one of the largest spectroscopic studies to date. Three robust machine learning techniques - random forest, partial least squares-discriminant analysis and support vector machine - have all provided promising results. The novel high-throughput technology has been validated by separating brain cancer and non-cancer with balanced accuracies of 90% which is comparable to the traditional fixed diamond crystal methodology. Furthermore, the differentiation of brain tumour type could be useful for neurologists, as some are difficult to distinguish through medical imaging alone. For example, the highly aggressive glioblastoma multiforme and primary cerebral lymphoma can appear similar on magnetic resonance imaging (MRI) scans, thus are often misdiagnosed. Here, we report the ability of infrared spectroscopy to distinguish between glioblastoma and lymphoma patients, at a sensitivity and specificity of 90.1% and 86.3%, respectively. A reliable serum diagnostic test could avoid the need for surgery and speed up time to definitive chemotherapy and radiotherapy

High Energy Afterglow Emission from Giant Flares of Soft Gamma-Ray Repeaters: The Case of the 2004 December 27 Event from SGR 1806-20

We discuss the high enegry afterglow emission (including high energy photons, neutrinos and cosmic rays) following the 2004 December 27 Giant Flare from SGR 1806-20. If the initial outflow is relativistic with a bulk Lorentz factor \Gamma_0\sim {\rm tens}, the high-energy tail of the synchrotron emission from electrons in the forward shock region gives rise to a prominent sub-GeV emission, if the electron spectrum is hard enough and if the intial Lorentz factor is high enough. This signal could serve as a diagnosis of the initial Lorentz factor of the giant flare outflow. This component is potentially detectable by GLAST if a similar giant flare occurs in the GLAST era. With the available 10 MeV data, we constrain that \Gamma_0 < 50 if the electron distribution is a single power law. For a broken power law distribution of electrons, a higher \Gamma_0 is allowed. At energies higher than 1 GeV, the flux is lower because of a high energy cut off of the synchrotron emission component. The synchrotron self-Compton emission component and the inverse Compton scattering component off the photons in the giant flare oscillation tail are also considered, but they are found not significant given a moderate \Gamma_0 (e.g. \leq 10). The forward shock also accelerates cosmic rays to the maximum energy 10^{17}eV, and generate neutrinos with a typical energy 10^{14}eV through photomeson interaction with the X-ray tail photons. However, they are too weak to be detectable.Comment: 6 pages (3 figures), accepted for publication in MNRA