Showing papers by "Queen's University Belfast published in 2013"
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Jean-Charles Lambert1, Jean-Charles Lambert2, Jean-Charles Lambert3, Carla A. Ibrahim-Verbaas4 +212 more•Institutions (75)
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
3,726 citations
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TL;DR: There are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
Abstract: Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
3,514 citations
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National Health Service1, University of Oslo2, Karolinska Institutet3, University of Bergen4, Queen's University Belfast5, Curie Institute6, Umeå University7, Mount Vernon Hospital8, Leeds Teaching Hospitals NHS Trust9, Cancer Research UK10, Norwegian University of Science and Technology11, Comenius University in Bratislava12, University of São Paulo13, Algeta14, Bayer Corporation15, Tulane University16
TL;DR: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival and was associated with low myelosuppression rates and fewer adverse events.
Abstract: efit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. Conclusions In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Phar -
2,614 citations
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TL;DR: The nitrogen-vacancy (NV) colour centre in diamond is an important physical system for emergent quantum technologies, including quantum metrology, information processing and communications, as well as for various nanotechnologies such as biological and sub-diffraction limit imaging, and for tests of entanglement in quantum mechanics as mentioned in this paper.
Abstract: The nitrogen-vacancy (NV) colour centre in diamond is an important physical system for emergent quantum technologies, including quantum metrology, information processing and communications, as well as for various nanotechnologies, such as biological and sub-diffraction limit imaging, and for tests of entanglement in quantum mechanics. Given this array of existing and potential applications and the almost 50 years of NV research, one would expect that the physics of the centre is well understood, however, the study of the NV centre has proved challenging, with many early assertions now believed false and many remaining issues yet to be resolved. This review represents the first time that the key empirical and ab initio results have been extracted from the extensive NV literature and assembled into one consistent picture of the current understanding of the centre. As a result, the key unresolved issues concerning the NV centre are identified and the possible avenues for their resolution are examined.
1,642 citations
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Clinical Trial Service Unit1, Glasgow Caledonian University2, Institut Gustave Roussy3, All India Institute of Medical Sciences4, Cairo University5, Monash University6, Queen's University Belfast7, University of Newcastle8, Tehran University of Medical Sciences9, Kaohsiung Medical University10, Tel Aviv Sourasky Medical Center11, Tata Memorial Hospital12, Charles University in Prague13, Cancer Institute14
TL;DR: Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status, and a further reduction in recurrence and mortality, particularly after year 10.
1,637 citations
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TL;DR: The nitrogen-vacancy (NV) colour centre in diamond is an important physical system for emergent quantum technologies, including quantum metrology, information processing and communications, as well as for various nanotechnologies such as biological and sub-diffraction limit imaging, and for tests of entanglement in quantum mechanics as mentioned in this paper.
1,625 citations
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TL;DR: The Southern Hemisphere SHCal04 radiocarbon calibration curve has been updated with the addition of new data sets extending measurements to 2145 cal BP and including the ANSTO Younger Dryas Huon pine data set as mentioned in this paper.
Abstract: The Southern Hemisphere SHCal04 radiocarbon calibration curve has been updated with the addition of new data sets extending measurements to 2145 cal BP and including the ANSTO Younger Dryas Huon pine data set. Outside the range of measured data, the curve is based upon the Northern Hemisphere data sets as presented in IntCal13, with an interhemispheric offset averaging 43 ± 23 yr modeled by an autoregressive process to represent the short-term correlations in the offset. DOI: 10.2458/azu_js_rc.55.16783
1,596 citations
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Panos Deloukas1, Stavroula Kanoni1, Christina Willenborg2, Martin Farrall3 +201 more•Institutions (64)
TL;DR: An association analysis in CAD cases and controls identifies 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants strongly associated with CAD at a 5% false discovery rate (FDR).
Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
1,518 citations
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Broad Institute1, Harvard University2, Karolinska Institutet3, Oslo University Hospital4, University of North Carolina at Chapel Hill5, Icahn School of Medicine at Mount Sinai6, University of Queensland7, deCODE genetics8, Aarhus University9, Lundbeck10, Aarhus University Hospital11, Trinity College, Dublin12, Cardiff University13, VU University Amsterdam14, Radboud University Nijmegen15, Russian Academy16, Statens Serum Institut17, Virginia Commonwealth University18, King's College London19, Queen's University Belfast20, University of Belgrade21, Erasmus University Rotterdam22, Martin Luther University of Halle-Wittenberg23, Ludwig Maximilian University of Munich24, University of Iceland25, Tbilisi State Medical University26, National Institutes of Health27, University of Verona28, University College London29
TL;DR: The authors conducted a multi-stage genome-wide association study (GWAS) for schizophrenia and found that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia.
Abstract: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
1,343 citations
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TL;DR: An overview of the state of the art of ion acceleration by laser pulses as well as an outlook on its future development and perspectives are given in this article. But the main features observed in the experiments, the observed scaling with laser and plasma parameters, and the main models used both to interpret experimental data and to suggest new research directions are described.
Abstract: Ion acceleration driven by superintense laser pulses is attracting an impressive and steadily increasing effort. Motivations can be found in the applicative potential and in the perspective to investigate novel regimes as available laser intensities will be increasing. Experiments have demonstrated, over a wide range of laser and target parameters, the generation of multi-MeV proton and ion beams with unique properties such as ultrashort duration, high brilliance, and low emittance. An overview is given of the state of the art of ion acceleration by laser pulses as well as an outlook on its future development and perspectives. The main features observed in the experiments, the observed scaling with laser and plasma parameters, and the main models used both to interpret experimental data and to suggest new research directions are described.
1,221 citations
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TL;DR: The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD, and incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care.
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TL;DR: This review aims to consolidate clinically relevant background information on the ESKAPE pathogens and provide a contemporary summary of bacterial resistance, alongside pertinent microbiological considerations necessary to face the mounting threat of antimicrobial resistance.
Abstract: In recent years, the Infectious Diseases Society of America has highlighted a faction of antibiotic-resistant bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) - acronymically dubbed 'the ESKAPE pathogens' - capable of 'escaping' the biocidal action of antibiotics and mutually representing new paradigms in pathogenesis, transmission and resistance. This review aims to consolidate clinically relevant background information on the ESKAPE pathogens and provide a contemporary summary of bacterial resistance, alongside pertinent microbiological considerations necessary to face the mounting threat of antimicrobial resistance.
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TL;DR: A new R package, diveRsity, for the calculation of various diversity statistics, including common diversity partitioning statistics (θ, GST) and population differentiation statistics (DJost, GST ' , χ2 test for population heterogeneity), among others.
Abstract: Summary
We present a new R package, diveRsity, for the calculation of various diversity statistics, including common diversity partitioning statistics (θ, GST) and population differentiation statistics (DJost, GST ', χ2 test for population heterogeneity), among others. The package calculates these estimators along with their respective bootstrapped confidence intervals for loci, sample population pairwise and global levels. Various plotting tools are also provided for a visual evaluation of estimated values, allowing users to critically assess the validity and significance of statistical tests from a biological perspective.
diveRsity has a set of unique features, which facilitate the use of an informed framework for assessing the validity of the use of traditional F-statistics for the inference of demography, with reference to specific marker types, particularly focusing on highly polymorphic microsatellite loci. However, the package can be readily used for other co-dominant marker types (e.g. allozymes, SNPs).
Detailed examples of usage and descriptions of package capabilities are provided. The examples demonstrate useful strategies for the exploration of data and interpretation of results generated by diveRsity. Additional online resources for the package are also described, including a GUI web app version intended for those with more limited experience using R for statistical analysis.
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TL;DR: The question of how to achieve a successful carrier grade network with software-defined networking is raised and specific focus is placed on the challenges of network performance, scalability, security, and interoperability with the proposal of potential solution directions.
Abstract: Cloud services are exploding, and organizations are converging their data centers in order to take advantage of the predictability, continuity, and quality of service delivered by virtualization technologies. In parallel, energy-efficient and high-security networking is of increasing importance. Network operators, and service and product providers require a new network solution to efficiently tackle the increasing demands of this changing network landscape. Software-defined networking has emerged as an efficient network technology capable of supporting the dynamic nature of future network functions and intelligent applications while lowering operating costs through simplified hardware, software, and management. In this article, the question of how to achieve a successful carrier grade network with software-defined networking is raised. Specific focus is placed on the challenges of network performance, scalability, security, and interoperability with the proposal of potential solution directions.
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TL;DR: The UMIST Database for Astrochemistry (UDfaa) as mentioned in this paper contains 6173 gas-phase reactions involving 467 species, 47 of which are new to this release.
Abstract: We present the fifth release of the UMIST Database for Astrochemistry (UDfA). The new reaction network contains 6173 gas-phase reactions, involving 467 species, 47 of which are new to this release. We have updated rate coefficients across all reaction types. We have included 1171 new anion reactions and updated and reviewed all photorates. In addition to the usual reaction network, we also now include, for download, state-specific deuterated rate coefficients, deuterium exchange reactions and a list of surface binding energies for many neutral species. Where possible, we have referenced the original source of all new and existing data. We have tested the main reaction network using a dark cloud model and a carbon-rich circumstellar envelope model. We present and briefly discuss the results of these models.
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TL;DR: A collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry, identifies 19 loci associated at P < 5 × 10−8, which show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis.
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD
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TL;DR: The development of metal deposition processes based on electroless nickel, alloy and composite coatings on various surfaces has witnessed a surge in interest among researchers, with many recent applications made possible from many excellent properties as mentioned in this paper.
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University of Cambridge1, University of Sheffield2, University of Oxford3, University of California, Berkeley4, University of Leeds5, Technion – Israel Institute of Technology6, Imperial College London7, Queen's University Belfast8, Swansea University9, University of Exeter10, University of Sussex11, University of Aberdeen12, Bangor University13, University of Warwick14, Australian National University15, Environmental Change Institute16, University of Reading17, University of Edinburgh18, Microsoft19, Rockefeller University20, University of Zurich21, Swedish University of Agricultural Sciences22, Helmholtz Centre for Environmental Research - UFZ23
TL;DR: The 100th anniversary of the British Ecological Society in 2013 is an opportune moment to reflect on the current status of ecology as a science and look forward to high-light priorities for future work.
Abstract: Summary 1. Fundamental ecological research is both intrinsically interesting and provides the basic knowledge required to answer applied questions of importance to the management of the natural world. The 100th anniversary of the British Ecological Society in 2013 is an opportune moment to reflect on the current status of ecology as a science and look forward to high-light priorities for future work.
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TL;DR: The findings in the Inhibition of VEGF in Age-related choroidal Neovascularisation trial highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.
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TL;DR: A genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry finds a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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University of Amsterdam1, Utrecht University2, Space Telescope Science Institute3, Johns Hopkins University4, Queen's University Belfast5, UK Astronomy Technology Centre6, University of Edinburgh7, Spanish National Research Council8, Open University9, University of Sheffield10, University of La Laguna11, University of Cambridge12, University of Bonn13, Armagh Observatory14
TL;DR: In this paper, the multiplicity properties of the massive O-type star population were analyzed using multi-epoch spectroscopy and variability analysis to identify spectroscopic binaries.
Abstract: Aims. We analyze the multiplicity properties of the massive O-type star population. With 360 O-type stars, this is the largest homogeneous sample of massive stars analyzed to date. Methods. We use multi-epoch spectroscopy and variability analysis to identify spectroscopic binaries. We also use a Monte-Carlo method to correct for observational biases. Results. We observe a spectroscopic binary fraction of 0.35\pm0.03, which corresponds to the fraction of objects displaying statistically significant radial velocity variations with an amplitude of at least 20km/s. We compute the intrinsic binary fraction to be 0.51\pm0.04. We adopt power-laws to describe the intrinsic period and mass-ratio distributions: f_P ~ (log P)^\pi\ (with 0.15 7.8', i.e. approx117 pc) and among the O9.7 I/II objects are however significantly lower than expected from statistical fluctuations. Conclusions. Using simple evolutionary considerations, we estimate that over 50% of the current O star population in 30 Dor will exchange mass with its companion within a binary system. This shows that binary interaction is greatly affecting the evolution and fate of massive stars, and must be taken into account to correctly interpret unresolved populations of massive stars.
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TL;DR: In this paper, the authors report extensive observational data for five of the lowest redshift super-Luminous Type Ic Supernovae (SL-SNe Ic) discovered to date, namely PTF10hgi, SN2011ke, PTF11rks, SN 2011kf and SN2012il.
Abstract: We report extensive observational data for five of the lowest redshift Super-Luminous Type Ic Supernovae (SL-SNe Ic) discovered to date, namely PTF10hgi, SN2011ke, PTF11rks, SN2011kf and SN2012il. Photometric imaging of the transients at +50 to +230 days after peak combined with host galaxy subtraction reveals a luminous tail phase for four of these SL-SNe. A high resolution, optical and near infrared spectrum from xshooter provides detection of a broad He I �10830 emission line in the spectrum (+50d) of SN2012il, revealing that at least some SL-SNe Ic are not completely helium free. At first sight, the tail luminosity decline rates that we measure are consistent with the radioactive decay of 56 Co, and would require 1-4 M⊙ of 56 Ni to produce the luminosity. These 56 Ni masses cannot be made consistent with the short diffusion times at peak, and indeed are insufficient to power the peak luminosity. We instead favour energy deposition by newborn magnetars as the power source for these objects. A semi-analytical diffusion model with energy input from the spindown of a magnetar reproduces the extensive lightcurve data well. The model predictions of ejecta velocities and temperatures which are required are in reasonable agreement with those determined from our observations. We derive magnetar energies of 0.4 . E(10 51 erg) . 6.9 and ejecta masses of 2.3 . Mej(M⊙) . 8.6. The sample of five SL-SNe Ic presented here, combined with SN 2010gx - the best sampled SL-SNe Ic so far - point toward an explosion driven by a magnetar as a viable explanation for all SL-SNe Ic. Subject headings: supernovae: general - supernovae: individual (PTF10hgi, SN 2011ke, PTF11rks, SN 2011kf, SN 2012il) - stars: magnetars
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01 Nov 2013TL;DR: This paper presents a comprehensive survey of the research relating to security in software-defined networking that has been carried out to date, and both the security enhancements to be derived from using the SDN framework and the security challenges introduced by the framework are discussed.
Abstract: The pull of Software-Defined Networking (SDN) is magnetic. There are few in the networking community who have escaped its impact. As the benefits of network visibility and network device programmability are discussed, the question could be asked as to who exactly will benefit? Will it be the network operator or will it, in fact, be the network intruder? As SDN devices and systems hit the market, security in SDN must be raised on the agenda. This paper presents a comprehensive survey of the research relating to security in software-defined networking that has been carried out to date. Both the security enhancements to be derived from using the SDN framework and the security challenges introduced by the framework are discussed. By categorizing the existing work, a set of conclusions and proposals for future research directions are presented.
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TL;DR: Recommendations of a European Panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence are reported, based upon published evidence up to the end of 2012.
Abstract: Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report updated recommendations of a European Panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007 and 2010. This second update of the guidelines is based upon published evidence up to the end of 2012. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is still not clear if the benefit of repeated courses on respiratory outcomes outweighs the risk of adverse outcomes in the short and long term. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not completely clear. In addition, use of very early continuous positive airway pressure (CPAP) has altered the indications for prophylactic surfactant administration. Respiratory support in the form of mechanical ventilation may be lifesaving but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using non-invasive respiratory support such as CPAP. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of normal body temperature, proper fluid management, good nutritional support, appropriate management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.
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21 Oct 2013
TL;DR: The third Audio-Visual Emotion recognition Challenge (AVEC 2013) has two goals logically organised as sub-challenges: the first is to predict the continuous values of the affective dimensions valence and arousal at each moment in time, and the second is to Predict the value of a single depression indicator for each recording in the dataset.
Abstract: Mood disorders are inherently related to emotion. In particular, the behaviour of people suffering from mood disorders such as unipolar depression shows a strong temporal correlation with the affective dimensions valence and arousal. In addition, psychologists and psychiatrists take the observation of expressive facial and vocal cues into account while evaluating a patient's condition. Depression could result in expressive behaviour such as dampened facial expressions, avoiding eye contact, and using short sentences with flat intonation. It is in this context that we present the third Audio-Visual Emotion recognition Challenge (AVEC 2013). The challenge has two goals logically organised as sub-challenges: the first is to predict the continuous values of the affective dimensions valence and arousal at each moment in time. The second sub-challenge is to predict the value of a single depression indicator for each recording in the dataset. This paper presents the challenge guidelines, the common data used, and the performance of the baseline system on the two tasks.
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TL;DR: It is estimated that the breast cancer lifetime risks for the5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk, and the ovarian cancer lifetime risk is 63% or higher, based on the known cancer risk-modifying loci.
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
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University of Edinburgh1, University of Sydney2, University of Otago3, University of Oxford4, University of Auckland5, National Health Service6, University of Melbourne7, NHS Lothian8, Queen's University Belfast9, Wellington Hospital10, University College London11, Royal Women's Hospital12, James Cook University Hospital13, Nottingham University Hospitals NHS Trust14
TL;DR: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death.
Abstract: Background The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. Methods In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. Results A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the highe...
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TL;DR: There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases and there was substantial heterogeneity in the definitions used to identifyperiodontitis.
Abstract: Aim: To critically appraise recent research into associations between periodontal disease and systemic diseases and conditions specifically respiratory disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. Methods: A MEDLINE literature search of papers published between 2002 and April 2012 was conducted. Studies that included periodontitis as an exposure were identified. Cross-sectional epidemiological investigations on large samples, prospective studies and systematic reviews formed the basis of the narrative review. A threshold set for the identification of periodontitis was used to identify those studies that contributed to the conclusions of the review. Results: Many of the investigations were cross-sectional secondary analyses of existing data sets in particular the NHANES studies. There were a small number of systematic reviews and prospective studies. There was substantial variability in the definitions of exposure to periodontitis. A small number of studies met the threshold set for periodontitis and supported associations; however, in some of the chronic diseases there were no such studies. There was strong evidence from randomized controlled trials that interventions, which improve oral hygiene have positive effects on the prevention of nosocomial pneumonias. Conclusions: There was substantial heterogeneity in the definitions used to identify periodontitis and very few studies met a stringent threshold for periodontitis. Published evidence supports modest associations between periodontitis and some, although not all, of the diseases and conditions reviewed. There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases.
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Joshua C. Randall1, Joshua C. Randall2, Thomas W. Winkler3, Zoltán Kutalik4 +305 more•Institutions (89)
TL;DR: The value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits is demonstrated, with no evidence for genetic effects with opposite directions in men versus women.
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
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Institute of Cancer Research1, Imperial College London2, University of Dundee3, King's College London4, University of Birmingham5, University of Southampton6, University of Manchester7, University of Sheffield8, University of Cambridge9, Cambridge University Hospitals NHS Foundation Trust10, Newcastle University11, University of Nottingham12, University of London13, Queen Mary University of London14, University of East Anglia15, University of Glasgow16, University College Dublin17, Cardiff University18, University of Leicester19, University College London20, Brunel University London21, Royal College of Surgeons in Ireland22, University of Stirling23, University of Chester24, University of Oxford25, University of Edinburgh26, National Cancer Research Institute27, Queen's University Belfast28, University College Cork29, University of Liverpool30, London Research Institute31, Brighton and Sussex Medical School32, University of Leeds33
TL;DR: With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
Abstract: Introduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. Methods: More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/ novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. (Continued on next page)