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Showing papers by "Queen's University Belfast published in 2018"


Journal ArticleDOI
TL;DR: Scolnic et al. as discussed by the authors presented optical light curves, redshifts, and classifications for 365 spectroscopically confirmed Type Ia supernovae (SNe Ia) discovered by the Pan-STARRS1 (PS1) Medium Deep Survey.
Abstract: Author(s): Scolnic, DM; Jones, DO; Rest, A; Pan, YC; Chornock, R; Foley, RJ; Huber, ME; Kessler, R; Narayan, G; Riess, AG; Rodney, S; Berger, E; Brout, DJ; Challis, PJ; Drout, M; Finkbeiner, D; Lunnan, R; Kirshner, RP; Sanders, NE; Schlafly, E; Smartt, S; Stubbs, CW; Tonry, J; Wood-Vasey, WM; Foley, M; Hand, J; Johnson, E; Burgett, WS; Chambers, KC; Draper, PW; Hodapp, KW; Kaiser, N; Kudritzki, RP; Magnier, EA; Metcalfe, N; Bresolin, F; Gall, E; Kotak, R; McCrum, M; Smith, KW | Abstract: We present optical light curves, redshifts, and classifications for 365 spectroscopically confirmed Type Ia supernovae (SNe Ia) discovered by the Pan-STARRS1 (PS1) Medium Deep Survey. We detail improvements to the PS1 SN photometry, astrometry, and calibration that reduce the systematic uncertainties in the PS1 SN Ia distances. We combine the subset of 279 PS1 SNe Ia (0.03 l z l 0.68) with useful distance estimates of SNe Ia from the Sloan Digital Sky Survey (SDSS), SNLS, and various low-z and Hubble Space Telescope samples to form the largest combined sample of SNe Ia, consisting of a total of 1048 SNe Ia in the range of 0.01 l z l 2.3, which we call the Pantheon Sample. When combining Planck 2015 cosmic microwave background (CMB) measurements with the Pantheon SN sample, we find Wm = 0.307 ± 0.012 and w = -1.026 ± 0.041 for the wCDM model. When the SN and CMB constraints are combined with constraints from BAO and local H0 measurements, the analysis yields the most precise measurement of dark energy to date: w0 = -1.007 ± 0.089 and wa = -0.222 ± 0.407 for the w0waCDM model. Tension with a cosmological constant previously seen in an analysis of PS1 and low-z SNe has diminished after an increase of 2× in the statistics of the PS1 sample, improved calibration and photometry, and stricter light-curve quality cuts. We find that the systematic uncertainties in our measurements of dark energy are almost as large as the statistical uncertainties, primarily due to limitations of modeling the low-redshift sample. This must be addressed for future progress in using SNe Ia to measure dark energy.

2,025 citations


Journal ArticleDOI
22 Jun 2018-Science
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

1,357 citations


Journal ArticleDOI
TL;DR: This review aims to outline the most up-to-date knowledge of pancreatic adenocarcinoma risk, diagnostics, treatment and outcomes, while identifying gaps that aim to stimulate further research in this understudied malignancy.
Abstract: This review aims to outline the most up-to-date knowledge of pancreatic adenocarcinoma risk, diagnostics, treatment and outcomes, while identifying gaps that aim to stimulate further research in this understudied malignancy. Pancreatic adenocarcinoma is a lethal condition with a rising incidence, predicted to become the second leading cause of cancer death in some regions. It often presents at an advanced stage, which contributes to poor five-year survival rates of 2%-9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Better understanding of the risk factors and symptoms associated with this disease is essential to inform both health professionals and the general population of potential preventive and/or early detection measures. The identification of high-risk patients who could benefit from screening to detect pre-malignant conditions such as pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms is urgently required, however an acceptable screening test has yet to be identified. The management of pancreatic adenocarcinoma is evolving, with the introduction of new surgical techniques and medical therapies such as laparoscopic techniques and neo-adjuvant chemoradiotherapy, however this has only led to modest improvements in outcomes. The identification of novel biomarkers is desirable to move towards a precision medicine era, where pancreatic cancer therapy can be tailored to the individual patient, while unnecessary treatments that have negative consequences on quality of life could be prevented for others. Research efforts must also focus on the development of new agents and delivery systems. Overall, considerable progress is required to reduce the burden associated with pancreatic cancer. Recent, renewed efforts to fund large consortia and research into pancreatic adenocarcinoma are welcomed, but further streams will be necessary to facilitate the momentum needed to bring breakthroughs seen for other cancer sites.

951 citations


Journal ArticleDOI
TL;DR: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer, and the benefit would be greatest in patients with a low metastatic burden.

794 citations


Journal ArticleDOI
TL;DR: Molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with “inflammageing” or parainflammation are highlighted and suggested to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation.
Abstract: Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.

663 citations


Journal ArticleDOI
Douglas M. Ruderfer1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +628 moreInstitutions (156)
14 Jun 2018-Cell
TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.

569 citations


Journal ArticleDOI
TL;DR: The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available, and is approved by the guideline group and the ESHRE Executive Committee.
Abstract: Study question What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? Summary answer The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. What is known already A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. Study design size duration The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. Participants/materials setting methods Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. Main results and the role of chance The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. Limitations reasons for caution Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. Wider implications of the findings The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. Study funding/competing interests The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

522 citations


Journal ArticleDOI
TL;DR: In this paper, the authors compared the conditional variance properties of Bitcoin and gold as well as other assets and found differences in their structure and concluded that Bitcoin and Gold feature fundamentally different properties as assets and linkages to equity markets.

520 citations


Journal ArticleDOI
01 Mar 2018
TL;DR: This work considers the cell-free massive multiple-input multiple-output (MIMO) downlink, where a very large number of distributed multiple-antenna access points (APs) serve many single-ant antenna users in the same time-frequency resource, and derives a closed-form expression for the spectral efficiency taking into account the effects of channel estimation errors and power control.
Abstract: We consider the cell-free massive multiple-input multiple-output (MIMO) downlink, where a very large number of distributed multiple-antenna access points (APs) serve many single-antenna users in the same time-frequency resource. A simple (distributed) conjugate beamforming scheme is applied at each AP via the use of local channel state information (CSI). This CSI is acquired through time-division duplex operation and the reception of uplink training signals transmitted by the users. We derive a closed-form expression for the spectral efficiency taking into account the effects of channel estimation errors and power control. This closed-form result enables us to analyze the effects of backhaul power consumption, the number of APs, and the number of antennas per AP on the total energy efficiency, as well as, to design an optimal power allocation algorithm. The optimal power allocation algorithm aims at maximizing the total energy efficiency, subject to a per-user spectral efficiency constraint and a per-AP power constraint. Compared with the equal power control, our proposed power allocation scheme can double the total energy efficiency. Furthermore, we propose AP selections schemes, in which each user chooses a subset of APs, to reduce the power consumption caused by the backhaul links. With our proposed AP selection schemes, the total energy efficiency increases significantly, especially for large numbers of APs. Moreover, under a requirement of good quality-of-service for all users, cell-free massive MIMO outperforms the colocated counterpart in terms of energy efficiency.

497 citations


Journal ArticleDOI
TL;DR: The changing cloud infrastructure is discussed and the use of infrastructure from multiple providers and the benefit of decentralising computing away from data centers is considered, leading to a roadmap of challenges that will need to be addressed for realising the potential of next generation cloud systems.

471 citations


Journal ArticleDOI
TL;DR: In this article, the prediction power of the economic policy uncertainty (EPU) index on the daily Bitcoin returns was analyzed using the Bayesian Graphical Structural Vector Autoregressive model as well as the Ordinary Least Squares and the Quantile-on-Quantile Regression estimations.

Journal ArticleDOI
TL;DR: This system, the "Asteroid Terrestrial-impact Last Alert System" (ATLAS), has been optimized to produce the best survey capability per unit cost, and therefore is an efficient and competitive system for finding potentially hazardous asteroids but also for tracking variables and finding transients.
Abstract: Technology has advanced to the point that it is possible to image the entire sky every night and process the data in real time. The sky is hardly static: many interesting phenomena occur, including variable stationary objects such as stars or QSOs, transient stationary objects such as supernovae or M dwarf flares, and moving objects such as asteroids and the stars themselves. Funded by NASA, we have designed and built a sky survey system for the purpose of finding dangerous near-Earth asteroids (NEAs). This system, the "Asteroid Terrestrial-impact Last Alert System" (ATLAS), has been optimized to produce the best survey capability per unit cost, and therefore is an efficient and competitive system for finding potentially hazardous asteroids (PHAs) but also for tracking variables and finding transients. While carrying out its NASA mission, ATLAS now discovers more bright ($m < 19$) supernovae candidates than any ground based survey, frequently detecting very young explosions due to its 2 day cadence. ATLAS discovered the afterglow of a gamma-ray burst independent of the high energy trigger and has released a variable star catalogue of 5$\times10^{6}$ sources. This, the first of a series of articles describing ATLAS, is devoted to the design and performance of the ATLAS system. Subsequent articles will describe in more detail the software, the survey strategy, ATLAS-derived NEA population statistics, transient detections, and the first data release of variable stars and transient lightcurves.

Journal ArticleDOI
TL;DR: Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001), and within the hyperinflammatory subphenotypes, patients treated with simVastatin had significantly higher 28- day survival than did those given placebo.

Journal ArticleDOI
TL;DR: Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms and may support the treatment of patients with myelofibrosis.
Abstract: Background Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. Methods We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort. Results A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy. Conclusions Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients’ outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.)

Journal ArticleDOI
TL;DR: The metabolic syndrome-otherwise called syndrome X, insulin resistance syndrome, Reaven syndrome, and "the deadly quartet"-is the name given to the aggregate of clinical conditions comprising central and abdominal obesity, systemic hypertension, insulin Resistance, and atherogenic dyslipidemia.

Journal ArticleDOI
TL;DR: A more physiologically–relevant model of the colonic milieu is created to study gut pathogen biology, incorporating human faecal water into growth media and assessing the physiological effects of this on C. difficile strain 630, and it is shown that interaction with FW causes fundamental changes in C. diffusion biology that will lead to increased disease transmissibility.
Abstract: Clostridium difficile virulence is driven primarily by the processes of toxinogenesis and sporulation, however many in vitro experimental systems for studying C. difficile physiology have arguably limited relevance to the human colonic environment. We therefore created a more physiologically–relevant model of the colonic milieu to study gut pathogen biology, incorporating human faecal water (FW) into growth media and assessing the physiological effects of this on C. difficile strain 630. We identified a novel set of C. difficile–derived metabolites in culture supernatants, including hexanoyl– and pentanoyl–amino acid derivatives by LC-MSn. Growth of C. difficile strain 630 in FW media resulted in increased cell length without altering growth rate and RNA sequencing identified 889 transcripts as differentially expressed (p < 0.001). Significantly, up to 300–fold increases in the expression of sporulation–associated genes were observed in FW media–grown cells, along with reductions in motility and toxin genes’ expression. Moreover, the expression of classical stress–response genes did not change, showing that C. difficile is well–adapted to this faecal milieu. Using our novel approach we have shown that interaction with FW causes fundamental changes in C. difficile biology that will lead to increased disease transmissibility.

Journal ArticleDOI
TL;DR: Asteroid Terrestrial-impact last alert system (ATLAS) as discussed by the authors was designed and built for sky survey system for the purpose of finding dangerous near-Earth asteroids (NEAs).
Abstract: Technology has advanced to the point that it is possible to image the entire sky every night and process the data in real time. The sky is hardly static: many interesting phenomena occur, including variable stationary objects such as stars or QSOs, transient stationary objects such as supernovae or M dwarf flares, and moving objects such as asteroids and the stars themselves. Funded by NASA, we have designed and built a sky survey system for the purpose of finding dangerous near-Earth asteroids (NEAs). This system, the "Asteroid Terrestrial-impact Last Alert System" (ATLAS), has been optimized to produce the best survey capability per unit cost, and therefore is an efficient and competitive system for finding potentially hazardous asteroids (PHAs) but also for tracking variables and finding transients. While carrying out its NASA mission, ATLAS now discovers more bright ($m < 19$) supernovae candidates than any ground based survey, frequently detecting very young explosions due to its 2 day cadence. ATLAS discovered the afterglow of a gamma-ray burst independent of the high energy trigger and has released a variable star catalogue of 5$\times10^{6}$ sources. This, the first of a series of articles describing ATLAS, is devoted to the design and performance of the ATLAS system. Subsequent articles will describe in more detail the software, the survey strategy, ATLAS-derived NEA population statistics, transient detections, and the first data release of variable stars and transient lightcurves.

Journal ArticleDOI
01 May 2018-Leukemia
TL;DR: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs), and both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea.
Abstract: This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Journal ArticleDOI
TL;DR: The ferroelectric, magnetic and ME properties of PFN/NZFO/PFN trilayer nanoscale heterostructure are reported, revealing them as potential candidates for nanoscales multifunctional and spintronics device applications.
Abstract: Multiferroic materials have attracted considerable attention as possible candidates for a wide variety of future microelectronic and memory devices, although robust magnetoelectric (ME) coupling between electric and magnetic orders at room temperature still remains difficult to achieve. In order to obtain robust ME coupling at room temperature, we studied the Pb(Fe0.5Nb0.5)O3/Ni0.65Zn0.35Fe2O4/Pb(Fe0.5Nb0.5)O3 (PFN/NZFO/PFN) trilayer structure as a representative FE/FM/FE system. We report the ferroelectric, magnetic and ME properties of PFN/NZFO/PFN trilayer nanoscale heterostructure having dimensions 70/20/70 nm, at room temperature. The presence of only (00l) reflection of PFN and NZFO in the X-ray diffraction (XRD) patterns and electron diffraction patterns in Transmission Electron Microscopy (TEM) confirm the epitaxial growth of multilayer heterostructure. The distribution of the ferroelectric loop area in a wide area has been studied, suggesting that spatial variability of ferroelectric switching behavior is low, and film growth is of high quality. The ferroelectric and magnetic phase transitions of these heterostructures have been found at ~575 K and ~650 K, respectively which are well above room temperature. These nanostructures exhibit low loss tangent, large saturation polarization (Ps ~ 38 µC/cm2) and magnetization (Ms ~ 48 emu/cm3) with strong ME coupling at room temperature revealing them as potential candidates for nanoscale multifunctional and spintronics device applications.

Journal ArticleDOI
TL;DR: A hybrid acceleration scheme based on the relativistic induced transparency mechanism using linearly polarised laser interaction with foil targets is demonstrated and its future implication in using high power lasers is explored.
Abstract: The range of potential applications of compact laser-plasma ion sources motivates the development of new acceleration schemes to increase achievable ion energies and conversion efficiencies. Whilst the evolving nature of laser-plasma interactions can limit the effectiveness of individual acceleration mechanisms, it can also enable the development of hybrid schemes, allowing additional degrees of control on the properties of the resulting ion beam. Here we report on an experimental demonstration of efficient proton acceleration to energies exceeding 94 MeV via a hybrid scheme of radiation pressure-sheath acceleration in an ultrathin foil irradiated by a linearly polarised laser pulse. This occurs via a double-peaked electrostatic field structure, which, at an optimum foil thickness, is significantly enhanced by relativistic transparency and an associated jet of super-thermal electrons. The range of parameters over which this hybrid scenario occurs is discussed and implications for ion acceleration driven by next-generation, multi-petawatt laser facilities are explored.

Journal ArticleDOI
TL;DR: Flux analysis can reveal tissue-specific NAD metabolism and isotope-tracer methods for NAD flux quantitation are presented, which have shown versatility across tissues.

Journal ArticleDOI
TL;DR: In this article, the authors measured an energy loss in the postcollision electron spectrum that is correlated with the detected signal of hard photons (gamma rays), consistent with a quantum description of radiation reaction.
Abstract: The dynamics of energetic particles in strong electromagnetic fields can be heavily influenced by the energy loss arising from the emission of radiation during acceleration, known as radiation reaction. When interacting with a high-energy electron beam, today's lasers are sufficiently intense to explore the transition between the classical and quantum radiation reaction regimes. We present evidence of radiation reaction in the collision of an ultrarelativistic electron beam generated by laser-wakefield acceleration (epsilon > 500 MeV) with an intense laser pulse (a(0) > 10). We measure an energy loss in the postcollision electron spectrum that is correlated with the detected signal of hard photons (gamma rays), consistent with a quantum description of radiation reaction. The generated gamma rays have the highest energies yet reported from an all-optical inverse Compton scattering scheme, with critical energy epsilon(crit) > 30 MeV.

Journal ArticleDOI
Anubha Mahajan1, Jennifer Wessel2, Sara M. Willems3, Wei Zhao4  +286 moreInstitutions (88)
TL;DR: Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes and fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.
Abstract: We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Journal ArticleDOI
TL;DR: It is concluded that glial, neural and microvascular dysfunction are interdependent and essential for the development of diabetic retinopathy and neuroprotection, itself, can be considered a therapeutic target, independently of its potential impact on microv vascular disease.
Abstract: The concept of diabetic retinopathy as a microvascular disease has evolved, in that it is now considered a more complex diabetic complication in which neurodegeneration plays a significant role. In this article we provide a critical overview of the role of microvascular abnormalities and neurodegeneration in the pathogenesis of diabetic retinopathy. A special emphasis is placed on the pathophysiology of the neurovascular unit (NVU), including the contributions of microvascular and neural elements. The potential mechanisms linking retinal neurodegeneration and early microvascular impairment, and the effects of neuroprotective drugs are summarised. Additionally, we discuss how the assessment of retinal neurodegeneration could be an important index of cognitive status, thus helping to identify individuals at risk of dementia, which will impact on current procedures for diabetes management. We conclude that glial, neural and microvascular dysfunction are interdependent and essential for the development of diabetic retinopathy. Despite this intricate relationship, retinal neurodegeneration is a critical endpoint and neuroprotection, itself, can be considered a therapeutic target, independently of its potential impact on microvascular disease. In addition, interventional studies targeting pathogenic pathways that impact the NVU are needed. Findings from these studies will be crucial, not only for increasing our understanding of diabetic retinopathy, but also to help to implement a timely and efficient personalised medicine approach for treating this diabetic complication.

Journal ArticleDOI
TL;DR: It is shown how a multi-time non-Markovian process can be reconstructed experimentally, and that it has a natural representation as a many body quantum state, where temporal correlations are mapped to spatial ones.
Abstract: Currently, there is no systematic way to describe a quantum process with memory solely in terms of experimentally accessible quantities However, recent technological advances mean we have control over systems at scales where memory effects are non-negligible The lack of such an operational description has hindered advances in understanding physical, chemical, and biological processes, where often unjustified theoretical assumptions are made to render a dynamical description tractable This has led to theories plagued with unphysical results and no consensus on what a quantum Markov (memoryless) process is Here, we develop a universal framework to characterize arbitrary non-Markovian quantum processes We show how a multitime non-Markovian process can be reconstructed experimentally, and that it has a natural representation as a many-body quantum state, where temporal correlations are mapped to spatial ones Moreover, this state is expected to have an efficient matrix-product-operator form in many cases Our framework constitutes a systematic tool for the effective description of memory-bearing open-system evolutions

Journal ArticleDOI
TL;DR: Tobacco smoking has the highest PAF because it greatly increases cancer risk and has a large number of cancer types associated with it, and overweight/obesity has the second-highest PAFs because it affects a high proportion of the UK population and is also linked with many cancer types.
Abstract: Changing population-level exposure to modifiable risk factors is a key driver of changing cancer incidence. Understanding these changes is therefore vital when prioritising risk-reduction policies, in order to have the biggest impact on reducing cancer incidence. UK figures on the number of risk factor-attributable cancers are updated here to reflect changing behaviour as assessed in representative national surveys, and new epidemiological evidence. Figures are also presented by UK constituent country because prevalence of risk factor exposure varies between them. Population attributable fractions (PAFs) were calculated for combinations of risk factor and cancer type with sufficient/convincing evidence of a causal association. Relative risks (RRs) were drawn from meta-analyses of cohort studies where possible. Prevalence of exposure to risk factors was obtained from nationally representative population surveys. Cancer incidence data for 2015 were sourced from national data releases and, where needed, personal communications. PAF calculations were stratified by age, sex and risk factor exposure level and then combined to create summary PAFs by cancer type, sex and country. Nearly four in ten (37.7%) cancer cases in 2015 in the UK were attributable to known risk factors. The proportion was around two percentage points higher in UK males (38.6%) than in UK females (36.8%). Comparing UK countries, the attributable proportion was highest in Scotland (41.5% for persons) and lowest in England (37.3% for persons). Tobacco smoking contributed by far the largest proportion of attributable cancer cases, followed by overweight/obesity, accounting for 15.1% and 6.3%, respectively, of all cases in the UK in 2015. For 10 cancer types, including two of the five most common cancer types in the UK (lung cancer and melanoma skin cancer), more than 70% of UK cancer cases were attributable to known risk factors. Tobacco and overweight/obesity remain the top contributors of attributable cancer cases. Tobacco smoking has the highest PAF because it greatly increases cancer risk and has a large number of cancer types associated with it. Overweight/obesity has the second-highest PAF because it affects a high proportion of the UK population and is also linked with many cancer types. Public health policy may seek to mitigate the level of harm associated with exposure or reduce exposure levels—both approaches may effectively impact cancer incidence. Differences in PAFs between countries and sexes are primarily due to varying prevalence of exposure to risk factors and varying proportions of specific cancer types. This variation in turn is affected by socio-demographic differences which drive differences in exposure to theoretically avoidable ‘lifestyle’ factors. PAFs at UK country level have not been available previously and they should be used by policymakers in devolved nations. PAFs are estimates based on the best available data, limitations in those data would generally bias toward underestimation of PAFs. Regular collection of risk factor exposure prevalence data which corresponds with epidemiological evidence is vital for analyses like this and should remain a priority for the UK Government and devolved Administrations.


Journal ArticleDOI
TL;DR: A novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling is defined and possible avenues for utilizing indoles as novel therapeutics in mucosal disease are identified.
Abstract: Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.

Journal ArticleDOI
Valérie Turcot1, Yingchang Lu2, Yingchang Lu3, Heather M. Highland4  +486 moreInstitutions (129)
TL;DR: Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index that confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Journal ArticleDOI
05 Jun 2018-JAMA
TL;DR: There was no significant difference between a lower SpO2 target range compared with a higher SpO 2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months.
Abstract: Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo 2 ) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures Spo 2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score Results A total of 4965 infants were randomized (2480 to the lower Spo 2 target range and 2485 to the higher Spo 2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo 2 target group and 1150 of 2229 infants (51.6%) in the higher Spo 2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo 2 target group, and 3 significantly favored the higher Spo 2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo 2 target group and 418 of 2440 infants (17.1%) in the higher Spo 2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo 2 target group and 308 of 2065 infants (14.9%) in the higher Spo 2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P 2 target group and 170 of 2465 infants (6.9%) in the higher Spo 2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo 2 target range compared with a higher Spo 2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo 2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.