Showing papers by "Cardiff University published in 2019"
TL;DR: Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD.
Abstract: Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
1,641 citations
Lundbeck1, Aarhus University2, Harvard University3, Broad Institute4, Karolinska Institutet5, Cardiff University6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, University of Iceland9, deCODE genetics10, Mental Health Services11, Charité12, University of California, Los Angeles13, Semel Institute for Neuroscience and Human Behavior14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Yale University21, Veterans Health Administration22, Children's Hospital of Philadelphia23, University of Bergen24, Haukeland University Hospital25, University of Pennsylvania26, University of Würzburg27, Maastricht University28, I.M. Sechenov First Moscow State Medical University29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
TL;DR: The FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis in cells.
Abstract: Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10, CoQ10): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis. In the absence of GPX4, FSP1 regenerates ubiquinol from the oxidized form, ubiquinone, using NAD(P)H and suppresses phospholipid peroxidation and ferroptosis in cells.
1,256 citations
Carleton University1, Michigan State University2, University of Saskatchewan3, University of California, Santa Barbara4, Federation University Australia5, University of Colorado Boulder6, McMaster University7, Mount Allison University8, University of Washington9, Cardiff University10, Queen's University11, Leibniz Association12, University of Hong Kong13
TL;DR: Efforts to reverse global trends in freshwater degradation now depend on bridging an immense gap between the aspirations of conservation biologists and the accelerating rate of species endangerment.
Abstract: In the 12 years since Dudgeon et al. (2006) reviewed major pressures on freshwater ecosystems, the biodiversity crisis in
the world’s lakes, reservoirs, rivers, streams and wetlands has deepened. While lakes, reservoirs and rivers cover only
2.3% of the Earth’s surface, these ecosystems host at least 9.5% of the Earth’s described animal species. Furthermore,
using the World Wide Fund for Nature’s Living Planet Index, freshwater population declines (83% between 1970 and
2014) continue to outpace contemporaneous declines in marine or terrestrial systems. The Anthropocene has brought
multiple new and varied threats that disproportionately impact freshwater systems. We document 12 emerging threats
to freshwater biodiversity that are either entirely new since 2006 or have since intensified: (i) changing climates; (ii)
e-commerce and invasions; (iii) infectious diseases; (iv) harmful algal blooms; (v) expanding hydropower; (vi) emerging
contaminants; (vii) engineered nanomaterials; (viii) microplastic pollution; (ix) light and noise; (x) freshwater salinisation;
(xi) declining calcium; and (xii) cumulative stressors. Effects are evidenced for amphibians, fishes, invertebrates, microbes,
plants, turtles and waterbirds, with potential for ecosystem-level changes through bottom-up and top-down processes.
In our highly uncertain future, the net effects of these threats raise serious concerns for freshwater ecosystems. However,
we also highlight opportunities for conservation gains as a result of novel management tools (e.g. environmental flows,
environmental DNA) and specific conservation-oriented actions (e.g. dam removal, habitat protection policies,managed
relocation of species) that have been met with varying levels of success.Moving forward, we advocate hybrid approaches
that manage fresh waters as crucial ecosystems for human life support as well as essential hotspots of biodiversity and
ecological function. Efforts to reverse global trends in freshwater degradation now depend on bridging an immense gap
between the aspirations of conservation biologists and the accelerating rate of species endangerment.
1,230 citations
Fraunhofer Society1, University of Manchester2, ETH Zurich3, Eindhoven University of Technology4, Erasmus University Rotterdam5, Chalmers University of Technology6, Lund University7, Vanderbilt University8, Aalto University9, University of Brighton10, University of Sussex11, École Polytechnique Fédérale de Lausanne12, Stockholm Environment Institute13, Université libre de Bruxelles14, Monash University15, Linköping University16, King's College London17, Cardiff University18
TL;DR: In this article, the authors provide an extensive review and an updated research agenda for the field, classified into nine main themes: understanding transitions; power, agency and politics; governing transitions; civil society, culture and social movements; businesses and industries; transitions in practice and everyday life; geography of transitions; ethical aspects; and methodologies.
Abstract: Research on sustainability transitions has expanded rapidly in the last ten years, diversified in terms of topics and geographical applications, and deepened with respect to theories and methods. This article provides an extensive review and an updated research agenda for the field, classified into nine main themes: understanding transitions; power, agency and politics; governing transitions; civil society, culture and social movements; businesses and industries; transitions in practice and everyday life; geography of transitions; ethical aspects; and methodologies. The review shows that the scope of sustainability transitions research has broadened and connections to established disciplines have grown stronger. At the same time, we see that the grand challenges related to sustainability remain unsolved, calling for continued efforts and an acceleration of ongoing transitions. Transition studies can play a key role in this regard by creating new perspectives, approaches and understanding and helping to move society in the direction of sustainability.
1,099 citations
TL;DR: Genome-wide analysis identifies 30 loci associated with bipolar disorder, allowing for comparisons of shared genes and pathways with other psychiatric disorders, including schizophrenia and depression.
Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
1,090 citations
TL;DR: This Review systematically documents the progresses and developments made in the understanding and design of heterogeneous catalysts for VOC oxidation over the past two decades and addresses in detail how catalytic performance is often drastically affected by the pollutant sources and reaction conditions.
Abstract: It is well known that urbanization and industrialization have resulted in the rapidly increasing emissions of volatile organic compounds (VOCs), which are a major contributor to the formation of secondary pollutants (e.g., tropospheric ozone, PAN (peroxyacetyl nitrate), and secondary organic aerosols) and photochemical smog. The emission of these pollutants has led to a large decline in air quality in numerous regions around the world, which has ultimately led to concerns regarding their impact on human health and general well-being. Catalytic oxidation is regarded as one of the most promising strategies for VOC removal from industrial waste streams. This Review systematically documents the progresses and developments made in the understanding and design of heterogeneous catalysts for VOC oxidation over the past two decades. It addresses in detail how catalytic performance is often drastically affected by the pollutant sources and reaction conditions. It also highlights the primary routes for catalyst deactivation and discusses protocols for their subsequent reactivation. Kinetic models and proposed oxidation mechanisms for representative VOCs are also provided. Typical catalytic reactors and oxidizers for industrial VOC destruction are further discussed. We believe that this Review will provide a great foundation and reference point for future design and development in this field.
1,074 citations
TL;DR: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s as mentioned in this paper.
Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of σ(r)=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
1,027 citations
Carlos III Health Institute1, University of Cologne2, University of Sydney3, Paris Descartes University4, Universidade Federal de Ciências da Saúde de Porto Alegre5, Pontifícia Universidade Católica do Rio Grande do Sul6, Medical University of Graz7, University of California, San Diego8, University of Copenhagen9, Katholieke Universiteit Leuven10, University of Bologna11, University of the Witwatersrand12, RMIT University13, McGill University14, Hacettepe University15, University of Paris16, Utrecht University17, Mazandaran University of Medical Sciences18, Tel Aviv University19, Hospital General de México20, Istituto Giannina Gaslini21, Mahidol University22, Federal University of São Paulo23, King's College, Aberdeen24, Comenius University in Bratislava25, Boston Children's Hospital26, Hospital General Universitario Gregorio Marañón27, Complutense University of Madrid28, University Hospital Heidelberg29, University of California, Los Angeles30, American University of Beirut31, Innsbruck Medical University32, University of Lausanne33, Catholic University of Korea34, Goethe University Frankfurt35, National and Kapodistrian University of Athens36, Erasmus University Rotterdam37, Monash University38, Federal University of Rio de Janeiro39, Catholic University of the Sacred Heart40, University of Health Sciences Antigua41, National Institutes of Health42, Amrita Institute of Medical Sciences and Research Centre43, University of Pittsburgh44, Peter MacCallum Cancer Centre45, University of Melbourne46, P. D. Hinduja Hospital and Medical Research Centre47, University of Southern California48, Duke University49, Singapore General Hospital50, NewYork–Presbyterian Hospital51, Cardiff University52, University of Texas Health Science Center at San Antonio53, Children's Hospital of Philadelphia54, Post Graduate Institute of Medical Education and Research55
TL;DR: Management of mucormycosis depends on recognising disease patterns and on early diagnosis, and limited availability of contemporary treatments burdens patients in low and middle income settings.
Abstract: Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
842 citations
Charité1, University of Groningen2, Cardiff University3, University of Rennes4, University of Milan5, National University of Singapore6, University of Liège7, Brigham and Women's Hospital8, Boston University9, Utrecht University10, University of Zurich11, University of Amsterdam12, University of Belgrade13, University of Cyprus14, National and Kapodistrian University of Athens15
TL;DR: A new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm', is recommended, which requires comprehensive echocardiography and requires comprehensive natriuretic peptide levels and is typically performed by a cardiologist.
Abstract: Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for heart failure symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular (LV) ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e'), LV filling pressure estimated using E/e', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1 : Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2 : Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.
825 citations
University College London1, International Institute for Applied Systems Analysis2, University of Reading3, Brighton and Sussex Medical School4, University of London5, Cooperative Institute for Research in Environmental Sciences6, Umeå University7, Tsinghua University8, Cardiff University9, University of Geneva10, University of New England (United States)11, University of Birmingham12, Yale University13, University of Washington14, Northeastern University15, Virginia Tech16, University of York17, Cayetano Heredia University18, University of Sussex19, Nelson Marlborough Institute of Technology20, Emory University21, Columbia University22, Centre for Environment, Fisheries and Aquaculture Science23, Babson College24, Iran University of Medical Sciences25, University of Exeter26, Imperial College London27, University of Colorado Boulder28, Griffith University29, University of Aberdeen30, European Centre for Disease Prevention and Control31, Universiti Teknologi MARA32, Atlantic Oceanographic and Meteorological Laboratory33
TL;DR: The 2019 report of The Lancet Countdown on health and climate change : ensuring that the health of a child born today is not defined by a changing climate is ensured.
TL;DR: In this paper, the authors improved initial estimates of the binary's properties, including component masses, spins, and tidal parameters, using the known source location, improved modeling, and recalibrated Virgo data.
Abstract: On August 17, 2017, the Advanced LIGO and Advanced Virgo gravitational-wave detectors observed a low-mass compact binary inspiral. The initial sky localization of the source of the gravitational-wave signal, GW170817, allowed electromagnetic observatories to identify NGC 4993 as the host galaxy. In this work, we improve initial estimates of the binary's properties, including component masses, spins, and tidal parameters, using the known source location, improved modeling, and recalibrated Virgo data. We extend the range of gravitational-wave frequencies considered down to 23 Hz, compared to 30 Hz in the initial analysis. We also compare results inferred using several signal models, which are more accurate and incorporate additional physical effects as compared to the initial analysis. We improve the localization of the gravitational-wave source to a 90% credible region of 16 deg2. We find tighter constraints on the masses, spins, and tidal parameters, and continue to find no evidence for nonzero component spins. The component masses are inferred to lie between 1.00 and 1.89 M when allowing for large component spins, and to lie between 1.16 and 1.60 M (with a total mass 2.73-0.01+0.04 M) when the spins are restricted to be within the range observed in Galactic binary neutron stars. Using a precessing model and allowing for large component spins, we constrain the dimensionless spins of the components to be less than 0.50 for the primary and 0.61 for the secondary. Under minimal assumptions about the nature of the compact objects, our constraints for the tidal deformability parameter Λ are (0,630) when we allow for large component spins, and 300-230+420 (using a 90% highest posterior density interval) when restricting the magnitude of the component spins, ruling out several equation-of-state models at the 90% credible level. Finally, with LIGO and GEO600 data, we use a Bayesian analysis to place upper limits on the amplitude and spectral energy density of a possible postmerger signal.
Ghent University1, University of California, San Diego2, Leiden University3, Dresden University of Technology4, Stanford University5, University of Maryland, College Park6, Indiana University7, University of Cambridge8, Cardiff University9, University of Western Ontario10, Monash University, Clayton campus11, University of Toronto12, University of Vermont13, University of Oregon14, University of Tasmania15, University of Oslo16, Utrecht University17, Katholieke Universiteit Leuven18, Yale University19, Vanderbilt University20, University of Amsterdam21, Anglia Ruskin University22, Indian Institute of Science23, Queen's University24, King's College London25, Michigan State University26, University of Iowa27, Trinity College, Dublin28
TL;DR: The goal is to facilitate a more accurate use of the stop-signal task and provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
Abstract: Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
International Agency for Research on Cancer1, University of Leicester2, Karolinska Institutet3, Cancer Institute of New South Wales4, Cancer Council Victoria5, Alberta Health Services6, St. John's University7, Nova Scotia Health Authority8, Cancer Care Ontario9, McGill University10, Public Health England11, Queen's University Belfast12, Cardiff University13, Canadian Partnership Against Cancer14, The Royal Marsden NHS Foundation Trust15, University of Oxford16, King's College London17
TL;DR: Progress in cancer control over the study period was evident for stomach, colon, lung (in males), and ovarian cancer, and the impact of comorbidity are likely the main determinants of patient outcomes.
Abstract: Summary Background Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.
TL;DR: Simulation results show the convergence of the algorithms and the effectiveness of the proposed model to handle P2P energy trading, and it is emerging as an alternative to cost-intensive energy storage systems.
Abstract: This paper proposes a novel game-theoretic model for peer-to-peer (P2P) energy trading among the prosumers in a community. The buyers can adjust the energy consumption behavior based on the price and quantity of the energy offered by the sellers. There exist two separate competitions during the trading process: 1) price competition among the sellers; and 2) seller selection competition among the buyers. The price competition among the sellers is modeled as a noncooperative game. The evolutionary game theory is used to model the dynamics of the buyers for selecting sellers. Moreover, an M-leader and N-follower Stackelberg game approach is used to model the interaction between buyers and sellers. Two iterative algorithms are proposed for the implementation of the games such that an equilibrium state exists in each of the games. The proposed method is applied to a small community microgrid with photo-voltaic and energy storage systems. Simulation results show the convergence of the algorithms and the effectiveness of the proposed model to handle P2P energy trading. The results also show that P2P energy trading provides significant financial and technical benefits to the community, and it is emerging as an alternative to cost-intensive energy storage systems.
TL;DR: In this paper, the mass, spin, and redshift distributions of binary black hole (BBH) mergers with LIGO and Advanced Virgo observations were analyzed using phenomenological population models.
Abstract: We present results on the mass, spin, and redshift distributions with phenomenological population models using the 10 binary black hole (BBH) mergers detected in the first and second observing runs completed by Advanced LIGO and Advanced Virgo. We constrain properties of the BBH mass spectrum using models with a range of parameterizations of the BBH mass and spin distributions. We find that the mass distribution of the more massive BH in such binaries is well approximated by models with no more than 1% of BHs more massive than 45 M and a power-law index of (90% credibility). We also show that BBHs are unlikely to be composed of BHs with large spins aligned to the orbital angular momentum. Modeling the evolution of the BBH merger rate with redshift, we show that it is flat or increasing with redshift with 93% probability. Marginalizing over uncertainties in the BBH population, we find robust estimates of the BBH merger rate density of R= (90% credibility). As the BBH catalog grows in future observing runs, we expect that uncertainties in the population model parameters will shrink, potentially providing insights into the formation of BHs via supernovae, binary interactions of massive stars, stellar cluster dynamics, and the formation history of BHs across cosmic time.
TL;DR: In this paper, the authors place constraints on the dipole radiation and possible deviations from GR in the post-Newtonian coefficients that govern the inspiral regime of a binary neutron star inspiral.
Abstract: The recent discovery by Advanced LIGO and Advanced Virgo of a gravitational wave signal from a binary neutron star inspiral has enabled tests of general relativity (GR) with this new type of source. This source, for the first time, permits tests of strong-field dynamics of compact binaries in the presence of matter. In this Letter, we place constraints on the dipole radiation and possible deviations from GR in the post-Newtonian coefficients that govern the inspiral regime. Bounds on modified dispersion of gravitational waves are obtained; in combination with information from the observed electromagnetic counterpart we can also constrain effects due to large extra dimensions. Finally, the polarization content of the gravitational wave signal is studied. The results of all tests performed here show good agreement with GR.
Chengdu University of Technology1, Charles University in Prague2, University of Potsdam3, University of Southern California4, University of Twente5, Cardiff University6, United States Geological Survey7, Hong Kong University of Science and Technology8, University of Waterloo9, China Earthquake Administration10
TL;DR: In this paper, the authors analyze how earthquakes trigger landslides and highlight research gaps, and suggest pathways toward a more complete understanding of the seismic effects on the Earth's surface, highlighting research gaps.
Abstract: Large earthquakes initiate chains of surface processes that last much longer than the brief moments of strong shaking. Most moderate‐ and large‐magnitude earthquakes trigger landslides, ranging from small failures in the soil cover to massive, devastating rock avalanches. Some landslides dam rivers and impound lakes, which can collapse days to centuries later, and flood mountain valleys for hundreds of kilometers downstream. Landslide deposits on slopes can remobilize during heavy rainfall and evolve into debris flows. Cracks and fractures can form and widen on mountain crests and flanks, promoting increased frequency of landslides that lasts for decades. More gradual impacts involve the flushing of excess debris downstream by rivers, which can generate bank erosion and floodplain accretion as well as channel avulsions that affect flooding frequency, settlements, ecosystems, and infrastructure. Ultimately, earthquake sequences and their geomorphic consequences alter mountain landscapes over both human and geologic time scales. Two recent events have attracted intense research into earthquake‐induced landslides and their consequences: the magnitude M 7.6 Chi‐Chi, Taiwan earthquake of 1999, and the M 7.9 Wenchuan, China earthquake of 2008. Using data and insights from these and several other earthquakes, we analyze how such events initiate processes that change mountain landscapes, highlight research gaps, and suggest pathways toward a more complete understanding of the seismic effects on the Earth's surface.
TL;DR: During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% and 50% respectively.
Abstract: The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).
TL;DR: This study is among the very few to date to explicitly explore how blockchains may transform supply chain practices, and demonstrates the usefulness of sensemaking theory as an alternative lens in investigating contemporary supply chain phenomena such as blockchains.
Heidelberg University1, University of Lausanne2, Chinese Academy of Sciences3, Skolkovo Institute of Science and Technology4, National Research University – Higher School of Economics5, Cardiff University6, École Polytechnique Fédérale de Lausanne7, Children's Mercy Hospital8, University of Kansas9, University of Porto10, Francis Crick Institute11, The University of Texas Rio Grande Valley12, Linköping University13, German Primate Center14, Newcastle University15, CAS-MPG Partner Institute for Computational Biology16, Stanford University17
TL;DR: It is found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase during development.
Abstract: The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.
Centre national de la recherche scientifique1, IFREMER2, ETH Zurich3, Cardiff University4, University of Bern5, Université Paris-Saclay6, University of Bordeaux7, Federal Fluminense University8, Leibniz Institute for Baltic Sea Research9, University of St Andrews10, University of New Hampshire11, Oregon State University12, École pratique des hautes études13, Royal Holloway, University of London14, University of Nantes15, Hofstra University16, Lamont–Doherty Earth Observatory17, Uppsala University18, Woods Hole Oceanographic Institution19, University of Edinburgh20, Geological Survey of Denmark and Greenland21, Instituto Geológico y Minero de España22, University of Connecticut23, Georgia Institute of Technology24, University of Colorado Boulder25, University of the Algarve26, British Antarctic Survey27, VU University Amsterdam28, University of Bremen29, Max Planck Society30, Thermo Fisher Scientific31, University of Cambridge32, University of Paris33, University College London34, Ghent University35, Aix-Marseille University36, Autonomous University of Barcelona37, University of California, Santa Barbara38, Utrecht University39
TL;DR: This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean.
Abstract: Rapid changes in ocean circulation and climate have been observed in marine-sediment and ice cores over the last glacial period and deglaciation, highlighting the non-linear character of the climate system and underlining the possibility of rapid climate shifts in response to anthropogenic greenhouse gas forcing. To date, these rapid changes in climate and ocean circulation are still not fully explained. One obstacle hindering progress in our understanding of the interactions between past ocean circulation and climate changes is the difficulty of accurately dating marine cores. Here, we present a set of 92 marine sediment cores from the Atlantic Ocean for which we have established age-depth models that are consistent with the Greenland GICC05 ice core chronology, and computed the associated dating uncertainties, using a new deposition modeling technique. This is the first set of consistently dated marine sediment cores enabling paleoclimate scientists to evaluate leads/lags between circulation and climate changes over vast regions of the Atlantic Ocean. Moreover, this data set is of direct use in paleoclimate modeling studies.
TL;DR: The findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.
Abstract: Tigecycline is a last-resort antibiotic that is used to treat severe infections caused by extensively drug-resistant bacteria. tet(X) has been shown to encode a flavin-dependent monooxygenase that modifies tigecycline1,2. Here, we report two unique mobile tigecycline-resistance genes, tet(X3) and tet(X4), in numerous Enterobacteriaceae and Acinetobacter that were isolated from animals, meat for consumption and humans. Tet(X3) and Tet(X4) inactivate all tetracyclines, including tigecycline and the newly FDA-approved eravacycline and omadacycline. Both tet(X3) and tet(X4) increase (by 64-128-fold) the tigecycline minimal inhibitory concentration values for Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. In addition, both Tet(X3) (A. baumannii) and Tet(X4) (E. coli) significantly compromise tigecycline in in vivo infection models. Both tet(X3) and tet(X4) are adjacent to insertion sequence ISVsa3 on their respective conjugative plasmids and confer a mild fitness cost (relative fitness of >0.704). Database mining and retrospective screening analyses confirm that tet(X3) and tet(X4) are globally present in clinical bacteria-even in the same bacteria as blaNDM-1, resulting in resistance to both tigecycline and carbapenems. Our findings suggest that both the surveillance of tet(X) variants in clinical and animal sectors and the use of tetracyclines in food production require urgent global attention.
Shanghai Jiao Tong University1, Broad Institute2, Harvard University3, Karolinska Institutet4, CAS-MPG Partner Institute for Computational Biology5, King's College London6, Fujita Health University7, University of Queensland8, University of South Australia9, Columbia University10, Peking University11, University of Tokyo12, Chonnam National University13, University of Indonesia14, National Taiwan University15, Utrecht University16, Xi'an Jiaotong University17, State University of New York System18, State University of New York Upstate Medical University19, Jinan University20, Icahn School of Medicine at Mount Sinai21, University of Western Australia22, Cardiff University23, University of North Carolina at Chapel Hill24, Charité25, Jining Medical University26, University of Hong Kong27, Li Ka Shing Faculty of Medicine, University of Hong Kong28, Samsung Medical Center29, Illawarra Health & Medical Research Institute30, University of Wollongong31, University of California, San Diego32, Genome Institute of Singapore33, National University of Singapore34
TL;DR: The largest study to date of East Asian participants is reported, identifying 21 genome-wide-significant associations in 19 genetic loci associated with schizophrenia and highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
Abstract: Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
TL;DR: Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy and clinical efficacy was evident across patients with diverse mutational profiles.
Abstract: Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.
Harvard University1, University of North Carolina at Chapel Hill2, University of Texas at Austin3, VU University Amsterdam4, Broad Institute5, Icahn School of Medicine at Mount Sinai6, Cardiff University7, Stanford University8, Federal University of São Paulo9, University of Pennsylvania10, University of Helsinki11, University of Illinois at Urbana–Champaign12, University of California, Los Angeles13, Centre for Addiction and Mental Health14, University Medical Center Groningen15, Universidade Federal do Rio Grande do Sul16, King's College London17, University of Edinburgh18, University of Oslo19, Lundbeck20, Indiana University21, Veterans Health Administration22, State University of New York Upstate Medical University23, Yale University24, University of Florida25, VA Boston Healthcare System26, Virginia Commonwealth University27, Maine Medical Center28, University of California, Berkeley29, University of Queensland30
TL;DR: A meta-analysis of genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders.
Abstract: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
TL;DR: To improve localization quality of the proposals while maintaining efficiency, a novel fast segmentation method is proposed and demonstrated its effectiveness for improving BING’s localization performance, when used in multi-thresholding straddling expansion (MTSE) post-processing.
Abstract: Training a generic objectness measure to produce object proposals has recently become of significant interest. We observe that generic objects with well-defined closed boundaries can be detected by looking at the norm of gradients, with a suitable resizing of their corresponding image windows to a small fixed size. Based on this observation and computational reasons, we propose to resize the window to 8 × 8 and use the norm of the gradients as a simple 64D feature to describe it, for explicitly training a generic objectness measure. We further show how the binarized version of this feature, namely binarized normed gradients (BING), can be used for efficient objectness estimation, which requires only a few atomic operations (e.g., add, bitwise shift, etc.). To improve localization quality of the proposals while maintaining efficiency, we propose a novel fast segmentation method and demonstrate its effectiveness for improving BING’s localization performance, when used in multi-thresholding straddling expansion (MTSE) post-processing. On the challenging PASCAL VOC2007 dataset, using 1000 proposals per image and intersection-over-union threshold of 0.5, our proposal method achieves a 95.6% object detection rate and 78.6% mean average best overlap in less than 0.005 second per image.
TL;DR: The 2018 Planck CMB likelihoods were presented in this paper, following a hybrid approach similar to the 2015 one, with different approximations at low and high multipoles, and implementing several methodological and analysis refinements.
Abstract: This paper describes the 2018 Planck CMB likelihoods, following a hybrid approach similar to the 2015 one, with different approximations at low and high multipoles, and implementing several methodological and analysis refinements. With more realistic simulations, and better correction and modelling of systematics, we can now make full use of the High Frequency Instrument polarization data. The low-multipole 100x143 GHz EE cross-spectrum constrains the reionization optical-depth parameter $\tau$ to better than 15% (in combination with with the other low- and high-$\ell$ likelihoods). We also update the 2015 baseline low-$\ell$ joint TEB likelihood based on the Low Frequency Instrument data, which provides a weaker $\tau$ constraint. At high multipoles, a better model of the temperature-to-polarization leakage and corrections for the effective calibrations of the polarization channels (polarization efficiency or PE) allow us to fully use the polarization spectra, improving the constraints on the $\Lambda$CDM parameters by 20 to 30% compared to TT-only constraints. Tests on the modelling of the polarization demonstrate good consistency, with some residual modelling uncertainties, the accuracy of the PE modelling being the main limitation. Using our various tests, simulations, and comparison between different high-$\ell$ implementations, we estimate the consistency of the results to be better than the 0.5$\sigma$ level. Minor curiosities already present before (differences between $\ell$ 800 parameters or the preference for more smoothing of the $C_\ell$ peaks) are shown to be driven by the TT power spectrum and are not significantly modified by the inclusion of polarization. Overall, the legacy Planck CMB likelihoods provide a robust tool for constraining the cosmological model and represent a reference for future CMB observations. (Abridged)
TL;DR: Key benefits are described, including reputational gains, increased chances of publication, and a broader increase in the reliability of research, which should benefit both the ECR and the quality of research.
Abstract: The movement towards open science is a consequence of seemingly pervasive failures to replicate previous research. This transition comes with great benefits but also significant challenges that are likely to affect those who carry out the research, usually early career researchers (ECRs). Here, we describe key benefits, including reputational gains, increased chances of publication, and a broader increase in the reliability of research. The increased chances of publication are supported by exploratory analyses indicating null findings are substantially more likely to be published via open registered reports in comparison to more conventional methods. These benefits are balanced by challenges that we have encountered and that involve increased costs in terms of flexibility, time, and issues with the current incentive structure, all of which seem to affect ECRs acutely. Although there are major obstacles to the early adoption of open science, overall open science practices should benefit both the ECR and improve the quality of research. We review 3 benefits and 3 challenges and provide suggestions from the perspective of ECRs for moving towards open science practices, which we believe scientists and institutions at all levels would do well to consider.
Netherlands Cancer Institute1, Radboud University Nijmegen2, Princess Margaret Cancer Centre3, Cardiff University4, Institut Jules Bordet5, University of Amsterdam6, Maastricht University7, Université de Montréal8, University Medical Center Groningen9, Ghent University10, Cliniques Universitaires Saint-Luc11, European Organisation for Research and Treatment of Cancer12, Bristol-Myers Squibb13
TL;DR: This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib and may identify patients with inherent resistance to systemic therapy before planned CN.
Abstract: Importance In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. Objective To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. Design, Setting, and Participants This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Interventions Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Main Outcomes and Measures Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. Results The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95;P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Conclusions and Relevance Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. Trial Registration ClinicalTrials.gov identifier:NCT01099423