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Showing papers by "University of Cambridge published in 2017"


Journal ArticleDOI
TL;DR: Quantitative assessments show that SegNet provides good performance with competitive inference time and most efficient inference memory-wise as compared to other architectures, including FCN and DeconvNet.
Abstract: We present a novel and practical deep fully convolutional neural network architecture for semantic pixel-wise segmentation termed SegNet. This core trainable segmentation engine consists of an encoder network, a corresponding decoder network followed by a pixel-wise classification layer. The architecture of the encoder network is topologically identical to the 13 convolutional layers in the VGG16 network [1] . The role of the decoder network is to map the low resolution encoder feature maps to full input resolution feature maps for pixel-wise classification. The novelty of SegNet lies is in the manner in which the decoder upsamples its lower resolution input feature map(s). Specifically, the decoder uses pooling indices computed in the max-pooling step of the corresponding encoder to perform non-linear upsampling. This eliminates the need for learning to upsample. The upsampled maps are sparse and are then convolved with trainable filters to produce dense feature maps. We compare our proposed architecture with the widely adopted FCN [2] and also with the well known DeepLab-LargeFOV [3] , DeconvNet [4] architectures. This comparison reveals the memory versus accuracy trade-off involved in achieving good segmentation performance. SegNet was primarily motivated by scene understanding applications. Hence, it is designed to be efficient both in terms of memory and computational time during inference. It is also significantly smaller in the number of trainable parameters than other competing architectures and can be trained end-to-end using stochastic gradient descent. We also performed a controlled benchmark of SegNet and other architectures on both road scenes and SUN RGB-D indoor scene segmentation tasks. These quantitative assessments show that SegNet provides good performance with competitive inference time and most efficient inference memory-wise as compared to other architectures. We also provide a Caffe implementation of SegNet and a web demo at http://mi.eng.cam.ac.uk/projects/segnet/ .

13,468 citations


Journal ArticleDOI
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016.

10,401 citations


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1131 moreInstitutions (123)
TL;DR: The association of GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short γ-ray bursts.
Abstract: On August 17, 2017 at 12∶41:04 UTC the Advanced LIGO and Advanced Virgo gravitational-wave detectors made their first observation of a binary neutron star inspiral. The signal, GW170817, was detected with a combined signal-to-noise ratio of 32.4 and a false-alarm-rate estimate of less than one per 8.0×10^{4} years. We infer the component masses of the binary to be between 0.86 and 2.26 M_{⊙}, in agreement with masses of known neutron stars. Restricting the component spins to the range inferred in binary neutron stars, we find the component masses to be in the range 1.17-1.60 M_{⊙}, with the total mass of the system 2.74_{-0.01}^{+0.04}M_{⊙}. The source was localized within a sky region of 28 deg^{2} (90% probability) and had a luminosity distance of 40_{-14}^{+8} Mpc, the closest and most precisely localized gravitational-wave signal yet. The association with the γ-ray burst GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short γ-ray bursts. Subsequent identification of transient counterparts across the electromagnetic spectrum in the same location further supports the interpretation of this event as a neutron star merger. This unprecedented joint gravitational and electromagnetic observation provides insight into astrophysics, dense matter, gravitation, and cosmology.

7,327 citations


Journal ArticleDOI
TL;DR: This article conducted an extensive literature review, employing bibliometric analysis and snowballing techniques to investigate the state of the art in the field and synthesise the similarities, differences and relationships between both terms.

3,508 citations


Journal ArticleDOI
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions as discussed by the authors.
Abstract: Summary Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services. Funding Bill & Melinda Gates Foundation.

2,995 citations


Journal ArticleDOI
TL;DR: An efficient and effective dense training scheme which joins the processing of adjacent image patches into one pass through the network while automatically adapting to the inherent class imbalance present in the data, and improves on the state-of-the‐art for all three applications.

2,842 citations


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1195 moreInstitutions (139)
TL;DR: In this paper, the authors used the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to constrain the difference between the speed of gravity and speed of light to be between $-3
Abstract: On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory. The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is $5.0\times {10}^{-8}$. We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between $-3\times {10}^{-15}$ and $+7\times {10}^{-16}$ times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1–1.4 per year during the 2018–2019 observing run and 0.3–1.7 per year at design sensitivity.

2,633 citations


Posted Content
TL;DR: A Bayesian deep learning framework combining input-dependent aleatoric uncertainty together with epistemic uncertainty is presented, which makes the loss more robust to noisy data, also giving new state-of-the-art results on segmentation and depth regression benchmarks.
Abstract: There are two major types of uncertainty one can model. Aleatoric uncertainty captures noise inherent in the observations. On the other hand, epistemic uncertainty accounts for uncertainty in the model -- uncertainty which can be explained away given enough data. Traditionally it has been difficult to model epistemic uncertainty in computer vision, but with new Bayesian deep learning tools this is now possible. We study the benefits of modeling epistemic vs. aleatoric uncertainty in Bayesian deep learning models for vision tasks. For this we present a Bayesian deep learning framework combining input-dependent aleatoric uncertainty together with epistemic uncertainty. We study models under the framework with per-pixel semantic segmentation and depth regression tasks. Further, our explicit uncertainty formulation leads to new loss functions for these tasks, which can be interpreted as learned attenuation. This makes the loss more robust to noisy data, also giving new state-of-the-art results on segmentation and depth regression benchmarks.

2,616 citations


Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1062 moreInstitutions (115)
TL;DR: The magnitude of modifications to the gravitational-wave dispersion relation is constrain, the graviton mass is bound to m_{g}≤7.7×10^{-23} eV/c^{2} and null tests of general relativity are performed, finding that GW170104 is consistent with general relativity.
Abstract: We describe the observation of GW170104, a gravitational-wave signal produced by the coalescence of a pair of stellar-mass black holes. The signal was measured on January 4, 2017 at 10∶11:58.6 UTC by the twin advanced detectors of the Laser Interferometer Gravitational-Wave Observatory during their second observing run, with a network signal-to-noise ratio of 13 and a false alarm rate less than 1 in 70 000 years. The inferred component black hole masses are 31.2^(8.4) _(−6.0)M_⊙ and 19.4^(5.3)_( −5.9)M_⊙ (at the 90% credible level). The black hole spins are best constrained through measurement of the effective inspiral spin parameter, a mass-weighted combination of the spin components perpendicular to the orbital plane, χ_(eff) = −0.12^(0.21)_( −0.30). This result implies that spin configurations with both component spins positively aligned with the orbital angular momentum are disfavored. The source luminosity distance is 880^(450)_(−390) Mpc corresponding to a redshift of z = 0.18^(0.08)_( −0.07) . We constrain the magnitude of modifications to the gravitational-wave dispersion relation and perform null tests of general relativity. Assuming that gravitons are dispersed in vacuum like massive particles, we bound the graviton mass to m_g ≤ 7.7 × 10^(−23) eV/c^2. In all cases, we find that GW170104 is consistent with general relativity.

2,569 citations


Journal ArticleDOI
TL;DR: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenIB treatment, and future trials should explore combinations of regorAFenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafanib and regorafinib.

2,543 citations


Journal ArticleDOI
Shadab Alam1, Metin Ata2, Stephen Bailey3, Florian Beutler3, Dmitry Bizyaev4, Dmitry Bizyaev5, Jonathan Blazek6, Adam S. Bolton7, Joel R. Brownstein7, Angela Burden8, Chia-Hsun Chuang2, Chia-Hsun Chuang9, Johan Comparat9, Antonio J. Cuesta10, Kyle S. Dawson7, Daniel J. Eisenstein11, Stephanie Escoffier12, Héctor Gil-Marín13, Héctor Gil-Marín14, Jan Niklas Grieb15, Nick Hand16, Shirley Ho1, Karen Kinemuchi5, D. Kirkby17, Francisco S. Kitaura16, Francisco S. Kitaura3, Francisco S. Kitaura2, Elena Malanushenko5, Viktor Malanushenko5, Claudia Maraston18, Cameron K. McBride11, Robert C. Nichol18, Matthew D. Olmstead19, Daniel Oravetz5, Nikhil Padmanabhan8, Nathalie Palanque-Delabrouille, Kaike Pan5, Marcos Pellejero-Ibanez20, Marcos Pellejero-Ibanez21, Will J. Percival18, Patrick Petitjean22, Francisco Prada9, Francisco Prada21, Adrian M. Price-Whelan23, Beth Reid3, Beth Reid16, Sergio Rodríguez-Torres21, Sergio Rodríguez-Torres9, Natalie A. Roe3, Ashley J. Ross18, Ashley J. Ross6, Nicholas P. Ross24, Graziano Rossi25, Jose Alberto Rubino-Martin20, Jose Alberto Rubino-Martin21, Shun Saito15, Salvador Salazar-Albornoz15, Lado Samushia26, Ariel G. Sánchez15, Siddharth Satpathy1, David J. Schlegel3, Donald P. Schneider27, Claudia G. Scóccola9, Claudia G. Scóccola28, Claudia G. Scóccola29, Hee-Jong Seo30, Erin Sheldon31, Audrey Simmons5, Anže Slosar31, Michael A. Strauss23, Molly E. C. Swanson11, Daniel Thomas18, Jeremy L. Tinker32, Rita Tojeiro33, Mariana Vargas Magaña34, Mariana Vargas Magaña1, Jose Alberto Vazquez31, Licia Verde, David A. Wake35, David A. Wake36, Yuting Wang18, Yuting Wang37, David H. Weinberg6, Martin White3, Martin White16, W. Michael Wood-Vasey38, Christophe Yèche, Idit Zehavi39, Zhongxu Zhai33, Gong-Bo Zhao18, Gong-Bo Zhao37 
TL;DR: In this article, the authors present cosmological results from the final galaxy clustering data set of the Baryon Oscillation Spectroscopic Survey, part of the Sloan Digital Sky Survey III.
Abstract: We present cosmological results from the final galaxy clustering data set of the Baryon Oscillation Spectroscopic Survey, part of the Sloan Digital Sky Survey III. Our combined galaxy sample comprises 1.2 million massive galaxies over an effective area of 9329 deg^2 and volume of 18.7 Gpc^3, divided into three partially overlapping redshift slices centred at effective redshifts 0.38, 0.51 and 0.61. We measure the angular diameter distance and Hubble parameter H from the baryon acoustic oscillation (BAO) method, in combination with a cosmic microwave background prior on the sound horizon scale, after applying reconstruction to reduce non-linear effects on the BAO feature. Using the anisotropic clustering of the pre-reconstruction density field, we measure the product D_MH from the Alcock–Paczynski (AP) effect and the growth of structure, quantified by fσ_8(z), from redshift-space distortions (RSD). We combine individual measurements presented in seven companion papers into a set of consensus values and likelihoods, obtaining constraints that are tighter and more robust than those from any one method; in particular, the AP measurement from sub-BAO scales sharpens constraints from post-reconstruction BAOs by breaking degeneracy between D_M and H. Combined with Planck 2016 cosmic microwave background measurements, our distance scale measurements simultaneously imply curvature Ω_K = 0.0003 ± 0.0026 and a dark energy equation-of-state parameter w = −1.01 ± 0.06, in strong affirmation of the spatially flat cold dark matter (CDM) model with a cosmological constant (ΛCDM). Our RSD measurements of fσ_8, at 6 per cent precision, are similarly consistent with this model. When combined with supernova Ia data, we find H_0 = 67.3 ± 1.0 km s^−1 Mpc^−1 even for our most general dark energy model, in tension with some direct measurements. Adding extra relativistic species as a degree of freedom loosens the constraint only slightly, to H_0 = 67.8 ± 1.2 km s^−1 Mpc^−1. Assuming flat ΛCDM, we find Ω_m = 0.310 ± 0.005 and H_0 = 67.6 ± 0.5 km s^−1 Mpc^−1, and we find a 95 per cent upper limit of 0.16 eV c^−2 on the neutrino mass sum.

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1113 moreInstitutions (117)
TL;DR: For the first time, the nature of gravitational-wave polarizations from the antenna response of the LIGO-Virgo network is tested, thus enabling a new class of phenomenological tests of gravity.
Abstract: On August 14, 2017 at 10∶30:43 UTC, the Advanced Virgo detector and the two Advanced LIGO detectors coherently observed a transient gravitational-wave signal produced by the coalescence of two stellar mass black holes, with a false-alarm rate of ≲1 in 27 000 years. The signal was observed with a three-detector network matched-filter signal-to-noise ratio of 18. The inferred masses of the initial black holes are 30.5-3.0+5.7M⊙ and 25.3-4.2+2.8M⊙ (at the 90% credible level). The luminosity distance of the source is 540-210+130 Mpc, corresponding to a redshift of z=0.11-0.04+0.03. A network of three detectors improves the sky localization of the source, reducing the area of the 90% credible region from 1160 deg2 using only the two LIGO detectors to 60 deg2 using all three detectors. For the first time, we can test the nature of gravitational-wave polarizations from the antenna response of the LIGO-Virgo network, thus enabling a new class of phenomenological tests of gravity.

Journal ArticleDOI
TL;DR: Treatment with lutetium‐177 (177Lu)–Dotatate resulted in markedly longer progression‐free survival and a significantly higher response rate than high‐dose octreotide LAR among patients with advanced midgut neuroendocrine tumors.
Abstract: BackgroundPatients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin-receptor–positive midgut neuroendocrine tumors. MethodsWe randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-ef...

Journal ArticleDOI
26 May 2017-Science
TL;DR: A subcellular map of the human proteome is presented to facilitate functional exploration of individual proteins and their role in human biology and disease and integrated into existing network models of protein-protein interactions for increased accuracy.
Abstract: Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map ...

Journal ArticleDOI
20 Jun 2017-JAMA
TL;DR: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location, a large cohort study recruited in 1997-2011 provides estimates of cancer risk based on BRCA1 and BRCa2 mutation carrier status.
Abstract: Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Journal ArticleDOI
TL;DR: This review describes this field of science with particular reference to the advances that have been made over the last decade in understanding of its fundamental nature and consequences and shows evidence that a complex proteostasis network actively combats protein aggregation.
Abstract: Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors a...

Journal ArticleDOI
TL;DR: The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA.
Abstract: Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

Proceedings ArticleDOI
05 May 2017
TL;DR: This article showed how universal sentence representations trained using the supervised data of the Stanford Natural Language Inference datasets can consistently outperform unsupervised methods like SkipThought vectors on a wide range of transfer tasks.
Abstract: Many modern NLP systems rely on word embeddings, previously trained in an unsupervised manner on large corpora, as base features. Efforts to obtain embeddings for larger chunks of text, such as sentences, have however not been so successful. Several attempts at learning unsupervised representations of sentences have not reached satisfactory enough performance to be widely adopted. In this paper, we show how universal sentence representations trained using the supervised data of the Stanford Natural Language Inference datasets can consistently outperform unsupervised methods like SkipThought vectors on a wide range of transfer tasks. Much like how computer vision uses ImageNet to obtain features, which can then be transferred to other tasks, our work tends to indicate the suitability of natural language inference for transfer learning to other NLP tasks. Our encoder is publicly available.

Journal ArticleDOI
Bin Zhou1, James Bentham1, Mariachiara Di Cesare2, Honor Bixby1  +787 moreInstitutions (231)
TL;DR: The number of adults with raised blood pressure increased from 594 million in 1975 to 1·13 billion in 2015, with the increase largely in low-income and middle-income countries, and the contributions of changes in prevalence versus population growth and ageing to the increase.

Journal ArticleDOI
TL;DR: The presence of CHIP in peripheral‐blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice.
Abstract: BackgroundClonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. MethodsWe used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case–control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. ResultsIn nested case–control analyses from two prospective cohorts, carriers of CHIP had a risk of c...

Journal ArticleDOI
23 Feb 2017-Nature
TL;DR: The observations reveal that at least seven planets with sizes and masses similar to those of Earth revolve around TRAPPIST-1, and the six inner planets form a near-resonant chain, such that their orbital periods are near-ratios of small integers.
Abstract: One aim of modern astronomy is to detect temperate, Earth-like exoplanets that are well suited for atmospheric characterization. Recently, three Earth-sized planets were detected that transit (that is, pass in front of) a star with a mass just eight per cent that of the Sun, located 12 parsecs away. The transiting configuration of these planets, combined with the Jupiter-like size of their host star—named TRAPPIST-1—makes possible in-depth studies of their atmospheric properties with present-day and future astronomical facilities. Here we report the results of a photometric monitoring campaign of that star from the ground and space. Our observations reveal that at least seven planets with sizes and masses similar to those of Earth revolve around TRAPPIST-1. The six inner planets form a near-resonant chain, such that their orbital periods (1.51, 2.42, 4.04, 6.06, 9.1 and 12.35 days) are near-ratios of small integers. This architecture suggests that the planets formed farther from the star and migrated inwards. Moreover, the seven planets have equilibrium temperatures low enough to make possible the presence of liquid water on their surfaces.

Journal ArticleDOI
Aviv Regev1, Aviv Regev2, Aviv Regev3, Sarah A. Teichmann4, Sarah A. Teichmann5, Sarah A. Teichmann6, Eric S. Lander1, Eric S. Lander2, Eric S. Lander7, Ido Amit8, Christophe Benoist7, Ewan Birney4, Bernd Bodenmiller4, Bernd Bodenmiller9, Peter J. Campbell6, Peter J. Campbell5, Piero Carninci6, Menna R. Clatworthy10, Hans Clevers11, Bart Deplancke12, Ian Dunham4, James Eberwine13, Roland Eils14, Roland Eils15, Wolfgang Enard16, Andrew Farmer, Lars Fugger17, Berthold Göttgens6, Nir Hacohen7, Nir Hacohen2, Muzlifah Haniffa18, Martin Hemberg5, Seung K. Kim19, Paul Klenerman20, Paul Klenerman17, Arnold R. Kriegstein21, Ed S. Lein22, Sten Linnarsson23, Emma Lundberg19, Emma Lundberg24, Joakim Lundeberg24, Partha P. Majumder, John C. Marioni5, John C. Marioni6, John C. Marioni4, Miriam Merad25, Musa M. Mhlanga26, Martijn C. Nawijn27, Mihai G. Netea28, Garry P. Nolan19, Dana Pe'er29, Anthony Phillipakis2, Chris P. Ponting30, Stephen R. Quake19, Wolf Reik6, Wolf Reik31, Wolf Reik5, Orit Rozenblatt-Rosen2, Joshua R. Sanes7, Rahul Satija32, Ton N. Schumacher33, Alex K. Shalek34, Alex K. Shalek2, Alex K. Shalek1, Ehud Shapiro8, Padmanee Sharma35, Jay W. Shin, Oliver Stegle4, Michael R. Stratton5, Michael J. T. Stubbington5, Fabian J. Theis36, Matthias Uhlen24, Matthias Uhlen37, Alexander van Oudenaarden11, Allon Wagner38, Fiona M. Watt39, Jonathan S. Weissman, Barbara J. Wold40, Ramnik J. Xavier, Nir Yosef38, Nir Yosef34, Human Cell Atlas Meeting Participants 
05 Dec 2017-eLife
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.

Journal ArticleDOI
TL;DR: Direct evidence for CAF heterogeneity in PDA tumor biology is provided, providing direct evidence for disease etiology and therapeutic development in mouse and human PDA tissue.
Abstract: Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

Journal ArticleDOI
Andrew I R Maas1, David K. Menon2, P. David Adelson3, Nada Andelic4  +339 moreInstitutions (110)
TL;DR: The InTBIR Participants and Investigators have provided informed consent for the study to take place in Poland.
Abstract: Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators

Journal ArticleDOI
TL;DR: Treatment with low‐dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo, and there were no significant between‐group differences in the incidence of neonatal adverse outcomes or other adverse events.
Abstract: BackgroundPreterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. MethodsIn this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. ResultsA total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidenc...

Journal ArticleDOI
B. P. Abbott1, Richard J. Abbott1, T. D. Abbott2, Fausto Acernese3  +1151 moreInstitutions (125)
TL;DR: In this article, a GW signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13.5%.
Abstract: On 2017 June 8 at 02:01:16.49 UTC, a gravitational-wave (GW) signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13. This system is the lightest black hole binary so far observed, with component masses of ${12}_{-2}^{+7}\,{M}_{\odot }$ and ${7}_{-2}^{+2}\,{M}_{\odot }$ (90% credible intervals). These lie in the range of measured black hole masses in low-mass X-ray binaries, thus allowing us to compare black holes detected through GWs with electromagnetic observations. The source's luminosity distance is ${340}_{-140}^{+140}\,\mathrm{Mpc}$, corresponding to redshift ${0.07}_{-0.03}^{+0.03}$. We verify that the signal waveform is consistent with the predictions of general relativity.

Proceedings Article
04 Dec 2017
TL;DR: In this paper, a Bayesian deep learning framework combining input-dependent aleatoric uncertainty together with epistemic uncertainty was proposed for semantic segmentation and depth regression tasks, which can be interpreted as learned attenuation.
Abstract: There are two major types of uncertainty one can model. Aleatoric uncertainty captures noise inherent in the observations. On the other hand, epistemic uncertainty accounts for uncertainty in the model - uncertainty which can be explained away given enough data. Traditionally it has been difficult to model epistemic uncertainty in computer vision, but with new Bayesian deep learning tools this is now possible. We study the benefits of modeling epistemic vs. aleatoric uncertainty in Bayesian deep learning models for vision tasks. For this we present a Bayesian deep learning framework combining input-dependent aleatoric uncertainty together with epistemic uncertainty. We study models under the framework with per-pixel semantic segmentation and depth regression tasks. Further, our explicit uncertainty formulation leads to new loss functions for these tasks, which can be interpreted as learned attenuation. This makes the loss more robust to noisy data, also giving new state-of-the-art results on segmentation and depth regression benchmarks.

Journal ArticleDOI
TL;DR: This research presents a meta-analyses of Gastroenterology and Hepatology at the cellular and molecular level, which shows clear trends in the development of immune-oncology-metabolical pathways towards “clinically checkpoints”.
Abstract: aDepartment of Pharmacology and Therapeutics, University of Porto; MedInUP, Centre for Drug Discovery and Innovative Medicines; Centro Hospitalar São João, Porto, Portugal bIBD Unit, DIMEC, University of Bologna, Bologna, Italy cDepartment of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel dGastrointestinal Unit ASST Fatebenefratelli Sacco—University of Milan—Milan, Italy eIBD Unit Complesso Integrato Columbus, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli Universita’ Cattolica del Sacro Cuore, Rome, Italy fDepartment of Gastroenterology, IBD Unit, University Hospital Santiago De Compostela (CHUS), A Coruña, Spain gDepartment of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark hFirst Department of Medicine, Semmelweis University, Budapest, Hungary iIBD Unit, St Mark’s Hospital, Middlesex, UK jDepartment of Gastroenterology, University Hospital of Ghent, Ghent, Belgium kInstitute of Pathology, Medical University of Graz, Graz, Austria lDepartment of Gastroenterology, Pennine Acute Hospitals NHS Trust; Institute of Inflammation and Repair, University of Manchester, Manchester, UK mUnit of General Surgery, Second University of Naples, Napoli, Italy nMaria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Oncological Gastroenterology Warsaw; Medical Centre for Postgraduate Education, Department of Gastroenterology, Hepatology and Clinical Oncology, Warsaw, Poland oDepartment of Medicine, University of Cambridge, Cambridge, UK pImperial College London; Chelsea and Westminster Hospital, London, UK qDepartment of Pathobiology /NC22, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition/A3, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Journal ArticleDOI
TL;DR: SDSS-IV as mentioned in this paper is a project encompassing three major spectroscopic programs: the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA), the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and the Time Domain Spectroscopy Survey (TDSS).
Abstract: We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median $z\sim 0.03$). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between $z\sim 0.6$ and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.

Journal ArticleDOI
TL;DR: A historical perspective of their discovery is provided and their established functions in sensing and responding to genotoxic stress are discussed, as well as emerging non-canonical roles and how knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.