Showing papers by "University of Melbourne published in 2017"

GW170817: observation of gravitational waves from a binary neutron star inspiral

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.

Health Effects of Overweight and Obesity in 195 Countries over 25 Years.

Abstract: BACKGROUND Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHOD ...

Neurotoxic reactive astrocytes are induced by activated microglia

Abstract: This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1).

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Abstract: BackgroundNivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. MethodsWe randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival a...

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.

Abstract: Summary Background The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. Methods We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. Findings We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa , and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus . Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori , and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae , and Salmonella typhi were included in the high-priority tier. Interpretation Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae , and H pylori . Funding World Health Organization.

Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016

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.

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.

Abstract: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Gravitational Waves and Gamma-Rays from a Binary Neutron Star Merger: GW170817 and GRB 170817A

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.

GW170104: Observation of a 50-Solar-Mass Binary Black Hole Coalescence at Redshift 0.2

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.

Consensus statement on concussion in sport—the 5th international conference on concussion in sport held in Berlin, October 2016

Abstract: The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps. A series of specific clinical questions were developed as part of the consensus process for the Berlin 2016 meeting. Each consensus question was the subject of a specific formal systematic review, which is published concurrently with this summary statement. Readers are directed to these background papers in conjunction with this summary statement as they provide the context for the issues and include the scope of published research, search strategy and citations reviewed for each question. This 2017 consensus statement also summarises each topic and recommendations in the context of all five CISG meetings (that is, 2001, 2004, 2008, 2012 as well as 2016). Approximately 60 000 published articles were screened by the expert panels for the Berlin …

Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads.

Abstract: The Illumina DNA sequencing platform generates accurate but short reads, which can be used to produce accurate but fragmented genome assemblies. Pacific Biosciences and Oxford Nanopore Technologies DNA sequencing platforms generate long reads that can produce complete genome assemblies, but the sequencing is more expensive and error-prone. There is significant interest in combining data from these complementary sequencing technologies to generate more accurate "hybrid" assemblies. However, few tools exist that truly leverage the benefits of both types of data, namely the accuracy of short reads and the structural resolving power of long reads. Here we present Unicycler, a new tool for assembling bacterial genomes from a combination of short and long reads, which produces assemblies that are accurate, complete and cost-effective. Unicycler builds an initial assembly graph from short reads using the de novo assembler SPAdes and then simplifies the graph using information from short and long reads. Unicycler uses a novel semi-global aligner to align long reads to the assembly graph. Tests on both synthetic and real reads show Unicycler can assemble larger contigs with fewer misassemblies than other hybrid assemblers, even when long-read depth and accuracy are low. Unicycler is open source (GPLv3) and available at github.com/rrwick/Unicycler.

GW170814: A three-detector observation of gravitational waves from a binary black hole coalescence

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.

mixOmics: An R package for 'omics feature selection and multiple data integration

Abstract: The advent of high throughput technologies has led to a wealth of publicly available 'omics data coming from different sources, such as transcriptomics, proteomics, metabolomics. Combining such large-scale biological data sets can lead to the discovery of important biological insights, provided that relevant information can be extracted in a holistic manner. Current statistical approaches have been focusing on identifying small subsets of molecules (a 'molecular signature') to explain or predict biological conditions, but mainly for a single type of 'omics. In addition, commonly used methods are univariate and consider each biological feature independently. We introduce mixOmics, an R package dedicated to the multivariate analysis of biological data sets with a specific focus on data exploration, dimension reduction and visualisation. By adopting a systems biology approach, the toolkit provides a wide range of methods that statistically integrate several data sets at once to probe relationships between heterogeneous 'omics data sets. Our recent methods extend Projection to Latent Structure (PLS) models for discriminant analysis, for data integration across multiple 'omics data or across independent studies, and for the identification of molecular signatures. We illustrate our latest mixOmics integrative frameworks for the multivariate analyses of 'omics data available from the package.

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

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.

Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015

Abstract: Importance Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures Mean SBP level, cause-specific deaths, and health burden related to SBP (≥110-115 mm Hg and also ≥140 mm Hg) by age, sex, country, and year. Results Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). Loss of disability-adjusted life-years (DALYs) associated with SBP of at least 110 to 115 mm Hg increased from 148 million (95% UI, 134-162 million) to 211 million (95% UI, 193-231 million), and for SBP of 140 mm Hg or higher, the loss increased from 95.9 million (95% UI, 87.0-104.9 million) to 143.0 million (95% UI, 130.2-157.0 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (≥110-115 and ≥140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher.

GW170608: Observation of a 19 solar-mass binary black hole coalescence

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.

The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level : results from the Global Burden of Disease Study 2015

Abstract: Importance Liver cancer is among the leading causes of cancer deaths globally. The most common causes for liver cancer include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and alcohol use. Objective To report results of the Global Burden of Disease (GBD) 2015 study on primary liver cancer incidence, mortality, and disability-adjusted life-years (DALYs) for 195 countries or territories from 1990 to 2015, and present global, regional, and national estimates on the burden of liver cancer attributable to HBV, HCV, alcohol, and an “other” group that encompasses residual causes. Design, Settings, and Participants Mortality was estimated using vital registration and cancer registry data in an ensemble modeling approach. Single-cause mortality estimates were adjusted for all-cause mortality. Incidence was derived from mortality estimates and the mortality-to-incidence ratio. Through a systematic literature review, data on the proportions of liver cancer due to HBV, HCV, alcohol, and other causes were identified. Years of life lost were calculated by multiplying each death by a standard life expectancy. Prevalence was estimated using mortality-to-incidence ratio as surrogate for survival. Total prevalence was divided into 4 sequelae that were multiplied by disability weights to derive years lived with disability (YLDs). DALYs were the sum of years of life lost and YLDs. Main Outcomes and Measures Liver cancer mortality, incidence, YLDs, years of life lost, DALYs by etiology, age, sex, country, and year. Results There were 854 000 incident cases of liver cancer and 810 000 deaths globally in 2015, contributing to 20 578 000 DALYs. Cases of incident liver cancer increased by 75% between 1990 and 2015, of which 47% can be explained by changing population age structures, 35% by population growth, and −8% to changing age-specific incidence rates. The male-to-female ratio for age-standardized liver cancer mortality was 2.8. Globally, HBV accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), HCV for 167 000 (21%), and other causes for 133 000 (16%) deaths, with substantial variation between countries in the underlying etiologies. Conclusions and Relevance Liver cancer is among the leading causes of cancer deaths in many countries. Causes of liver cancer differ widely among populations. Our results show that most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use. In line with the Sustainable Development Goals, the identification and elimination of risk factors for liver cancer will be required to achieve a sustained reduction in liver cancer burden. The GBD study can be used to guide these prevention efforts.

Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies

Abstract: Objective To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment. Design Systematic review and meta-analysis. Data sources Medline, Embase, PsycINFO, and LILACS to September 2016. Study selection Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine. Data extraction and synthesis Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis. Results There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment. Conclusions Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.

iFogSim: A toolkit for modeling and simulation of resource management techniques in the Internet of Things, Edge and Fog computing environments

Abstract: Summary Internet of Things (IoT) aims to bring every object (eg, smart cameras, wearable, environmental sensors, home appliances, and vehicles) online, hence generating massive volume of data that can overwhelm storage systems and data analytics applications. Cloud computing offers services at the infrastructure level that can scale to IoT storage and processing requirements. However, there are applications such as health monitoring and emergency response that require low latency, and delay that is caused by transferring data to the cloud and then back to the application can seriously impact their performances. To overcome this limitation, Fog computing paradigm has been proposed, where cloud services are extended to the edge of the network to decrease the latency and network congestion. To realize the full potential of Fog and IoT paradigms for real-time analytics, several challenges need to be addressed. The first and most critical problem is designing resource management techniques that determine which modules of analytics applications are pushed to each edge device to minimize the latency and maximize the throughput. To this end, we need an evaluation platform that enables the quantification of performance of resource management policies on an IoT or Fog computing infrastructure in a repeatable manner. In this paper we propose a simulator, called iFogSim, to model IoT and Fog environments and measure the impact of resource management techniques in latency, network congestion, energy consumption, and cost. We describe two case studies to demonstrate modeling of an IoT environment and comparison of resource management policies. Moreover, scalability of the simulation toolkit of RAM consumption and execution time is verified under different circumstances.

A look at the density functional theory zoo with the advanced GMTKN55 database for general main group thermochemistry, kinetics and noncovalent interactions

Abstract: We present the GMTKN55 benchmark database for general main group thermochemistry, kinetics and noncovalent interactions. Compared to its popular predecessor GMTKN30 [Goerigk and Grimme J. Chem. Theory Comput., 2011, 7, 291], it allows assessment across a larger variety of chemical problems—with 13 new benchmark sets being presented for the first time—and it also provides reference values of significantly higher quality for most sets. GMTKN55 comprises 1505 relative energies based on 2462 single-point calculations and it is accessible to the user community via a dedicated website. Herein, we demonstrate the importance of better reference values, and we re-emphasise the need for London-dispersion corrections in density functional theory (DFT) treatments of thermochemical problems, including Minnesota methods. We assessed 217 variations of dispersion-corrected and -uncorrected density functional approximations, and carried out a detailed analysis of 83 of them to identify robust and reliable approaches. Double-hybrid functionals are the most reliable approaches for thermochemistry and noncovalent interactions, and they should be used whenever technically feasible. These are, in particular, DSD-BLYP-D3(BJ), DSD-PBEP86-D3(BJ), and B2GPPLYP-D3(BJ). The best hybrids are ωB97X-V, M052X-D3(0), and ωB97X-D3, but we also recommend PW6B95-D3(BJ) as the best conventional global hybrid. At the meta-generalised-gradient (meta-GGA) level, the SCAN-D3(BJ) method can be recommended. Other meta-GGAs are outperformed by the GGA functionals revPBE-D3(BJ), B97-D3(BJ), and OLYP-D3(BJ). We note that many popular methods, such as B3LYP, are not part of our recommendations. In fact, with our results we hope to inspire a change in the user community's perception of common DFT methods. We also encourage method developers to use GMTKN55 for cross-validation studies of new methodologies.

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

Abstract: BackgroundThe Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period ResultsThe median frequency of convulsive seizures per month decreased from 124 to 59 with cannabidiol, as compared with a decrease from 149 to 141 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −228 percentage points; 95% confidence i

Association analysis identifies 65 new breast cancer risk loci

Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Cross-validation strategies for data with temporal, spatial, hierarchical, or phylogenetic structure

Abstract: Ecological data often show temporal, spatial, hierarchical (random effects), or phylogenetic structure. Modern statistical approaches are increasingly accounting for such dependencies. However, when performing cross-validation, these structures are regularly ignored, resulting in serious underestimation of predictive error. One cause for the poor performance of uncorrected (random) cross-validation, noted often by modellers, are dependence structures in the data that persist as dependence structures in model residuals, violating the assumption of independence. Even more concerning, because often overlooked, is that structured data also provides ample opportunity for overfitting with non-causal predictors. This problem can persist even if remedies such as autoregressive models, generalized least squares, or mixed models are used. Block cross-validation, where data are split strategically rather than randomly, can address these issues. However, the blocking strategy must be carefully considered. Blocking in space, time, random effects or phylogenetic distance, while accounting for dependencies in the data, may also unwittingly induce extrapolations by restricting the ranges or combinations of predictor variables available for model training, thus overestimating interpolation errors. On the other hand, deliberate blocking in predictor space may also improve error estimates when extrapolation is the modelling goal. Here, we review the ecological literature on non-random and blocked cross-validation approaches. We also provide a series of simulations and case studies, in which we show that, for all instances tested, block cross-validation is nearly universally more appropriate than random cross-validation if the goal is predicting to new data or predictor space, or for selecting causal predictors. We recommend that block cross-validation be used wherever dependence structures exist in a dataset, even if no correlation structure is visible in the fitted model residuals, or if the fitted models account for such correlations.