Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Author Correction: Global status and conservation potential of reef sharks

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.</p

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 t

Search for narrow resonances in the <math display="inline"><mi>b</mi></math>-tagged dijet mass spectrum in proton-proton collisions at <math display="inline"><msqrt><mi>s</mi></msqrt><mo>=</mo><mn>13</mn><mtext> </mtext><mtext> </mtext><mi>TeV</mi></math>

International audienceA search is performed for narrow resonances decaying to final states of two jets, with at least one jet originating from a b quark, in proton-proton collisions at s=13  TeV. The data set corresponds to an integrated luminosity of 138  fb-1 collected with the CMS detector at the LHC. Jets originating from energetic b hadrons are identified through a b-tagging algorithm that utilizes a deep neural network or the presence of a muon inside a jet. The invariant mass spectrum of jet pairs is well described by a smooth parametrization and no evidence for the production of new particles is observed. Upper limits on the production cross section are set for excited b quarks and other resonances decaying to dijet final states containing b quarks. These limits exclude at 95% confidence level models of Z′ bosons with masses from 1.8 TeV to 2.4 TeV and of excited b quarks with masses from 1.8 TeV to 4.0 TeV. This is the most stringent exclusion of excited b quarks to date

Search for pair production of vector-like quarks in leptonic final states in proton-proton collisions at s \sqrt{s} = 13 TeV

A search is presented for vector-like $\mathrm{T}$ and $\mathrm{B}$ quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016-2018, with an integrated luminosity of 138 fb$^{-1}$. Events are separated into single-lepton, same-sign charge dilepton, and multilepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for $\mathrm{T}$ quark masses up to 1.54 TeV and $\mathrm{B}$ quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\mathrm{T} \overline{\mathrm{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\mathrm{B} \overline{\mathrm{B}}$ production with $\mathrm{B}$ quark decays to tW.A search is presented for vector-like T and B quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016–2018, with an integrated luminosity of 138 fb$^{−1}$. Events are separated into single-lepton, same-sign charge dilepton, and multi-lepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for T quark masses up to 1.54 TeV and B quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\textrm{T}\overline{\textrm{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\textrm{B}\overline{\textrm{B}}$ production with B quark decays to tW.[graphic not available: see fulltext]A search is presented for vector-like T and B quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016-2018, with an integrated luminosity of 138 fb$^{-1}$. Events are separated into single-lepton, same-sign charge dilepton, and multilepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for T quark masses up to 1.54 TeV and B quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\mathrm{T\overline{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\mathrm{B\overline{B}}$ production with B quark decays to tW

Search for Higgs boson decays to a Z boson and a photon in proton-proton collisions at s \sqrt{s} = 13 TeV

International audienceResults are presented from a search for the Higgs boson decay H → Zγ, where Z → ℓ$^{+}$ℓ$^{−}$ with ℓ = e or μ. The search is performed using a sample of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138 fb$^{−1}$. Events are assigned to mutually exclusive categories, which exploit differences in both event topology and kinematics of distinct Higgs production mechanisms to enhance signal sensitivity. The signal strength μ, defined as the product of the cross section and the branching fraction \left[\sigma \left(\textrm{pp}\to \textrm{H}\right)\mathcal{B}\left(\textrm{H}\to \textrm{Z}\upgamma \right)\right] relative to the standard model prediction, is extracted from a simultaneous fit to the ℓ$^{+}$ℓ$^{−}$γ invariant mass distributions in all categories and is measured to be μ = 2.4 ± 0.9 for a Higgs boson mass of 125.38 GeV. The statistical significance of the observed excess of events is 2.7 standard deviations. This measurement corresponds to \left[\sigma \left(\textrm{pp}\to \textrm{H}\right)\mathcal{B}\left(\textrm{H}\to \textrm{Z}\upgamma \right)\right]=0.21\pm 0.08 pb. The observed (expected) upper limit at 95% confidence level on μ is 4.1 (1.8), where the expected limit is calculated under the background-only hypothesis. The ratio of branching fractions \mathcal{B}\left(\textrm{H}\to \textrm{Z}\upgamma \right)/\mathcal{B}\left(\textrm{H}\to \upgamma \upgamma \right) is measured to be ${1.5}_{-0.6}^{+0.7}$, which agrees with the standard model prediction of 0.69 ± 0.04 at the 1.5 standard deviation level.[graphic not available: see fulltext