Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications

Background Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. Findings AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. Interpretation There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. Funding NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Measurements of the production cross-section for a Z boson in association with b- or c-jets in proton–proton collisions at √s = 13 TeV with the ATLAS detector

This paper presents a measurement of the production cross-section of a Z boson in association with bor c-jets, in proton–proton collisions at √s = 13 TeV with the ATLAS experiment at the Large Hadron Collider using data corresponding to an integrated luminosity of 140 fb−1. Inclusive and differential cross-sections are measured for events containing a Z boson decaying into electrons or muons and produced in association with at least one b-jet, at least one c-jet, or at least two b-jets with transverse momentum pT > 20 GeV and rapidity |y| < 2.5. Predictions from several Monte Carlo generators based on next-to-leading-order matrix elements interfaced with a parton-shower simulation, with different choices of flavour schemes for initial-state partons, are compared with the measured cross-sections. The results are also compared with novel predictions, based on infrared and collinear safe jet flavour dressing algorithms. Selected Z+ ≥ 1 c-jet observables, optimized for sensitivity to intrinsic-charm, are compared with benchmark models with different intrinsic-charm fractions

The ATLAS trigger system for LHC Run 3 and trigger performance in 2022

The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022–2025)

Measurement of the VH,H → ττ process with the ATLAS detector at 13 TeV

A measurement of the Standard Model Higgs boson produced in association with a W or Z boson and decaying into a pair of τ-leptons is presented. This search is based on proton-proton collision data collected at √s = 13 TeV by the ATLAS experiment at the LHC corresponding to an integrated luminosity of 140 fb−1. For the Higgs boson candidate, only final states with at least one τ-lepton decaying hadronically (τ →hadrons + vτ ) are considered. For the vector bosons, only leptonic decay channels are considered: Z → ℓℓ and W → ℓvℓ, with ℓ = e, μ. An excess of events over the expected background is found with an observed (expected) significance of 4.2 (3.6) standard deviations, providing evidence of the Higgs boson produced in association with a vector boson and decaying into a pair of τ-leptons. The ratio of the measured cross-section to the Standard Model prediction is μττ VH = 1.28 +0.30 −0.29 (stat.) +0.25 −0.21 (syst.). This result represents the most accurate measurement of the VH(ττ) process achieved to date

Measurement of diferential cross-sections in tt¯ and tt¯+jets production in the lepton+jets fnal state in pp collisions at √s = 13 TeV using 140 fb−1 of ATLAS data

Diferential cross-sections for top-quark pair production, inclusively and in association with jets, are measured in pp collisions at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 140 fb−1. The events are selected with one charged lepton (electron or muon) and at least four jets. The differential cross-sections are presented at particle level as functions of several jet observables, including angular correlations, jet transverse momenta and invariant masses of the jets in the final state, which characterise the kinematics and dynamics of the top-antitop system and the hard QCD radiation in the system with associated jets. The typical precision is 5%–15% for the absolute differential cross-sections and 2%–4% for the normalised differential cross-sections. Next-to-leading-order and next-to-next-to-leading-order QCD predictions are found to provide an adequate description of the rate and shape of the jet-angular observables. The description of the transverse momentum and invariant mass observables is improved when next-to-next-to-leading-order QCD corrections are included

Search for non-resonant Higgs boson pair production in final states with leptons, taus, and photons in pp collisions at √s = 13 TeV with the ATLAS detector

A search is presented for non-resonant Higgs boson pair production, targeting the bbZZ, 4V (V = W or Z), V V τ τ , 4τ , γγV V and γγτ τ decay channels. Events are categorised based on the multiplicity of light charged leptons (electrons or muons), hadronically decaying tau leptons, and photons. The search is based on a data sample of proton-proton collisions at √s = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 140 fb−1. No evidence of the signal is found and the observed (expected) upper limit on the cross-section for non-resonant Higgs boson pair production is determined to be 17 (11) times the Standard Model predicted cross-section at 95% confidence level under the background-only hypothesis. The observed (expected) constraints on the HHH coupling modifier, κλ, are determined to be −6.2 < κλ < 11.6 (−4.5 < κλ < 9.6) at 95% confidence level, assuming the Standard Model for the expected limits and that new physics would only affect κλ

Searches for exclusive Higgs boson decays into D⁎γ and Z boson decays into D0γ and Ks0γ in pp collisions at √s = 13 TeV with the ATLAS detector

Searches for exclusive decays of the Higgs boson into D⁎γ and of the Z boson into D0γ and Ks0γ can probe flavour-violating Higgs boson and Z boson couplings to light quarks. Searches for these decays are performed with a pp collision data sample corresponding to an integrated luminosity of 136.3 fb−1 collected at s=13TeV between 2016–2018 with the ATLAS detector at the CERN Large Hadron Collider. In the D⁎γ and D0γ channels, the observed (expected) 95% confidence-level upper limits on the respective branching fractions are B(H→D⁎γ)&lt;1.0(1.2)×10−3, B(Z→D0γ)&lt;4.0(3.4)×10−6, while the corresponding results in the Ks0γ channel are B(Z→Ks0γ)&lt;3.1(3.0)×10−6

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at √s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into diferent pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at √s = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, tt¯, and tb) or third-generation leptons (τν and τ τ ) are included in this kind of combination for the frst time. A simplifed model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confdence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Differential cross-sections for events with missing transverse momentum and jets measured with the ATLAS detector in 13 TeV proton-proton collisions

Measurements of inclusive, diferential cross-sections for the production of events with missing transverse momentum in association with jets in proton-proton collisions at √s = 13 TeV are presented. The measurements are made with the ATLAS detector using an integrated luminosity of 140 fb−1 and include measurements of dijet distributions in a region in which vector-boson fusion processes are enhanced. They are unfolded to correct for detector resolution and efficiency within the fiducial acceptance, and are designed to allow robust comparisons with a wide range of theoretical predictions. A measurement of differential cross sections for the Z → νν process is made. The measurements are generally well-described by Standard Model predictions except for the dijet invariant mass distribution. Auxiliary measurements of the hadronic system recoiling against isolated leptons, and photons, are also made in the same phase space. Ratios between the measured distributions are then derived, to take advantage of cancellations in modelling effects and some of the major systematic uncertainties. These measurements are sensitive to new phenomena, and provide a mechanism to easily set constraints on phenomenological models. To illustrate the robustness of the approach, these ratios are compared with two common Dark Matter models, where the constraints derived from the measurement are comparable to those set by dedicated detector-level searches