Airway mucus hyperconcentration in non–cystic fibrosis bronchiectasis

Rationale: Non–cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized. Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity. Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured. Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non–cystic fibrosis bronchiectasis mucus concentration by 5%. Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy

Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

Background Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding Vertex Pharmaceuticals

Azimuthal anisotropies of charged particles with high transverse momentum in Pb+Pb collisions at √sNN=5.02 TeV with the ATLAS detector

A measurement is presented of elliptic (v2) and triangular (v3) azimuthal anisotropy coefficients for charged particles produced in Pb+Pb collisions at √sNN = 5.02 TeV using a dataset corresponding to an integrated luminosity of 0.44 nb−1 collected with the ATLAS detector at the LHC in 2018. The values of v2 and v3 are measured for charged particles over a wide range of transverse momentum (pT), 1–400 GeV, and Pb+Pb collision centrality, 0–60%, using the scalar-product and multiparticle cumulant methods. These methods are sensitive to event-by-event fluctuations and nonflow effects in the measurements of azimuthal anisotropies. Positive values of v2 are observed up to a pT of approximately 100 GeV from both methods across all centrality intervals. Positive values of v3 are observed up to approximately 25 GeV using both methods, though the application of the three-subevent technique to the multiparticle cumulant method leads to significant changes at the highest pT. At high pT (pT 10 GeV), charged particles are dominantly from jet fragmentation. These jets, and hence the measurements presented here, are sensitive to the path-length dependence of parton energy loss in the quark-gluon plasma produced in Pb+Pb collisions

A precise measurement of the jet energy scale derived from single-particle measurements and in situ techniques in proton–proton collisions at √s= 13 TeV with the ATLAS detector

The jet energy calibration and its uncertainties are derived from measurements of the calorimeter response to single particles in both data and Monte Carlo simulation using proton–proton collisions at √s = 13 TeV collected with the ATLAS detector during Run 2 at the Large Hadron Collider. The jet calibration uncertainty for anti-kT jets with a jet radius parameter of Rjet = 0.4 and in the central jet rapidity region is about 2.5% for transverse momenta (pT) of 20 GeV, about 0.5% for pT = 300 GeV and 0.7% for pT = 4 TeV. Excellent agreement is found with earlier determinations obtained from pT-balance based in situ methods (Z/γ +jets). The combination of these two independent methods results in the most precise jet energy measurement achieved so far with the ATLAS detector with a relative uncertainty of 0.3% at pT = 300 GeV and 0.6% at 4 TeV. The jet energy calibration is also derived with the single-particle calorimeter response measurements separately for quark- and gluon-induced jets and furthermore for jets with Rjet varying from 0.2 to 1.0 retaining the correlations between these measurements. Differences between inclusive jets and jets from boosted top-quark decays, with and without grooming the soft jet constituents, are also studied

Energy scale and resolution for anti-kt jets with radius parameters R = 0.2 and 0.6 measured in proton-proton collisions at s = 13 TeV with the ATLAS detector

Jets with different radius parameters R are an important tool for probing quantum chromodynamics processes at different angular scales. Jets with small R = 0.2 are instrumental in measurements of the substructure of largeR jets resulting from collimated hadronic decays of energetic W, Z, and Higgs bosons, top quarks, and of potential new resonances. This paper presents measurements of the energy scale, resolution, and associated uncertainties of jets with radius parameters R = 0.2 and 0.6, obtained using the ATLAS detector. The results are based on 37 fb−1 of proton– proton collision data from the Large Hadron Collider at a centre-of-mass energy of √s = 13 TeV. A new in situ method for measuring jet energy scale differences between data and Monte Carlo simulations is presented. The systematic uncertainties in the jet energy scale for central jets (|η| < 1.2) typically vary from 1% to about 5% as a function of |η| at very low transverse momentum, pT, of around 20 GeV for both R = 0.2 and 0.6 jets. The relative energy resolution ranges from (35 ± 6)% at pT = 20 GeV to (6 ± 0.5)% at pT = 300 GeV for central R = 0.2 jets, and is found to be slightly worse for R = 0.6 jets. Finally, the effect of close-by hadronic activity on the jet energy scale is investigated and is found to be well modelled by the ATLAS Monte Carlo simulations

Deep generative models for fast photon shower simulation in ATLAS

The need for large-scale production of highly accurate simulated event samples for the extensive physics programme of the ATLAS experiment at the Large Hadron Collider motivates the development of new simulation techniques. Building on the recent success of deep learning algorithms, variational autoencoders and generative adversarial networks are investigated for modelling the response of the central region of the ATLAS electromagnetic calorimeter to photons of various energies. The properties of synthesised showers are compared with showers from a full detector simulation using geant4. Both variational autoencoders and generative adversarial networks are capable of quickly simulating electromagnetic showers with correct total energies and stochasticity, though the modelling of some shower shape distributions requires more refinement. This feasibility study demonstrates the potential of using such algorithms for ATLAS fast calorimeter simulation in the future and shows a possible way to complement current simulation techniques

Search for heavy Majorana or Dirac neutrinos and right-handed W gauge bosons in final states with charged leptons and jets in pp collisions at √s = 13 TeV with the ATLAS detector

A search for heavy right-handed Majorana or Dirac neutrinos NR and heavy right-handed gauge bosons WR is performed in events with energetic electrons or muons, with the same or opposite electric charge, and energetic jets. The search is carried out separately for topologies of clearly separated final-state products (“resolved” channel) and topologies with boosted final states with hadronic and/or leptonic products partially overlapping and reconstructed as a large-radius jet (“boosted” channel). The events are selected from pp collision data at the LHC with an integrated luminosity of 139 fb−1 collected by the ATLAS detector at √s = 13 TeV. No significant deviations from the Standard Model predictions are observed. The results are interpreted within the theoretical framework of a left-right symmetric model, and lower limits are set on masses in the heavy righthanded WR boson and NR plane. The excluded region extends to about m(WR) = 6.4 TeV for both Majorana and Dirac NR neutrinos at m(NR) < 1 TeV. NR with masses of less than 3.5 (3.6) TeV are excluded in the electron (muon) channel at m(WR) = 4.8 TeV for the Majorana neutrinos, and limits of m(NR) up to 3.6 TeV for m(WR) = 5.2 (5.0) TeV in the electron (muon) channel are set for the Dirac neutrinos. These constitute the most stringent exclusion limits to date for the model considered

Search for doubly charged Higgs boson production in multi-lepton final states using 139 fb−1 of proton–proton collisions at s√ = 13 TeV with the ATLAS detector

A search for pair production of doubly charged Higgs bosons (H±± ), each decaying into a pair of prompt, isolated, and highly energetic leptons with the same electric charge, is presented. The search uses a proton–proton collision data sample at a centre-of-mass energy of 13 TeV corresponding to an integrated luminosity of 139 fb−1 recorded by the ATLAS detector during Run 2 of the Large Hadron Collider (LHC). This analysis focuses on same-charge leptonic decays, H±±→ℓ±ℓ′± where ℓ,ℓ′=e,μ,τ, in two-, three-, and four-lepton channels, but only considers final states which include electrons or muons. No evidence of a signal is observed. Corresponding upper limits on the production cross-section of a doubly charged Higgs boson are derived, as a function of its mass m(H±±), at 95% confidence level. Assuming that the branching ratios to each of the possible leptonic final states are equal, B(H±±→e±e±)=B(H±±→e±μ±)=B(H±±→μ±μ±)=B(H±±→e±τ±)=B(H±±→μ±τ±)=B(H±±→τ±τ±)=1/6, the observed (expected) lower limit on the mass of a doubly charged Higgs boson is 1080 GeV (1065 GeV) within the left-right symmetric type-II seesaw model, which is the strongest limit to date produced by the ATLAS Collaboration. Additionally, this paper provides the first direct test of the Zee–Babu neutrino mass model at the LHC, yielding an observed (expected) lower limit of m(H±±) = 900 GeV (880 GeV)