Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Measurement of the cross section of high transverse momentum Z→bb̄ production in proton–proton collisions at √s = 8 TeV with the ATLAS detector

This Letter reports the observation of a high transverse momentum Z→bb̄ signal in proton–proton collisions at √s=8 TeV and the measurement of its production cross section. The data analysed were collected in 2012 with the ATLAS detector at the LHC and correspond to an integrated luminosity of 19.5 fb−¹. The Z→bb̄ decay is reconstructed from a pair of b -tagged jets, clustered with the anti-ktkt jet algorithm with R=0.4R=0.4, that have low angular separation and form a dijet with pT>200 GeVpT>200 GeV. The signal yield is extracted from a fit to the dijet invariant mass distribution, with the dominant, multi-jet background mass shape estimated by employing a fully data-driven technique that reduces the dependence of the analysis on simulation. The fiducial cross section is determined to be σZ→bb¯fid=2.02±0.20 (stat.) ±0.25 (syst.)±0.06 (lumi.) pb=2.02±0.33 pb, in good agreement with next-to-leading-order theoretical predictions

Measurement of the branching ratio Γ(Λb⁰ → ψ(2S)Λ0)/Γ(Λb⁰ → J/ψΛ0) with the ATLAS detector

An observation of the $\Lambda_b^0 \rightarrow \psi(2S) \Lambda^0$ decay and a comparison of its branching fraction with that of the $\Lambda_b^0 \rightarrow J/\psi \Lambda^0$ decay has been made with the ATLAS detector in proton--proton collisions at $\sqrt{s}=8\,$TeV at the LHC using an integrated luminosity of $20.6\,$fb$^{-1}$. The $J/\psi$ and $\psi(2S)$ mesons are reconstructed in their decays to a muon pair, while the $\Lambda^0\rightarrow p\pi^-$ decay is exploited for the $\Lambda^0$ baryon reconstruction. The $\Lambda_b^0$ baryons are reconstructed with transverse momentum $p_{\rm T}>10\,$GeV and pseudorapidity $|\eta|<2.1$. The measured branching ratio of the $\Lambda_b^0 \rightarrow \psi(2S) \Lambda^0$ and $\Lambda_b^0 \rightarrow J/\psi \Lambda^0$ decays is $\Gamma(\Lambda_b^0 \rightarrow \psi(2S)\Lambda^0)/\Gamma(\Lambda_b^0 \rightarrow J/\psi\Lambda^0) = 0.501\pm 0.033 ({\rm stat})\pm 0.019({\rm syst})$, lower than the expectation from the covariant quark model.Comment: 12 pages plus author list (28 pages total), 5 figures, 1 table, published on Physics Letters B 751 (2015) 63-80. All figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/BPHY-2013-08

Search for strong gravity in multijet final states produced in pp collisions at √s=13 TeV using the ATLAS detector at the LHC

A search is conducted for new physics in multijet final states using 3.6 inverse femtobarns of data from proton-proton collisions at √s = 13TeV taken at the CERN Large Hadron Collider with the ATLAS detector. Events are selected containing at least three jets with scalar sum of jet transverse momenta (HT) greater than 1TeV. No excess is seen at large HT and limits are presented on new physics: models which produce final states containing at least three jets and having cross sections larger than 1.6 fb with HT > 5.8 TeV are excluded. Limits are also given in terms of new physics models of strong gravity that hypothesize additional space-time dimensions

Search for H→γγ produced in association with top quarks and constraints on the Yukawa coupling between the top quark and the Higgs boson using data taken at 7 TeV and 8 TeV with the ATLAS detector

A search is performed for Higgs bosons produced in association with top quarks using the diphoton decay mode of the Higgs boson. Selection requirements are optimized separately for leptonic and fully hadronic final states from the top quark decays. The dataset used corresponds to an integrated luminosity of 4.5 fb−14.5 fb−1 of proton–proton collisions at a center-of-mass energy of 7 TeV and 20.3 fb−1 at 8 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess over the background prediction is observed and upper limits are set on the tt¯H production cross section. The observed exclusion upper limit at 95% confidence level is 6.7 times the predicted Standard Model cross section value. In addition, limits are set on the strength of the Yukawa coupling between the top quark and the Higgs boson, taking into account the dependence of the tt¯H and tH cross sections as well as the H→γγ branching fraction on the Yukawa coupling. Lower and upper limits at 95% confidence level are set at −1.3 and +8.0 times the Yukawa coupling strength in the Standard Model

Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

Peer reviewe

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Fiducial and differential cross sections of Higgs boson production measured in the four-lepton decay channel in pp collisions at √s = 8 TeV with the ATLAS detector

Measurements of fiducial and differential cross sections of Higgs boson production in the H→ZZ∗ → 4ℓ decay channel are presented. The cross sections are determined within a fiducial phase space and corrected for detection efficiency and resolution effects. They are based on 20.3 fb−¹ of pp collision data, produced at √s = 8 TeV centre-of-mass energy at the LHC and recorded by the ATLAS detector. The differential measurements are performed in bins of transverse momentum and rapidity of the four-lepton system, the invariant mass of the subleading lepton pair and the decay angle of the leading lepton pair with respect to the beam line in the four-lepton rest frame, as well as the number of jets and the transverse momentum of the leading jet. The measured cross sections are compared to selected theoretical calculations of the Standard Model expectations. No significant deviation from any of the tested predictions is found