Co-occurrence of Noonan and Cardio-facio-cutaneous syndrome features in a patient with KRAS variant

We report the case of a 3-year-old girl, who is the third child of nonconsanguineous parents with short stature, hypertrophic cardiomyopathy and mild dysmorphic features; all suggestive of Noonan syndrome. In addition, the patient presents with feeding difficulties, deep palmar and plantar creases, sparse hair, and delayed psychomotor and language development, all characteristics frequently observed in Cardio-facio-cutaneous syndrome. Molecular analysis of the Ras/MAPK pathway genes using high resolution melting curve analysis and gene sequencing revealed a de novo KRAS amino acid substitution of leucine to tryptophan at codon 53 (p.L53W). This substitution was recently described in an Iranian patient with Noonan syndrome. The findings described in the present report expand the phenotypic heterogeneity observed in RASopathy patients harbouring a KRAS substitution, and advocate for the inclusion of genes with low mutational frequency in genetic screening protocols for Noonan syndrome and other RASophaties

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for a CP-odd Higgs boson decaying to Zh in pp collisions at √s=8TeV with the ATLAS detector

A search for a heavy, CP-odd Higgs boson, A, decaying into a Zboson and a 125GeV Higgs boson, h, with the ATLAS detector at the LHC is presented. The search uses proton–proton collision data at a centre-of-mass energy of 8TeV corresponding to an integrated luminosity of 20.3fb−1. Decays of CP-even hbosons to ττor bbpairs with the Zboson decaying to electron or muon pairs are considered, as well as h →bbdecays with the Zboson decaying to neutrinos. No evidence for the production of an Aboson in these channels is found and the 95% confidence level upper limits derived for σ(gg→A) ×BR(A →Zh) ×BR(h →f¯f)are 0.098–0.013pb for f=τand 0.57–0.014pb for f=bin a range of mA=220–1000GeV. The results are combined and interpreted in the context of two-Higgs-doublet models. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons

Observation of top-quark pair production in association with a photon and measurement of the ttγ production cross section in pp collisions at √s = 7 TeV using the ATLAS detector

A search is performed for top-quark pairs (tt) produced together with a photon (γ) with transverse energy greater than 20 GeV using a sample of tt candidate events in final states with jets, missing transverse momentum, and one isolated electron or muon. The data set used corresponds to an integrated luminosity of 4.59 fb −1 of proton-proton collisions at a center-of-mass energy of 7 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. In total, 140 and 222 ttγ candidate events are observed in the electron and muon channels, to be compared to the expectation of 79 +/- 26 and 120 +/- 39 non-ttγ background events, respectively. The production of ttγ events is observed with a significance of 5.3 standard deviations away from the null hypothesis. The ttγ production cross section times the branching ratio (BR) of the single-lepton decay channel is measured in a fiducial kinematic region within the ATLAS acceptance. The measured value is σ (fid/tty) × BR = 63 +/- 8(stat) (+17/-13)(syst) +/- 1 lumi fb per lepton flavor, in good agreement with the leading-order theoretical calculation normalized to the next-to-leading-order theoretical prediction of 48 +/- 10 fb

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Combined measurement of the Higgs Boson Mass in pp collisions at √s=7 and 8 TeV with the ATLAS and CMS experiments

A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4ℓ decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is mH=125.09±0.21 (stat)±0.11 (syst)  GeV