Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Observation of electroweak production of two jets in association with an isolated photon and missing transverse momentum, and search for a Higgs boson decaying into invisible particles at 13 TeV with the ATLAS detector

This paper presents the measurement of the electroweak production of two jets in association with a $Z\gamma$ pair with the $Z$ boson decaying into two neutrinos. It also presents the search for invisible or partially invisible decays of a Higgs boson with a mass of 125 GeV produced through vector-boson fusion with a photon in the final state. These results use data from LHC proton-proton collisions at $\sqrt{s}$ = 13 TeV collected with the ATLAS detector corresponding to an integrated luminosity of 139 fb$^{-1}$. The event signature, shared by all benchmark processes considered for measurements and searches, is characterized by a significant amount of unbalanced transverse momentum and a photon in the final state, in addition to a pair of forward jets. For electroweak production of $Z\gamma$ in association with two jets, the background-only hypothesis is rejected with an observed (expected) significance of 5.2 (5.1) standard deviations. The measured fiducial cross-section for this process is 1.31$\pm$0.29 fb. Observed (expected) upper limit of 0.37 (0.34) at 95% confidence level is set on the branching ratio of a 125 GeV Higgs boson to invisible particles, assuming the Standard Model production cross-section. The signature is also interpreted in the context of decays of a Higgs boson to a photon and a dark photon. An observed (expected) 95% CL upper limit on the branching ratio for this decay is set at 0.018 (0.017), assuming the 125 GeV Standard Model Higgs boson production cross-section

The ATLAS inner detector trigger performance in pp collisions at 13 TeV during LHC Run 2

The design and performance of the inner detector trigger for the high level trigger of the ATLAS experiment at the Large Hadron Collider during the 2016-18 data taking period is discussed. In 2016, 2017, and 2018 the ATLAS detector recorded 35.6 fb$^{-1}$, 46.9 fb$^{-1}$, and 60.6 fb$^{-1}$ respectively of proton-proton collision data at a centre-of-mass energy of 13 TeV. In order to deal with the very high interaction multiplicities per bunch crossing expected with the 13 TeV collisions the inner detector trigger was redesigned during the long shutdown of the Large Hadron Collider from 2013 until 2015. An overview of these developments is provided and the performance of the tracking in the trigger for the muon, electron, tau and $b$-jet signatures is discussed. The high performance of the inner detector trigger with these extreme interaction multiplicities demonstrates how the inner detector tracking continues to lie at the heart of the trigger performance and is essential in enabling the ATLAS physics programme

The ATLAS inner detector trigger performance in pp collisions at 13 TeV during LHC Run 2

The design and performance of the inner detector trigger for the high level trigger of the ATLAS experiment at the Large Hadron Collider during the 2016-18 data taking period is discussed. In 2016, 2017, and 2018 the ATLAS detector recorded 35.6 fb$^{-1}$, 46.9 fb$^{-1}$, and 60.6 fb$^{-1}$ respectively of proton-proton collision data at a centre-of-mass energy of 13 TeV. In order to deal with the very high interaction multiplicities per bunch crossing expected with the 13 TeV collisions the inner detector trigger was redesigned during the long shutdown of the Large Hadron Collider from 2013 until 2015. An overview of these developments is provided and the performance of the tracking in the trigger for the muon, electron, tau and $b$-jet signatures is discussed. The high performance of the inner detector trigger with these extreme interaction multiplicities demonstrates how the inner detector tracking continues to lie at the heart of the trigger performance and is essential in enabling the ATLAS physics programme

BiodosEPR-2006 Meeting: Acute dosimetry consensus committee recommendations on biodosimetry applications in events involving uses of radiation by terrorists and radiation accidents

In the aftermath of a radiological terrorism incident or mass-casualty radiation accident, first responders and receivers require prior guidance and pre-positioned resources for assessment, triage and medical management of affected individuals [NCRP, 2005. Key elements of preparing emergency responders for nuclear and radiological terrorism. NCRP Commentary No. 19, Bethesda, Maryland, USA]. Several recent articles [Dainiak, N., Waselenko, J.K., Armitage, J.O., MacVittie, T.J., Farese, A.M., 2003. The hematologist and radiation casualties. Hematology (Am. Soc. Hematol. Educ. Program) 473-496; Waselenko, J.K., MacVittie, T.J., Blakely, W.F., Pesik, N., Wiley, A.L., Dickerson, W.E., Tsu, H., Confer, D.L., Coleman, C.N., Seed, T., Lowry, P., Armitage, J.O., Dainiak, N., Strategic National Stockpile Radiation Working Group, 2004. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann. Intern. Med. 140(12), 1037-1051; Blakely, W.F., Salter, C.A., Prasanna, P.G., 2005. Early-response biological dosimetry-recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism. Health Phys. 89(5), 494-504; Goans, R.E., Waselenko, J.K., 2005. Medical management of radiation casualties. Health Phys. 89(5), 505-512; Swartz, H.M., Iwasaki, A., Walczak, T., Demidenko, E., Salikhov, I., Lesniewski, P., Starewicz, P., Schauer, D., Romanyukha, A., 2005. Measurements of clinically significant doses of ionizing radiation using non-invasive in vivo EPR spectroscopy of teeth in situ. Appl. Radiat. Isot. 62, 293-299; Weisdorf, D., Chao, N., Waselenko, J.K., Dainiak, N., Armitage, J.O., McNiece, I., Confer, D., 2006. Acute radiation injury: contingency planning for triage, supportive care, and transplantation. Biol. Blood Marrow Transplant. 12(6), 672-682], national [National Council of Radiation Protection and Measurements (NCRP), 1994. Management of persons accidentally contaminated with radionuclides. NCRP Report No. 65, Bethesda, Maryland, USA; NCRP, 2001. Management of terrorist events involving radioactive material. NCRP Report No. 138, Bethesda, Maryland, USA; NCRP, 2005. Key elements of preparing emergency responders for nuclear and radiological terrorism. NCRP Commentary No. 19, Bethesda, Maryland, USA] and international [IAEA, 2005. Generic procedures for medical response during a nuclear or radiological emergency. EPR-Medical 2005, IAEA, Vienna, Austria] agencies have reviewed strategies for acute-phase biodosimetry. Consensus biodosimetric guidelines include: (a) clinical signs and symptoms, including peripheral blood counts, time to onset of nausea and vomiting and presence of impaired cognition and neurological deficits, (b) radioactivity assessment, (c) personal and area dosimetry, (d) cytogenetics, (e) in vivo electron paramagnetic resonance (EPR) and (f) other dosimetry approaches (i.e. blood protein assays, etc.). Emerging biodosimetric technologies may further refine triage and dose assessment strategies. However, guidance is needed regarding which biodosimetry techniques are most useful for different radiological scenarios and consensus protocols must be developed. The Local Organizing Committee for the Second International Conference on Biodosimetry and Seventh International Symposium on EPR Dosimetry and Applications (BiodosEPR-2006 Meeting) convened an Acute Dosimetry Consensus Committee composed of national and international experts to: (a) review the current literature for biodosimetry applications for acute-phase applications in radiological emergencies, (b) describe the strengths and weaknesses of each technique, (c) provide recommendations for the use of biodosimetry assays for selected defined radiation scenarios, and (d) develop protocols to apply these recommended biological dosimetry techniques with currently available supplies and equipment for first responders. The Acute Dosimetry Consensus Committee developed recommendations for use of a prioritized multiple-assay biodosimetric-based strategy, concluding that no single assay is sufficiently robust to address all of the potential radiation scenarios including management of mass casualties and diagnosis for early medical treatment. These recommendations may be used by first responders/first receivers that span time-windows of (i.e. 0-5 days) after the radiological incident for three radiological scenarios including: (a) radiation exposure device (RED), (b) radiological dispersal device (RDD), and (c) an improvised (or otherwise acquired) nuclear device (IND). Consensus protocols for various bioassays (i.e. signs and symptoms recording, bioassay sampling for radioactivity analysis, nail-clipping sampling for EPR analysis and blood collection for hematology, cytogenetics, and blood chemistry analyses) are presented as Appendix materials. As stated in NCRP Commentary No. 19 [NCRP, 2005. Key elements of preparing emergency responders for nuclear and radiological terrorism. NCRP Commentary No. 19, Bethesda, Maryland, USA], multi-parameter triage (i.e. time to vomiting, lymphocyte kinetics, and other biodosimetry indicators) offers the current best strategy for early assessment of absorbed dose