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.

Search for Dark Matter and Supersymmetry with a Compressed Mass Spectrum in the Vector Boson Fusion Topology in Proton-Proton Collisions at root s=8 TeV

Peer reviewe

Inadequate prenatal care and its association with adverse pregnancy outcomes: A comparison of indices

<p>Abstract</p> <p>Background</p> <p>The objectives of this study were to determine rates of prenatal care utilization in Winnipeg, Manitoba, Canada from 1991 to 2000; to compare two indices of prenatal care utilization in identifying the proportion of the population receiving inadequate prenatal care; to determine the association between inadequate prenatal care and adverse pregnancy outcomes (preterm birth, low birth weight [LBW], and small-for-gestational age [SGA]), using each of the indices; and, to assess whether or not, and to what extent, gestational age modifies this association.</p> <p>Methods</p> <p>We conducted a population-based study of women having a hospital-based singleton live birth from 1991 to 2000 (N = 80,989). Data sources consisted of a linked mother-baby database and a physician claims file maintained by Manitoba Health. Rates of inadequate prenatal care were calculated using two indices, the R-GINDEX and the APNCU. Logistic regression analysis was used to determine the association between inadequate prenatal care and adverse pregnancy outcomes. Stratified analysis was then used to determine whether the association between inadequate prenatal care and LBW or SGA differed by gestational age.</p> <p>Results</p> <p>Rates of inadequate/no prenatal care ranged from 8.3% using APNCU to 8.9% using R-GINDEX. The association between inadequate prenatal care and preterm birth and LBW varied depending on the index used, with adjusted odds ratios (AOR) ranging from 1.0 to 1.3. In contrast, both indices revealed the same strength of association of inadequate prenatal care with SGA (AOR 1.4). Both indices demonstrated heterogeneity (non-uniformity) across gestational age strata, indicating the presence of effect modification by gestational age.</p> <p>Conclusion</p> <p>Selection of a prenatal care utilization index requires careful consideration of its methodological underpinnings and limitations. The two indices compared in this study revealed different patterns of utilization of prenatal care, and should not be used interchangeably. Use of these indices to study the association between utilization of prenatal care and pregnancy outcomes affected by the duration of pregnancy should be approached cautiously.</p

Four plant defensins from an indigenous South African Brassicaceae species display divergent activities against two test pathogens despite high sequence similarity in the encoding genes

<p>Abstract</p> <p>Background</p> <p>Plant defensins are an important component of the innate defence system of plants where they form protective antimicrobial barriers between tissue types of plant organs as well as around seeds. These peptides also have other activities that are important for agricultural applications as well as the medical sector. Amongst the numerous plant peptides isolated from a variety of plant species, a significant number of promising defensins have been isolated from Brassicaceae species. Here we report on the isolation and characterization of four defensins from <it>Heliophila coronopifolia</it>, a native South African Brassicaceae species.</p> <p>Results</p> <p>Four defensin genes (<it>Hc-AFP1</it>-<it>4) </it>were isolated with a homology based PCR strategy. Analysis of the deduced amino acid sequences showed that the peptides were 72% similar and grouped closest to defensins isolated from other Brassicaceae species. The Hc-AFP1 and 3 peptides shared high homology (94%) and formed a unique grouping in the Brassicaceae defensins, whereas Hc-AFP2 and 4 formed a second homology grouping with defensins from <it>Arabidopsis </it>and <it>Raphanus</it>. Homology modelling showed that the few amino acids that differed between the four peptides had an effect on the surface properties of the defensins, specifically in the alpha-helix and the loop connecting the second and third beta-strands. These areas are implicated in determining differential activities of defensins. Comparing the activities after recombinant production of the peptides, Hc-AFP2 and 4 had IC₅₀values of 5-20 μg ml^-1against two test pathogens, whereas Hc-AFP1 and 3 were less active. The activity against <it>Botrytis cinerea </it>was associated with membrane permeabilization, hyper-branching, biomass reduction and even lytic activity. In contrast, only Hc-AFP2 and 4 caused membrane permeabilization and severe hyper-branching against the wilting pathogen <it>Fusarium solani</it>, while Hc-AFP1 and 3 had a mild morphogenetic effect on the fungus, without any indication of membrane activity. The peptides have a tissue-specific expression pattern since differential gene expression was observed in the native host. <it>Hc-AFP1 </it>and <it>3 </it>expressed in mature leaves, stems and flowers, whereas <it>Hc-AFP2 </it>and <it>4 </it>exclusively expressed in seedpods and seeds.</p> <p>Conclusions</p> <p>Two novel Brassicaceae defensin sequences were isolated amongst a group of four defensin encoding genes from the indigenous South African plant <it>H. coronopifolia</it>. All four peptides were active against two test pathogens, but displayed differential activities and modes of action. The expression patterns of the peptide encoding genes suggest a role in protecting either vegetative or reproductive structures in the native host against pathogen attack, or roles in unknown developmental and physiological processes in these tissues, as was shown with other defensins.</p

Gastrointestinal decontamination in the acutely poisoned patient

ObjectiveTo define the role of gastrointestinal (GI) decontamination of the poisoned patient.Data sourcesA computer-based PubMed/MEDLINE search of the literature on GI decontamination in the poisoned patient with cross referencing of sources.Study selection and data extractionClinical, animal and in vitro studies were reviewed for clinical relevance to GI decontamination of the poisoned patient.Data synthesisThe literature suggests that previously, widely used, aggressive approaches including the use of ipecac syrup, gastric lavage, and cathartics are now rarely recommended. Whole bowel irrigation is still often recommended for slow-release drugs, metals, and patients who "pack" or "stuff" foreign bodies filled with drugs of abuse, but with little quality data to support it. Activated charcoal (AC), single or multiple doses, was also a previous mainstay of GI decontamination, but the utility of AC is now recognized to be limited and more time dependent than previously practiced. These recommendations have resulted in several treatment guidelines that are mostly based on retrospective analysis, animal studies or small case series, and rarely based on randomized clinical trials.ConclusionsThe current literature supports limited use of GI decontamination of the poisoned patient

Measurement of the Zγ production cross section in pp collisions at 8 TeV and search for anomalous triple gauge boson couplings

Open Access, Copyright CERN, for the benefit of the CMS Collaboration. Article funded by SCOAP3.Abstract: The cross section for the production of Zγ in proton-proton collisions at 8 TeV is measured based on data collected by the CMS experiment at the LHC corresponding to an integrated luminosity of 19.5 fb−1. Events with an oppositely-charged pair of muons or electrons together with an isolated photon are selected. The differential cross section as a function of the photon transverse momentum is measured inclusively and exclusively, where the exclusive selection applies a veto on central jets. The observed cross sections are compatible with the expectations of next-to-next-to-leading-order quantum chromodynamics. Limits on anomalous triple gauge couplings of ZZγ and Zγγ are set that improve on previous experimental results obtained with the charged lepton decay modes of the Z boson

Search for Higgs boson pair production in the gamma gamma b(b)over-bar final state in pp collisions at root s=13 TeV

A search is presented for the production of a pair of Higgs bosons, where one decays into two photons and the other one into a bottom quark-antiquark pair. The analysis is performed using proton-proton collision data at root s = 13 TeV recorded in 2016 by the CMS detector at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1) . The results are in agreement with standard model (SM) predictions. In a search for resonant production, upper limits are set on the cross section for new spin-0 or spin-2 particles. For the SM-like nonresonant production hypothesis, the data exclude a product of cross section and branching fraction larger than 2.0 fb at 95% confidence level (CL), corresponding to about 24 times the SM prediction. Values of the effective Higgs boson self-coupling K X are constrained to be within the range -11 < K-lambda < 17 at 95% CL, assuming all other Higgs boson couplings are at their SM value. The constraints on K-lambda, are the most restrictive to date. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe

Measurement of quarkonium production cross sections in pp collisions at root s=13 TeV

Differential production cross sections of prompt J/psi and psi(2S) charmonium and Upsilon(nS) (n = 1, 2, 3) bottomonium states are measured in proton-proton collisions at root s = 13 TeV, with data collected by the CMS detector at the LHC, corresponding to an integrated luminosity of 2.3 fb(-1) for the J/psi and 2.7 fb(-1) for the other mesons. The five quarkonium states are reconstructed in the dimuon decay channel, for dimuon rapidity vertical bar y vertical bar <1.2. The double-differential cross sections for each state are measured as a function of y and transverse momentum, and compared to theoretical expectations. In addition, ratios are presented of cross sections for prompt psi(2S) to J/psi, Upsilon(2S) to Upsilon(1S), and Upsilon(3S) to Upsilon(1S) production. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe