Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages

Macrophages play an essential role in the early immune response against Toxoplasma and are the cell type preferentially infected by the parasite in vivo. Interferon gamma (IFNγ) elicits a variety of anti-Toxoplasma activities in macrophages. Using a genome-wide CRISPR screen we identify 353 Toxoplasma genes that determine parasite fitness in naїve or IFNγ-activated murine macrophages, seven of which are further confirmed. We show that one of these genes encodes dense granule protein GRA45, which has a chaperone-like domain, is critical for correct localization of GRAs into the PVM and secretion of GRA effectors into the host cytoplasm. Parasites lacking GRA45 are more susceptible to IFNγ-mediated growth inhibition and have reduced virulence in mice. Together, we identify and characterize an important chaperone-like GRA in Toxoplasma and provide a resource for the community to further explore the function of Toxoplasma genes that determine fitness in IFNγ-activated macrophages

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Search for dark matter produced in association with a single top quark or a top quark pair in proton-proton collisions at s=13 TeV

A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search for dark matter produced in association with top quarks in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. The data set used corresponds to an integrated luminosity of 35.9 fb(-1) recorded with the CMS detector at the LHC. Whereas previous searches for neutral scalar or pseudoscalar mediators considered dark matter production in association with a top quark pair only, this analysis also includes production modes with a single top quark. The results are derived from the combination of multiple selection categories that are defined to target either the single top quark or the top quark pair signature. No significant deviations with respect to the standard model predictions are observed. The results are interpreted in the context of a simplified model in which a scalar or pseudoscalar mediator particle couples to a top quark and subsequently decays into dark matter particles. Scalar and pseudoscalar mediator particles with masses below 290 and 300 GeV, respectively, are excluded at 95% confidence level, assuming a dark matter particle mass of 1 GeV and mediator couplings to fermions and dark matter particles equal to unity.Peer reviewe

Search for the pair production of light top squarks in the e(+/-)mu(-/+) final state in proton-proton collisions at root s=13 TeV

A search for the production of a pair of top squarks at the LHC is presented. This search targets a region of parameter space where the kinematics of top squark pair production and top quark pair production are very similar, because of the mass difference between the top squark and the neutralino being close to the top quark mass. The search is performed with 35.9 fb(-1) of proton-proton collisions at a centre-of-mass energy of root s = 13 TeV, collected by the CMS detector in 2016, using events containing one electron-muon pair with opposite charge. The search is based on a precise estimate of the top quark pair background, and the use of the M-T2 variable, which combines the transverse mass of each lepton and the missing transverse momentum. No excess of events is found over the standard model predictions. Exclusion limits are placed at 95% confidence level on the production of top squarks up to masses of 208 GeV for models with a mass difference between the top squark and the lightest neutralino close to that of the top quark.Peer reviewe

Combination of CMS searches for heavy resonances decaying to pairs of bosons or leptons

CMS Collaboration: et al.A statistical combination of searches for heavy resonances decaying to pairs of bosons or leptons is presented. The data correspond to an integrated luminosity of 35.9 fb collected during 2016 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. The data are found to be consistent with expectations from the standard model background. Exclusion limits are set in the context of models of spin-1 heavy vector triplets and of spin-2 bulk gravitons. For mass-degenerate W′ and Z′ resonances that predominantly couple to the standard model gauge bosons, the mass exclusion at 95% confidence level of heavy vector bosons is extended to 4.5 TeV as compared to 3.8 TeV determined from the best individual channel. This excluded mass increases to 5.0 TeV if the resonances couple predominantly to fermions.Individuals have received support from the Marie-Curie program and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 752730, and 765710 (European Union); the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2015-0509 and the Programa Severo Ochoa del Principado de Asturias

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

Search for an exotic decay of the Higgs boson to a pair of light pseudoscalars in the final state with two bquarks and two tau leptons in proton-proton collisions at root s=13 TeV The CMS Collaboration

A search for an exotic decay of the Higgs boson to a pair of light pseudoscalar bosons is performed for the first time in the final state with two b quarks and two tau leptons. The search is motivated in the context of models of physics beyond the standard model (SM), such as two Higgs doublet models extended with a complex scalar singlet (2HDM + S), which include the next-to-minimal supersymmetric SM (NMSSM). The results are based on a data set of proton-proton collisions corresponding to an integrated luminosity of 35.9 fb(-1), accumulated by the CMS experiment at the LHC in 2016 at a center-of-mass energy of 13 TeV. Masses of the pseudoscalar boson between 15 and 60 GeVare probed, and no excess of events above the SM expectation is observed. Upper limits between 3 and 12% are set on the branching fraction B(h -> aa -> 2 tau 2b) assuming the SM production of the Higgs boson. Upper limits are also set on the branching fraction of the Higgs boson to two light pseudoscalar bosons in different 2HDM + S scenarios. Assuming the SM production cross section for the Higgs boson, the upper limit on this quantity is as low as 20% for a mass of the pseudoscalar of 40 GeV in the NMSSM. (C) 2018 The Author(s). Published by Elsevier B.V.Peer reviewe

Search for standard model production of four top quarks in the lepton + jets channel in pp collisions at √s = 8 TeV

Open Access, Copyright CERN, for the benefit of the CMS Collaboration. Article funded by SCOAP3.Abstract: A search is presented for standard model (SM) production of four top quarks (Formula presented.) in pp collisions in the lepton + jets channel. The data correspond to an integrated luminosity of 19.6 fb−1 recorded at a centre-of-mass energy of 8 TeV with the CMS detector at the CERN LHC. The expected cross section for SM (Formula presented.) production is (Formula presented.). A combination of kinematic reconstruction and multivariate techniques is used to distinguish between the small signal and large background. The data are consistent with expectations of the SM, and an upper limit of 32 fb is set at a 95% confidence level on the cross section for producing four top quarks in the SM, where a limit of 32 ± 17 fb is expected