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  1. Tiede A, Abdul-Karim F, Carcao M, Persson P, Clausen WHO, Kearney S, et al.
    Haemophilia, 2017 Jul;23(4):547-555.
    PMID: 28233381 DOI: 10.1111/hae.13191
    INTRODUCTION: Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (FIX) with an extended half-life developed for routine prophylaxis and the prevention and treatment of bleeding episodes in patients with haemophilia B.

    AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP.

    METHODS: Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL-1) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg-1or 40 IU kg-1in adolescents/adults and 40 IU kg-1in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed.

    RESULTS: Incremental recoveries were 0.02 (IU mL-1)/(IU kg-1) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL-1for adolescents/adults and 0.17 IU mL-1for children at steady-state after weekly dosing at 40 IU kg-1. The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL-1at all times and 6.4 days week-1in children.

    CONCLUSION: N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

  2. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, et al.
    J Thromb Haemost, 2015 Nov;13(11):1989-98.
    PMID: 26362483 DOI: 10.1111/jth.13141
    BACKGROUND: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa.

    OBJECTIVES: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors.

    METHODS/PATIENTS: This was a post hoc analysis of adept(™) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs.

    RESULTS: Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care.

    CONCLUSIONS: Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.

  3. Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, et al.
    Blood, 2014 Dec 18;124(26):3880-6.
    PMID: 25261199 DOI: 10.1182/blood-2014-05-573055
    This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111.
  4. Kenet G, Nolan B, Zülfikar OB, Antmen B, Kampmann P, Matsushita T, et al.
    Blood, 2024 Mar 07.
    PMID: 38452197 DOI: 10.1182/blood.2023021864
    Fitusiran, a subcutaneous (SC) investigational siRNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This Phase 3, open-label study (NCT03549871) evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥ 12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary endpoint was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary endpoints included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor/non-inhibitor, n = 19/46) were eligible for ABR analyses. Observed median (IQR) ABRs were 6.5 (2.2, 19.6)/4.4 (2.2, 8.7) with BPA/CFC prophylaxis versus 0.0 (0.0, 0.0)/0.0 (0.0, 2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = 0.0021) and 46.4% (P = 0.0598) versus BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced zero treated bleeds with fitusiran versus 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events versus BPA/CFC prophylaxis in PwHA/B, with or without inhibitors and reported adverse events were generally consistent with previously identified risks of fitusiran.
  5. Matsushita T, Shapiro A, Abraham A, Angchaisuksiri P, Castaman G, Cepo K, et al.
    N Engl J Med, 2023 Aug 31;389(9):783-794.
    PMID: 37646676 DOI: 10.1056/NEJMoa2216455
    BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors.

    METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.

    RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.

    CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

  6. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2016 Feb 19;116(7):071801.
    PMID: 26943527 DOI: 10.1103/PhysRevLett.116.071801
    A search for narrow resonances in proton-proton collisions at sqrt[s]=13  TeV is presented. The invariant mass distribution of the two leading jets is measured with the CMS detector using a data set corresponding to an integrated luminosity of 2.4  fb^{-1}. The highest observed dijet mass is 6.1 TeV. The distribution is smooth and no evidence for resonant particles is observed. Upper limits at 95% confidence level are set on the production cross section for narrow resonances with masses above 1.5 TeV. When interpreted in the context of specific models, the limits exclude string resonances with masses below 7.0 TeV, scalar diquarks below 6.0 TeV, axigluons and colorons below 5.1 TeV, excited quarks below 5.0 TeV, color-octet scalars below 3.1 TeV, and W^{'} bosons below 2.6 TeV. These results significantly extend previously published limits.
  7. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2016 Jan 22;116(3):032301.
    PMID: 26849587 DOI: 10.1103/PhysRevLett.116.032301
    The production cross sections of the B^{+}, B^{0}, and B_{s}^{0} mesons, and of their charge conjugates, are measured via exclusive hadronic decays in p+Pb collisions at the center-of-mass energy sqrt[s_{NN}]=5.02  TeV with the CMS detector at the CERN LHC. The data set used for this analysis corresponds to an integrated luminosity of 34.6  nb^{-1}. The production cross sections are measured in the transverse momentum range between 10 and 60  GeV/c. No significant modification is observed compared to proton-proton perturbative QCD calculations scaled by the number of incoherent nucleon-nucleon collisions. These results provide a baseline for the study of in-medium b quark energy loss in Pb+Pb collisions.
  8. Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.
    Phys Rev Lett, 2018 Apr 06;120(14):142301.
    PMID: 29694144 DOI: 10.1103/PhysRevLett.120.142301
    The relative yields of ϒ mesons produced in pp and Pb-Pb collisions at sqrt[s_{NN}]=5.02  TeV and reconstructed via the dimuon decay channel are measured using data collected by the CMS experiment. Double ratios are formed by comparing the yields of the excited states, ϒ(2S) and ϒ(3S), to the ground state, ϒ(1S), in both Pb-Pb and pp collisions at the same center-of-mass energy. The double ratios, [ϒ(nS)/ϒ(1S)]_{Pb-Pb}/[ϒ(nS)/ϒ(1S)]_{pp}, are measured to be 0.308±0.055(stat)±0.019(syst) for the ϒ(2S) and less than 0.26 at 95% confidence level for the ϒ(3S). No significant ϒ(3S) signal is found in the Pb-Pb data. The double ratios are studied as a function of collision centrality, as well as ϒ transverse momentum and rapidity. No significant dependencies are observed.
  9. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 May 18;120(20):202005.
    PMID: 29864318 DOI: 10.1103/PhysRevLett.120.202005
    A search for resonancelike structures in the B_{s}^{0}π^{±} invariant mass spectrum is performed using proton-proton collision data collected by the CMS experiment at the LHC at sqrt[s]=8  TeV, corresponding to an integrated luminosity of 19.7  fb^{-1}. The B_{s}^{0} mesons are reconstructed in the decay chain B_{s}^{0}→J/ψϕ, with J/ψ→μ^{+}μ^{-} and ϕ→K^{+}K^{-}. The B_{s}^{0}π^{±} invariant mass distribution shows no statistically significant peaks for different selection requirements on the reconstructed B_{s}^{0} and π^{±} candidates. Upper limits are set on the relative production rates of the X(5568) and B_{s}^{0} states times the branching fraction of the decay X(5568)^{±}→B_{s}^{0}π^{±}. In addition, upper limits are obtained as a function of the mass and the natural width of possible exotic states decaying into B_{s}^{0}π^{±}.
  10. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 May 18;120(20):201801.
    PMID: 29864370 DOI: 10.1103/PhysRevLett.120.201801
    A search for narrow resonances decaying to bottom quark-antiquark pairs is presented, using a data sample of proton-proton collisions at sqrt[s]=8  TeV corresponding to an integrated luminosity of 19.7  fb^{-1}. The search is extended to masses lower than those reached in typical searches for resonances decaying into jet pairs at the LHC, by taking advantage of triggers that identify jets originating from bottom quarks. No significant excess of events is observed above the background predictions. Limits are set on the product of cross section and branching fraction to bottom quarks for spin 0, 1, and 2 resonances in the mass range of 325-1200 GeV. These results improve on the limits for resonances decaying into jet pairs in the 325-500 GeV mass range.
  11. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 May 18;120(20):202301.
    PMID: 29864330 DOI: 10.1103/PhysRevLett.120.202301
    The prompt D^{0} meson azimuthal anisotropy coefficients, v_{2} and v_{3}, are measured at midrapidity (|y|<1.0) in Pb-Pb collisions at a center-of-mass energy sqrt[s_{NN}]=5.02  TeV per nucleon pair with data collected by the CMS experiment. The measurement is performed in the transverse momentum (p_{T}) range of 1 to 40  GeV/c, for central and midcentral collisions. The v_{2} coefficient is found to be positive throughout the p_{T} range studied. The first measurement of the prompt D^{0} meson v_{3} coefficient is performed, and values up to 0.07 are observed for p_{T} around 4  GeV/c. Compared to measurements of charged particles, a similar p_{T} dependence, but smaller magnitude for p_{T}<6  GeV/c, is found for prompt D^{0} meson v_{2} and v_{3} coefficients. The results are consistent with the presence of collective motion of charm quarks at low p_{T} and a path length dependence of charm quark energy loss at high p_{T}, thereby providing new constraints on the theoretical description of the interactions between charm quarks and the quark-gluon plasma.
  12. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Dec 14;121(24):242301.
    PMID: 30608764 DOI: 10.1103/PhysRevLett.121.242301
    Measurements of fragmentation functions for jets associated with an isolated photon are presented for the first time in pp and Pb-Pb collisions. The analysis uses data collected with the CMS detector at the CERN LHC at a nucleon-nucleon center-of-mass energy of 5.02 TeV. Fragmentation functions are obtained for jets with p_{T}^{jet}>30  GeV/c in events containing an isolated photon with p_{T}^{γ}>60  GeV/c, using charged tracks with transverse momentum p_{T}^{trk}>1  GeV/c in a cone around the jet axis. The association with an isolated photon constrains the initial p_{T} and azimuthal angle of the parton whose shower produced the jet. For central Pb-Pb collisions, modifications of the jet fragmentation functions are observed when compared to those measured in pp collisions, while no significant differences are found in the 50% most peripheral collisions. Jets in central Pb-Pb events show an excess (depletion) of low (high) p_{T} particles, with a transition around 3  GeV/c. This measurement shows for the first time the in-medium shower modifications of partons (quark dominated) with well-defined initial kinematics. It constitutes a new well-controlled reference for testing theoretical models of the parton passage through the quark-gluon plasma.
  13. Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.
    Phys Rev Lett, 2017 Apr 21;118(16):162301.
    PMID: 28474955 DOI: 10.1103/PhysRevLett.118.162301
    The relative modification of the prompt ψ(2S) and J/ψ yields from pp to PbPb collisions, at the center-of-mass energy of 5.02 TeV per nucleon pair, is presented. The analysis is based on pp and PbPb data samples collected by the CMS experiment at the LHC in 2015, corresponding to integrated luminosities of 28.0  pb^{-1} and 464  μb^{-1}, respectively. The double ratio of measured yields of prompt charmonia reconstructed through their decays into muon pairs, (N_{ψ(2S)}/N_{J/ψ})_{PbPb}/(N_{ψ(2S)}/N_{J/ψ})_{pp}, is determined as a function of PbPb collision centrality and charmonium transverse momentum p_{T}, in two kinematic intervals: |y|<1.6 covering 6.5T}<30  GeV/c and 1.6T}<30  GeV/c. The centrality-integrated double ratios are 0.36±0.08(stat)±0.05(syst) in the first interval and 0.24±0.22(stat)±0.09(syst) in the second. The double ratio is lower than unity in all the measured bins, suggesting that the ψ(2S) yield is more suppressed than the J/ψ yield in the explored phase space.
  14. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2017 Mar 24;118(12):122301.
    PMID: 28388204 DOI: 10.1103/PhysRevLett.118.122301
    Charge-dependent azimuthal particle correlations with respect to the second-order event plane in p-Pb and PbPb collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV have been studied with the CMS experiment at the LHC. The measurement is performed with a three-particle correlation technique, using two particles with the same or opposite charge within the pseudorapidity range |η|<2.4, and a third particle measured in the hadron forward calorimeters (4.4
  15. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Apr 06;120(14):142302.
    PMID: 29694107 DOI: 10.1103/PhysRevLett.120.142302
    Data from heavy ion collisions suggest that the evolution of a parton shower is modified by interactions with the color charges in the dense partonic medium created in these collisions, but it is not known where in the shower evolution the modifications occur. The momentum ratio of the two leading partons, resolved as subjets, provides information about the parton shower evolution. This substructure observable, known as the splitting function, reflects the process of a parton splitting into two other partons and has been measured for jets with transverse momentum between 140 and 500 GeV, in pp and PbPb collisions at a center-of-mass energy of 5.02 TeV per nucleon pair. In central PbPb collisions, the splitting function indicates a more unbalanced momentum ratio, compared to peripheral PbPb and pp collisions.. The measurements are compared to various predictions from event generators and analytical calculations.
  16. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Jun 15;120(24):241801.
    PMID: 29956995 DOI: 10.1103/PhysRevLett.120.241801
    A search for physics beyond the standard model in events with one or more high-momentum Higgs bosons, H, decaying to pairs of b quarks in association with missing transverse momentum is presented. The data, corresponding to an integrated luminosity of 35.9  fb^{-1}, were collected with the CMS detector at the LHC in proton-proton collisions at the center-of-mass energy sqrt[s]=13  TeV. The analysis utilizes a new b quark tagging technique based on jet substructure to identify jets from H→bb[over ¯]. Events are categorized by the multiplicity of H-tagged jets, jet mass, and the missing transverse momentum. No significant deviation from standard model expectations is observed. In the context of supersymmetry (SUSY), limits on the cross sections of pair-produced gluinos are set, assuming that gluinos decay to quark pairs, H (or Z), and the lightest SUSY particle, LSP, through an intermediate next-to-lightest SUSY particle, NLSP. With large mass splitting between the NLSP and LSP, and 100% NLSP branching fraction to H, the lower limit on the gluino mass is found to be 2010 GeV.
  17. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Jun 01;120(22):221801.
    PMID: 29906166 DOI: 10.1103/PhysRevLett.120.221801
    A search for a heavy neutral lepton N of Majorana nature decaying into a W boson and a charged lepton is performed using the CMS detector at the LHC. The targeted signature consists of three prompt charged leptons in any flavor combination of electrons and muons. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV, with an integrated luminosity of 35.9  fb^{-1}. The search is performed in the N mass range between 1 GeV and 1.2 TeV. The data are found to be consistent with the expected standard model background. Upper limits are set on the values of |V_{eN}|^{2} and |V_{μN}|^{2}, where V_{ℓN} is the matrix element describing the mixing of N with the standard model neutrino of flavor ℓ. These are the first direct limits for N masses above 500 GeV and the first limits obtained at a hadron collider for N masses below 40 GeV.
  18. Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Eur Phys J C Part Fields, 2017;77(11):751.
    PMID: 31999282 DOI: 10.1140/epjc/s10052-017-5140-y
    Measurements of the associated production of a
    Z
    boson with at least one jet originating from a b quark in proton-proton collisions at


    s

    =
    8

    TeV

    are presented. Differential cross sections are measured with data collected by the CMS experiment corresponding to an integrated luminosity of 19.8



    fb

    -
    1



    .
    Z
    bosons are reconstructed through their decays to electrons and muons. Cross sections are measured as a function of observables characterizing the kinematics of the
    b
    jet and the
    Z
    boson. Ratios of differential cross sections for the associated production with at least one
    b
    jet to the associated production with any jet are also presented. The production of a
    Z
    boson with at least two
    b
    jets is investigated, and differential cross sections are measured for the dijet system. Results are compared to theoretical predictions, testing two different flavour schemes for the choice of initial-state partons.
  19. Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.
    Eur Phys J C Part Fields, 2017;77(12):845.
    PMID: 31985736 DOI: 10.1140/epjc/s10052-017-5317-4
    A search is presented for an excess of events with heavy-flavor quark pairs (

    t

    t
    ¯


    and

    b

    b
    ¯


    ) and a large imbalance in transverse momentum in data from proton-proton collisions at a center-of-mass energy of 13


    TeV

    . The data correspond to an integrated luminosity of 2.2



    fb

    -
    1



    collected with the CMS detector at the CERN LHC. No deviations are observed with respect to standard model predictions. The results are used in the first interpretation of dark matter production in

    t

    t
    ¯


    and

    b

    b
    ¯


    final states in a simplified model. This analysis is also the first to perform a statistical combination of searches for dark matter produced with different heavy-flavor final states. The combination provides exclusions that are stronger than those achieved with individual heavy-flavor final states.
  20. Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Eur Phys J C Part Fields, 2018;78(2):140.
    PMID: 31265001 DOI: 10.1140/epjc/s10052-018-5607-5
    A search for standard model production of four top quarks ( t t ¯ t t ¯ ) is reported using events containing at least three leptons ( e , μ ) or a same-sign lepton pair. The events are produced in proton-proton collisions at a center-of-mass energy of 13 TeV at the LHC, and the data sample, recorded in 2016, corresponds to an integrated luminosity of 35.9 fb - 1 . Jet multiplicity and flavor are used to enhance signal sensitivity, and dedicated control regions are used to constrain the dominant backgrounds. The observed and expected signal significances are, respectively, 1.6 and 1.0 standard deviations, and the t t ¯ t t ¯ cross section is measured to be 16 . 9 - 11.4 + 13.8 fb , in agreement with next-to-leading-order standard model predictions. These results are also used to constrain the Yukawa coupling between the top quark and the Higgs boson to be less than 2.1 times its expected standard model value at 95% confidence level.
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