279 research outputs found

    A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine.

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    Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures

    Search for disappearing tracks in proton-proton collisions at √s=8 TeV

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    Search for the production of dark matter in association with top-quark pairs in the single-lepton final state in proton-proton collisions at √s=8 TeV

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    Search for vector-like T quarks decaying to top quarks and Higgs bosons in the all-hadronic channel using jet substructure

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    High-dose rifapentine with moxifloxacin for pulmonary tuberculosis

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    BACKGROUND: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. METHODS: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. RESULTS: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). CONCLUSIONS: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.)

    Precise determination of the mass of the Higgs boson and tests of compatibility of its couplings with the standard model predictions using proton collisions at 7 and 8 TeV

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    Search for physics beyond the standard model in dilepton mass spectra in proton-proton collisions at √s=8 TeV

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    Global baryon number conservation encoded in net-proton fluctuations measured in Pb–Pb collisions at √sNN = 2.76 TeV

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    Experimental results are presented on event-by-event net-proton fluctuation measurements in Pb–Pb collisions at √SNN=2.76 TeV, recorded by the ALICE detector at the CERN LHC. These measurements have as their ultimate goal an experimental test of Lattice QCD (LQCD) predictions on second and higher order cumulants of net-baryon distributions to search for critical behavior near the QCD phase boundary. Before confronting them with LQCD predictions, account has to be taken of correlations stemming from baryon number conservation as well as fluctuations of participating nucleons. Both effects influence the experimental measurements and are usually not considered in theoretical calculations. For the first time, it is shown that event-by-event baryon number conservation leads to subtle long-range correlations arising from very early interactions in the collisions.publishedVersio

    Searches for supersymmetry using the M-T2 variable in hadronic events produced in pp collisions at 8 TeV

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