Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.
The aim of this study was to evaluate a new method to quantify longitudinal mandibular bone remodeling three-dimensionally by superimposition of cone beam computed tomography images.
Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top quark (the top squark) and the Higgs boson (Higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 fb-1 of proton-proton collision data at s=8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the top squark mass below 360 to 410 GeV, depending on the Higgsino mass.
Measurements are reported of the WZ and ZZ production cross sections in proton-proton collisions at [Formula: see text][Formula: see text] in final states where one Z boson decays to b-tagged jets. The other gauge boson, either W or Z, is detected through its leptonic decay (either [Formula: see text], [Formula: see text] or [Formula: see text], [Formula: see text], or [Formula: see text]). The results are based on data corresponding to an integrated luminosity of 18.9 fb[Formula: see text] collected with the CMS detector at the Large Hadron Collider. The measured cross sections, [Formula: see text] and [Formula: see text], are consistent with next-to-leading order quantum chromodynamics calculations.
The normalised differential top quark-antiquark production cross section is measured as a function of the jet multiplicity in proton-proton collisions at a centre-of-mass energy of 7[Formula: see text] at the LHC with the CMS detector. The measurement is performed in both the dilepton and lepton+jets decay channels using data corresponding to an integrated luminosity of 5.0[Formula: see text]. Using a procedure to associate jets to decay products of the top quarks, the differential cross section of the [Formula: see text] production is determined as a function of the additional jet multiplicity in the lepton+jets channel. Furthermore, the fraction of events with no additional jets is measured in the dilepton channel, as a function of the threshold on the jet transverse momentum. The measurements are compared with predictions from perturbative quantum chromodynamics and no significant deviations are observed.
A measurement of the cross section for the production of top quark-antiquark pairs ([Formula: see text]) in association with a vector boson V (W or Z) in proton-proton collisions at [Formula: see text][Formula: see text] is presented. The results are based on a dataset corresponding to an integrated luminosity of 19.5 fb[Formula: see text] recorded with the CMS detector at the LHC. The measurement is performed in three leptonic (e and [Formula: see text]) channels: a same-sign dilepton analysis targeting [Formula: see text] events, and trilepton and four-lepton analyses designed for [Formula: see text] events. In the same-sign dilepton channel, the [Formula: see text] cross section is measured as [Formula: see text], corresponding to a significance of 1.6 standard deviations over the background-only hypothesis. Combining the trilepton and four-lepton channels, a direct measurement of the [Formula: see text] cross section, [Formula: see text], is obtained with a significance of 3.1 standard deviations. The measured cross sections are compatible with standard model predictions within their experimental uncertainties. The inclusive [Formula: see text] process is observed with a significance of 3.7 standard deviations from the combination of all three leptonic channels.
Searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and [Formula: see text], [Formula: see text], and Higgs bosons are presented. Results are based on a sample of proton-proton collision data collected at center-of-mass energy [Formula: see text] with the CMS detector in 2012, corresponding to an integrated luminosity of 19.5 [Formula: see text]. The observed event rates are in agreement with expectations from the standard model. These results probe charginos and neutralinos with masses up to 720 [Formula: see text], and sleptons up to 260 [Formula: see text], depending on the model details.
Nanog is a potential stem cell marker and is considered a regeneration factor during tissue repair. In the present study, we investigated expression patterns of nanog in the rat heart after acute myocardial infarction by semi-quantitative RT-PCR, immunohistochemistry and Western blot analyses. Our results show that nanog at both mRNA and protein levels is positively expressed in myocardial cells, fibroblasts and small round cells in different myocardial zones at different stages after myocardial infarction, showing a spatio-temporal and dynamic change. After myocardial infarction, the nanog expression in fibroblasts and small round cells in the infarcted zone (IZ) is much stronger than that in the margin zone (MZ) and remote infarcted zone (RIZ). From day 7 after myocardial infarction, the fibroblasts and small cells strongly expressed nanog protein in the IZ, and a few myocardial cells in the MZ and the RIZ and the numbers of nanog-positive fibroblasts and small cells reached the highest peak at 21 days after myocardial infarction, but in this period the number of nanog-positive myocardial cells decreased gradually. At 28 days after myocardial infarction, the numbers of all nanog-positive cells decreased into a low level. Therefore, our data suggest that all myocardial cells, fibroblasts and small round cells are involved in myocardial reconstruction after cardiac infarction. The nanog-positive myocardial cells may respond to early myocardial repair, and the nanog-positive fibroblasts and small round cells are the main source for myocardial reconstruction after cardiac infarction.
A measurement of differential cross sections for the production of a pair of isolated photons in proton-proton collisions at [Formula: see text] is presented. The data sample corresponds to an integrated luminosity of 5.0[Formula: see text] collected with the CMS detector. A data-driven isolation template method is used to extract the prompt diphoton yield. The measured cross section for two isolated photons, with transverse energy above 40 and 25[Formula: see text] respectively, in the pseudorapidity range [Formula: see text], [Formula: see text] and with an angular separation [Formula: see text], is [Formula: see text][Formula: see text]. Differential cross sections are measured as a function of the diphoton invariant mass, the diphoton transverse momentum, the azimuthal angle difference between the two photons, and the cosine of the polar angle in the Collins-Soper reference frame of the diphoton system. The results are compared to theoretical predictions at leading, next-to-leading, and next-to-next-to-leading order in quantum chromodynamics.
A search for invisible decays of Higgs bosons is performed using the vector boson fusion and associated ZH production modes. In the ZH mode, the Z boson is required to decay to a pair of charged leptons or a [Formula: see text] quark pair. The searches use the 8 [Formula: see text] pp collision dataset collected by the CMS detector at the LHC, corresponding to an integrated luminosity of up to 19.7 [Formula: see text]. Certain channels include data from 7 [Formula: see text] collisions corresponding to an integrated luminosity of 4.9 [Formula: see text]. The searches are sensitive to non-standard-model invisible decays of the recently observed Higgs boson, as well as additional Higgs bosons with similar production modes and large invisible branching fractions. In all channels, the observed data are consistent with the expected standard model backgrounds. Limits are set on the production cross section times invisible branching fraction, as a function of the Higgs boson mass, for the vector boson fusion and ZH production modes. By combining all channels, and assuming standard model Higgs boson cross sections and acceptances, the observed (expected) upper limit on the invisible branching fraction at [Formula: see text] [Formula: see text] is found to be 0.58 (0.44) at 95 % confidence level. We interpret this limit in terms of a Higgs-portal model of dark matter interactions.
Observation of the diphoton decay mode of the recently discovered Higgs boson and measurement of some of its properties are reported. The analysis uses the entire dataset collected by the CMS experiment in proton-proton collisions during the 2011 and 2012 LHC running periods. The data samples correspond to integrated luminosities of 5.1[Formula: see text]at [Formula: see text] and 19.7[Formula: see text]at 8[Formula: see text] . A clear signal is observed in the diphoton channel at a mass close to 125[Formula: see text] with a local significance of [Formula: see text], where a significance of [Formula: see text] is expected for the standard model Higgs boson. The mass is measured to be [Formula: see text] , and the best-fit signal strength relative to the standard model prediction is [Formula: see text][Formula: see text][Formula: see text]. Additional measurements include the signal strength modifiers associated with different production mechanisms, and hypothesis tests between spin-0 and spin-2 models.
A search for heavy, right-handed neutrinos, [Formula: see text] ([Formula: see text]), and right-handed [Formula: see text] bosons, which arise in the left-right symmetric extensions of the standard model, has been performed by the CMS experiment. The search was based on a sample of two lepton plus two jet events collected in proton-proton collisions at a center-of-mass energy of 8[Formula: see text] corresponding to an integrated luminosity of 19.7 [Formula: see text]. For models with strict left-right symmetry, and assuming only one [Formula: see text] flavor contributes significantly to the [Formula: see text] decay width, the region in the two-dimensional [Formula: see text] mass plane excluded at a 95 % confidence level extends to approximately [Formula: see text] and covers a large range of neutrino masses below the [Formula: see text] boson mass, depending on the value of [Formula: see text]. This search significantly extends the [Formula: see text] exclusion region beyond previous results.
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Although implant-retained overdenture allows edentulous patients to take higher occlusal forces than the conventional complete dentures, the biomechanical influences have not been explored yet. Clinically, there is limited knowledge and means for predicting localized bone remodelling after denture treatment with and without implant support. By using finite element (FE) analysis, this article provides an in-silico approach to exploring the treatment effects on the oral mucosa and potential resorption of residual ridge under three different denture configurations in a patient-specific manner. Based on cone beam computerized tomography (CBCT) scans, a 3D heterogeneous FE model was created; and the supportive tissue, mucosa, was characterized as a hyperelastic material. A measured occlusal load (63N) was applied onto three virtual models, namely complete denture, two and four implant-retained overdentures. Clinically, the bone resorption was measured after one year in the two implant-retained overdenture treatment. Despite the improved stability and enhanced masticatory function, the implant-retained overdentures demonstrated higher hydrostatic stress in mucosa (43.6kPa and 39.9kPa for two and four implants) at the posterior ends of the mandible due to the cantilever effect, than the complete denture (33.4kPa). Hydrostatic pressure in the mucosa signifies a critical indicator and can be correlated with clinically measured bone resorption, pointing to severer mandibular ridge resorption posteriorly with implant-retained overdentures. This study provides a biomechanical basis for denture treatment planning to improve long-term outcomes with minimal residual ridge resorption.
A study of vector boson scattering in pp collisions at a center-of-mass energy of 8 TeV is presented. The data sample corresponds to an integrated luminosity of 19.4 fb(-1) collected with the CMS detector. Candidate events are selected with exactly two leptons of the same charge, two jets with large rapidity separation and high dijet mass, and moderate missing transverse energy. The signal region is expected to be dominated by electroweak same-sign W-boson pair production. The observation agrees with the standard model prediction. The observed significance is 2.0 standard deviations, where a significance of 3.1 standard deviations is expected based on the standard model. Cross section measurements for W(±)W(±) and WZ processes in the fiducial region are reported. Bounds on the structure of quartic vector-boson interactions are given in the framework of dimension-eight effective field theory operators, as well as limits on the production of doubly charged Higgs bosons.
The purely electroweak (EW) cross section for the production of two jets in association with a Z boson, in proton-proton collisions at [Formula: see text], is measured using data recorded by the CMS experiment at the CERN LHC, corresponding to an integrated luminosity of 19.7[Formula: see text]. The electroweak cross section for the [Formula: see text] final state (with [Formula: see text] or [Formula: see text] and j representing the quarks produced in the hard interaction) in the kinematic region defined by [Formula: see text][Formula: see text], [Formula: see text][Formula: see text], transverse momentum [Formula: see text][Formula: see text], and pseudorapidity [Formula: see text], is found to be [Formula: see text], in agreement with the standard model prediction. The associated jet activity of the selected events is studied, in particular in a signal-enriched region of phase space, and the measurements are found to be in agreement with QCD predictions.
Results are presented from a search for new decaying massive particles whose presence is inferred from an imbalance in transverse momentum and which are produced in association with a single top quark that decays into a bottom quark and two light quarks. The measurement is performed using 19.7 fb^{-1} of data from proton-proton collisions at a center-of-mass energy of 8 TeV, collected with the CMS detector at the CERN LHC. No deviations from the standard model predictions are observed and lower limits are set on the masses of new invisible bosons. In particular, scalar and vector particles, with masses below 330 and 650 GeV, respectively, are excluded at 95% confidence level, thereby substantially extending a previous limit published by the CDF Collaboration.
Measurements of the differential and double-differential Drell-Yan cross sections in the dielectron and dimuon channels are presented. They are based on proton-proton collision data at [Formula: see text] recorded with the CMS detector at the LHC and corresponding to an integrated luminosity of 19.7[Formula: see text]. The measured inclusive cross section in the [Formula: see text] peak region (60-120[Formula: see text]), obtained from the combination of the dielectron and dimuon channels, is [Formula: see text], where the statistical uncertainty is negligible. The differential cross section [Formula: see text] in the dilepton mass range 15-2000[Formula: see text] is measured and corrected to the full phase space. The double-differential cross section [Formula: see text] is also measured over the mass range 20 to 1500[Formula: see text] and absolute dilepton rapidity from 0 to 2.4. In addition, the ratios of the normalized differential cross sections measured at [Formula: see text] and 8[Formula: see text] are presented. These measurements are compared to the predictions of perturbative QCD at next-to-leading and next-to-next-to-leading (NNLO) orders using various sets of parton distribution functions (PDFs). The results agree with the NNLO theoretical predictions computed with fewz 3.1 using the CT10 NNLO and NNPDF2.1 NNLO PDFs. The measured double-differential cross section and ratio of normalized differential cross sections are sufficiently precise to constrain the proton PDFs.
A search has been performed for long-lived particles that could have come to rest within the CMS detector, using the time intervals between LHC beam crossings. The existence of such particles could be deduced from observation of their decays via energy deposits in the CMS calorimeter appearing at times that are well separated from any proton-proton collisions. Using a data set corresponding to an integrated luminosity of 18.6[Formula: see text] of 8[Formula: see text] proton-proton collisions, and a search interval corresponding to 281 h of trigger livetime, 10 events are observed, with a background prediction of [Formula: see text] events. Limits are presented at 95 % confidence level on gluino and top squark production, for over 13 orders of magnitude in the mean proper lifetime of the stopped particle. Assuming a cloud model of R-hadron interactions, a gluino with mass [Formula: see text]1000[Formula: see text] and a top squark with mass [Formula: see text]525[Formula: see text] are excluded, for lifetimes between 1 [Formula: see text]s and 1000[Formula: see text]. These results are the most stringent constraints on stopped particles to date.
This paper presents a measurement of the inclusive 3-jet production differential cross section at a proton-proton centre-of-mass energy of 7 TeV using data corresponding to an integrated luminosity of 5[Formula: see text]collected with the CMS detector. The analysis is based on the three jets with the highest transverse momenta. The cross section is measured as a function of the invariant mass of the three jets in a range of 445-3270 GeV and in two bins of the maximum rapidity of the jets up to a value of 2. A comparison between the measurement and the prediction from perturbative QCD at next-to-leading order is performed. Within uncertainties, data and theory are in agreement. The sensitivity of the observable to the strong coupling constant [Formula: see text] is studied. A fit to all data points with 3-jet masses larger than 664 GeV gives a value of the strong coupling constant of [Formula: see text].