Pharmacokinetics-pharmacodynamics of tazobactam in combination with cefepime in an in vitro infection model

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%T>threshold). Using data from studies of Enterobacteriaceae-producing ESBL, a relationship between tazobactam %T>threshold and reduction in log10 CFU from baseline, for which tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae, known to produce CTX-M-15 β-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/L in the presence of 4 mg/L tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625-1 times the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %T>threshold and change in log10 CFU from baseline was the product of 0.125 and the cefepime-tazobactam MIC (R2=0.813). The magnitude of %T>threshold associated with net bacterial stasis and a 1-log10 CFU/mL reduction from baseline at 24 hours was 21.9 and 52.8%, respectively. These data will be useful to support the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies

Effects and Implications of Wearing a Face Mask on Cardiopulmonary Performance During Exercise

The coronavirus disease 2019 (COVID-19) pandemic has prompted the use of a face mask (FM) to minimize the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. The use of an FM being an accepted precautionary measure to reduce viral transmission, there is a need for examining the physiological effects of wearing an FM, specifically during exercise. PURPOSE: To assess the impact of wearing a surgical FM on cardiopulmonary parameters and exercise performance. METHODS: Nine males and 9 females (age = 21.6 ± 2.5 yrs; BMI = 24.4 ± 3.1 kg/m2) participated in 2 laboratory visits where they completed a graded maximal exercise test using a modified Bruce Protocol. Participants were randomized to which laboratory visit they would complete first, with face mask (WFM) or without face mask (WOFM), which were performed at least 48 hours apart. Expired gases, blood pressure, heart rate, blood O2 saturation including perfusion index, and the Borg Rating of Perceived Exertion (RPE) were measured and compared between the WFM and WOFM trials at 6 different intensities (rest, 40%, 55%, 70%, 80%, and 100% VO2max), using a two-way repeated measures ANOVA. RESULTS: There was a significant difference in VO2 (p = 0.001 and n2 = 0.73) between the WFM (38.5 ± 6.8 mL/kg/min) and WOFM (44.3 ± 7.4 mL/kg/min) trials only at the 100% VO2max intensity, where significantly lower values were also found during the WFM trial for respiratory rate (40.0 ± 6.8 vs 47.8 ± 8.9 bpm, p = 0.001, n2 = 0.62), respiratory exchange ratio (1.07 ± 0.08 vs 1.14 ± 0.64, p = 0.001, n2 = 0.52), and the partial pressure of expired oxygen (125.7 ± 3.5 vs 129.4 ± 3.1 mmHg, p = 0.0001, n2 = 0.54). In contrast, the partial pressure of expired carbon dioxide (32.8 ± 3.1 vs 30.8 ± 3.3 mmHg, p = 0.01, n2 = 0.33) was significantly higher during the WFM trial only at 100% VO2max intensity. No other parameters significantly differed at any of the intensities. CONCLUSION: Oxygen consumption was lower with face masks only as participants advanced from 80% to maximal effort. Notably, participants had a slower respiratory rate and exhaled a higher concentration of carbon dioxide with face masks. This result suggests that expired carbon dioxide accumulated under the face masks and participants subsequently rebreathed this expired carbon dioxide. There is no evidence that suggests exercise below 80% of VO2max while wearing face masks will cause any concerning changes in cardiopulmonary parameters. However, it is recommended that future studies examine how different types of face masks may affect cardiopulmonary function during exercise in a variety of subject populations

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5

BACKGROUND: The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene × environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem. METHODS: We used multiple-trait analysis for quantitative trait locus mapping of loci having different effects on systolic blood pressure with NaCl exposure. Animals studied were 188 rats, the progenies of an F2 rat intercross between the hypertensive and normotensive strain, genotyped in 179 polymorphic markers across the rat genome. To accommodate the correlational structure from measurements taken in the same animals, we applied univariate and multivariate strategies for analyzing the data. RESULTS: We detected a new quantitative train locus on a region close to marker R589 in chromosome 5 of the rat genome, not previously identified through serial analysis of individual traits. In addition, we were able to justify analytically the parametric restrictions in terms of regression coefficients responsible for the gain in precision with the adopted analytical approach. CONCLUSION: Future work should focus on fine mapping and the identification of the causative variant responsible for this quantitative trait locus signal. The multivariable strategy might be valuable in the study of genetic determinants of interindividual variation of antihypertensive drug effectiveness

Mediation in the Law Curriculum

Cited by Lord Neuberger in ‘Educating Future Mediators’ at the 4th Civil Mediation Council National Conference, May 201

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Lung cancer in never smokers (LCINS): development of a UK national research strategy

Introduction Lung cancer in never smokers (LCINS) accounts for 15% of lung cancers diagnosed in the UK, making it the 8th most common cancer. There are few robust studies specific to the LCINS population making data surrounding the incidence and mortality of LCINS incomplete, leaving many gaps in our understanding of the needs of this population. Methods To address a lack of research in this important area, the UK National Cancer Research Institute Lung Study Group (NCRI-LSG) undertook a national survey and hosted a research strategy day to define key research priorities. A wide cross section of stakeholders, including patient advocates, the charitable sector, basic and translational researchers, and multi-disciplinary healthcare professionals contributed highlighting their research priorities. Results One-hundred twenty-seven surveys were completed (52 by patients/patient advocates) prior to the strategy day. These identified themes for expert review presentations and subsequent workshop discussions at the national research strategy day, which registered 190 attendees (50 patients/patient advocates). The four key themes that emerged to form the basis of a research strategy for LCINS are (1) Raising awareness, (2) Risk assessment and early detection, (3) Disease biology, (4) Living with and beyond. Conclusion This paper summarises current evidence and important gaps in our knowledge related to LCINS. We present recommendations for a national research strategy aimed at improving outcomes for patients

Search for anomalous t t-bar production in the highly-boosted all-hadronic final state

A search is presented for a massive particle, generically referred to as a Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are sufficiently massive to produce highly Lorentz-boosted top quarks, which yield collimated decay products that are partially or fully merged into single jets. The analysis uses new methods to analyze jet substructure, providing suppression of the non-top multijet backgrounds. The analysis is based on a data sample of proton-proton collisions at a center-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits in the range of 1 pb are set on the product of the production cross section and branching fraction for a topcolor Z' modeled for several widths, as well as for a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any enhancement in t t-bar production beyond expectations of the standard model for t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version includes a minor typo correction that will be submitted as an erratu

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV