Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia

Objectives: Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients. Methods: This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by noncompartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: similar to 30% and similar to 20% of the dosing interval, respectively). Results: Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam T-max (6 and 2 h, respectively) were delayed in ELF compared with plasma (1h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1mg/L, respectively, for 100% of the dosing interval. Therewere no deaths or adverse event-related study discontinuations. Conclusions: In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens

Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals

Importance: Sepsis is present in many hospitalizations that culminate in death. The contribution of sepsis to these deaths, and the extent to which they are preventable, is unknown. Objective: To estimate the prevalence, underlying causes, and preventability of sepsis-associated mortality in acute care hospitals. Design, Setting, and Participants: Cohort study in which a retrospective medical record review was conducted of 568 randomly selected adults admitted to 6 US academic and community hospitals from January 1, 2014, to December 31, 2015, who died in the hospital or were discharged to hospice and not readmitted. Medical records were reviewed from January 1, 2017, to March 31, 2018. Main Outcomes and Measures: Clinicians reviewed cases for sepsis during hospitalization using Sepsis-3 criteria, hospice-qualifying criteria on admission, immediate and underlying causes of death, and suboptimal sepsis-related care such as inappropriate or delayed antibiotics, inadequate source control, or other medical errors. The preventability of each sepsis-associated death was rated on a 6-point Likert scale. Results: The study cohort included 568 patients (289 [50.9%] men; mean [SD] age, 70.5 [16.1] years) who died in the hospital or were discharged to hospice. Sepsis was present in 300 hospitalizations (52.8%; 95% CI, 48.6%-57.0%) and was the immediate cause of death in 198 cases (34.9%; 95% CI, 30.9%-38.9%). The next most common immediate causes of death were progressive cancer (92 [16.2%]) and heart failure (39 [6.9%]). The most common underlying causes of death in patients with sepsis were solid cancer (63 of 300 [21.0%]), chronic heart disease (46 of 300 [15.3%]), hematologic cancer (31 of 300 [10.3%]), dementia (29 of 300 [9.7%]), and chronic lung disease (27 of 300 [9.0%]). Hospice-qualifying conditions were present on admission in 121 of 300 sepsis-associated deaths (40.3%; 95% CI 34.7%-46.1%), most commonly end-stage cancer. Suboptimal care, most commonly delays in antibiotics, was identified in 68 of 300 sepsis-associated deaths (22.7%). However, only 11 sepsis-associated deaths (3.7%) were judged definitely or moderately likely preventable; another 25 sepsis-associated deaths (8.3%) were considered possibly preventable. Conclusions and Relevance: In this cohort from 6 US hospitals, sepsis was the most common immediate cause of death. However, most underlying causes of death were related to severe chronic comorbidities and most sepsis-associated deaths were unlikely to be preventable through better hospital-based care. Further innovations in the prevention and care of underlying conditions may be necessary before a major reduction in sepsis-associated deaths can be achieved

Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication

Centrosome duplication is tightly controlled in coordination with DNA replication. The molecular mechanism of centrosome duplication remains unclear. Previous studies found that a fraction of human proline-directed phosphatase Cdc14B associates with centrosomes. However, Cdc14B's involvement in centrosome cycle control has never been explored. Here, we show that depletion of Cdc14B by RNA interference leads to centriole amplification in both HeLa and normal human fibroblast BJ and MRC-5 cells. Induction of Cdc14B expression through a regulatable promoter significantly attenuates centriole amplification in prolonged S phase–arrested cells and proteasome inhibitor Z-L3VS–treated cells. This inhibitory function requires centriole-associated Cdc14B catalytic activity. Together, these results suggest a potential function for Cdc14B phosphatase in maintaining the fidelity of centrosome duplication cycle

Blood Eosinophil Count Predicts Treatment Failure and Hospital Readmission for COPD

ACKNOWLEDGEMENTS This study was funded by AstraZeneca. Editorial support was provided by Joanne M. Faysal, MS, and Jennie G. Jacobson, PhD, CMPP, of JK Associates, Inc., and Michael A. Nissen, ELS, of AstraZeneca. This support was funded by AstraZeneca. DATA-SHARING STATEMENT Data underlying the findings described in this manuscript may be requested in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagroupdt.pharmacm.com/DT/HomePeer reviewedPublisher PD

A Two Micron All-Sky Survey View of the Sagittarius Dwarf Galaxy: II. Swope Telescope Spectroscopy of M Giant Stars in the Dynamically Cold Sagittarius Tidal Stream

We present moderate resolution (~6 km/s) spectroscopy of 284 M giant candidates selected from the Two Micron All Sky Survey photometry. Radial velocities (RVs) are presented for stars mainly in the south, with a number having positions consistent with association to the trailing tidal tail of the Sagittarius (Sgr) dwarf galaxy. The latter show a clear RV trend with orbital longitude, as expected from models of the orbit and destruction of Sgr. A minimum 8 kpc width of the trailing stream about the Sgr orbital midplane is implied by verified RV members. The coldness of this stream (dispersion ~10 km/s) provides upper limits on the combined contributions of stream heating by a lumpy Galactic halo and the intrinsic dispersion of released stars, which is a function of the Sgr core mass. The Sgr trailing arm is consistent with a Galactic halo containing one dominant, LMC-like lump, however some lumpier halos are not ruled out. An upper limit to the total M/L of the Sgr core is 21 in solar units. A second structure that roughly mimics expectations for wrapped, leading Sgr arm debris crosses the trailing arm in the Southern Hemisphere; however, this may also be an unrelated tidal feature. Among the <13 kpc M giants toward the South Galactic Pole are some with large RVs that identify them as halo stars, perhaps part of the Sgr leading arm near the Sun. The positions and RVs of Southern Hemisphere M giants are compared with those of southern globular clusters potentially stripped from the Sgr system and support for association of Pal 2 and Pal 12 with Sgr debris is found. Our discussion includes description of a masked-filtered cross-correlation methodology that achieves better than 1/20 of a resolution element RVs in moderate resolution spectra.Comment: 41 pages, 6 figures, Astronomical Journal, in press (submitted Nov. 24, 2003; tentatively scheduled for July 2004 issue

Physical properties of Heusler-like Fe2VAl

A comprehensive characterization of the compound Fe2VAl was carried out. Samples grown by arc melting or the Bridgman method have Al and Fe deficiencies of up to 5 at. %. Czochralski-grown samples were Fe rich and Al deficient. X-ray diffraction implies appreciable antisite disorder in all of our samples. Fourier-transform infrared (FTIR) spectroscopy measurements showed that the carrier density and scattering time had little sample-to-sample variation or temperature dependence for near-stoichiometric samples. FTIR and dc resistivity suggest that the transport properties of Fe2VAl are influenced by both localized and delocalized carriers, with the former primarily responsible for the negative temperature coefficient of resistivity. Magnetization measurements reveal that near-stoichiometric samples have superparamagnetic clusters with at least two sizes of moments. We conclude that in Fe2VAl, antisite disorder causes significant modification to the semimetallic band structure proposed theoretically. With antisite disorder considered, we are now able to explain most of the physical properties of Fe2VAl. None of our data suggest heavy-fermion behavior in our samples

Vlasov-Maxwell, self-consistent electromagnetic wave emission simulations in the solar corona

1.5D Vlasov-Maxwell simulations are employed to model electromagnetic emission generation in a fully self-consistent plasma kinetic model for the first time in the solar physics context. The simulations mimic the plasma emission mechanism and Larmor drift instability in a plasma thread that connects the Sun to Earth with the spatial scales compressed appropriately. The effects of spatial density gradients on the generation of electromagnetic radiation are investigated. It is shown that 1.5D inhomogeneous plasma with a uniform background magnetic field directed transverse to the density gradient is aperiodically unstable to Larmor-drift instability. The latter results in a novel effect of generation of electromagnetic emission at plasma frequency. When density gradient is removed (i.e. when plasma becomes stable to Larmor-drift instability) and a $low$ density, super-thermal, hot beam is injected along the domain, in the direction perpendicular to the magnetic field, plasma emission mechanism generates non-escaping Langmuir type oscillations which in turn generate escaping electromagnetic radiation. It is found that in the spatial location where the beam is injected, the standing waves, oscillating at the plasma frequency, are excited. These can be used to interpret the horizontal strips observed in some dynamical spectra. Quasilinear theory predictions: (i) the electron free streaming and (ii) the beam long relaxation time, in accord with the analytic expressions, are corroborated via direct, fully-kinetic simulation. Finally, the interplay of Larmor-drift instability and plasma emission mechanism is studied by considering $dense$ electron beam in the Larmor-drift unstable (inhomogeneous) plasma. http://www.maths.qmul.ac.uk/~tsiklauri/movie1.mpg * http://www.maths.qmul.ac.uk/~tsiklauri/movie2.mpg * http://www.maths.qmul.ac.uk/~tsiklauri/movie3.mpgComment: Solar Physics (in press, the final, accepted version

Adequacy of therapy for people with both COPD and heart failure in the UK : historical cohort study

Acknowledgments We thank Derek Skinner for his contributions to the data acquisition and handling and Carole Nicholls and Priyanka Raju Konduru for statistical support. Writing and editorial support was provided by Elizabeth V. Hillyer, DVM, supported by Novartis Pharma AG, Basel, Switzerland. Funding This work was supported by Novartis. Employees of the sponsor (listed as authors) participated in the study design, interpretation of the results, writing of the report, and the decision to submit the paper for publication.Peer reviewedPublisher PD

Does Changing Inhaler Device Impact Real-Life Asthma Outcomes? : Clinical and Economic Evaluation

This study was funded by Mundipharma Korea Limited (Seoul, Korea).Peer reviewedPostprin

Nonspecific Protein-DNA Binding Is Widespread in the Yeast Genome

Recent genome-wide measurements of binding preferences of ~200 transcription regulators in the vicinity of transcription start sites in yeast, have provided a unique insight into the cis- regulatory code of a eukaryotic genome (Venters et al., Mol. Cell 41, 480 (2011)). Here, we show that nonspecific transcription factor (TF)-DNA binding significantly influences binding preferences of the majority of transcription regulators in promoter regions of the yeast genome. We show that promoters of SAGA-dominated and TFIID-dominated genes can be statistically distinguished based on the landscape of nonspecific protein-DNA binding free energy. In particular, we predict that promoters of SAGA-dominated genes possess wider regions of reduced free energy compared to promoters of TFIID-dominated genes. We also show that specific and nonspecific TF-DNA binding are functionally linked and cooperatively influence gene expression in yeast. Our results suggest that nonspecific TF-DNA binding is intrinsically encoded into the yeast genome, and it may play a more important role in transcriptional regulation than previously thought