How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

The pharmacokinetics (PK) of antimicrobial agents administered to critically ill patients exhibit marked variability. This variability results from pathophysiological changes that occur in critically ill patients. Changes in volume of distribution, clearance, and tissue penetration all affect the drug concentrations at the site of infection. PK-pharmacodynamic indices (fC(max):MIC; AUC(0-24):MIC; fT(>MIC); fC(min):MIC) for both antimicrobial effect and suppression of emergence of resistance are described for many antimicrobial drugs. Changing the regimen by which antimicrobial drugs are delivered can help overcome the PK variability and optimise target attainment. This will deliver optimised antimicrobial chemotherapy to individual critically ill patients. Delivery of beta-lactams antimicrobial agents by infusions, rather than bolus dosing, is effective at increasing the duration of the dosing interval that the drug concentration is above the MIC. Therapeutic drug monitoring, utilising population PK mathematical models with Bayesian estimation, can also be used to optimise regimens following measurement of plasma drug concentrations. Clinical trials are required to establish if patient outcomes can be improved by implementing these techniques. (C) 2014 Elsevier Inc. All rights reserved

Effects of low energy electron irradiation on formation of nitrogen-vacancy centers in single-crystal diamond

Exposure to beams of low energy electrons (2 to 30 keV) in a scanning electron microscope locally induces formation of NV-centers without thermal annealing in diamonds that have been implanted with nitrogen ions. We find that non-thermal, electron beam induced NV-formation is about four times less efficient than thermal annealing. But NV-center formation in a consecutive thermal annealing step (800C) following exposure to low energy electrons increases by a factor of up to 1.8 compared to thermal annealing alone. These observations point to reconstruction of nitrogen-vacancy complexes induced by electronic excitations from low energy electrons as an NV-center formation mechanism and identify local electronic excitations as a means for spatially controlled room-temperature NV-center formation

Additive Manufacturing of Next Generation Electrical Machine Windings - Opportunities in Fusion Engineering?

More electric propulsion across automotive and aerospace has lead to a demand for significant improvement in thepower density of electrical machines. This has, in turn, triggered research into advanced manufacturing methods for higher performance magnet systems in machines. The application of Laser Powder Bed Fusion (LPBF), a form of Additive Manufacture (AM), to the current carrying coils of the electromagnetic circuit of a machine has allowed several significant improvements to the design of these parts. One benefit which can be realised in this way is the tailoring of conductor form to the operating field and the alteration of conductor topolgy to reduce AC loss. Another advantage of these manufacturing techniques is the ability to introduce methods of direct cooling to the coil, including highly efficient heat exchangers derived from generative design techniques. It is significant that the electrical conductivity achieved is now equivalent to that of conventional drawn Cu wire. This paper hypothesises that the lessons learned in developing production methods for next generation, high performance components for electric machines might also find utility in the very demanding electromagnetic circuits found in magnetic confinement fusion. Potential benefits for the production of Cable-in-Conduit Conductor (CICC) superconducting (SC) bus-bar joints, or even larger elements of conductors are discussed. This is used to motivate future experimental studies of the mechanical and electrical performance of AM Cu at cryogenic temperatures as well as the further development of the manufacturing state of the art

Individualization of piperacillin dosing for critically ill patients: Dosing software to optimize antimicrobial therapy

Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r2 of > 0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required. Copyrigh

The High Resolution X-ray Spectrum of SS 433 using the Chandra HETGS

We present observations of SS 433 using the Chandra High Energy Transmission Grating Spectrometer. Many emission lines of highly ionized elements are detected with the relativistic blue and red Doppler shifts. The lines are measurably broadened to 1700 km/s (FWHM) and the widths do not depend significantly on the characteristic emission temperature, suggesting that the emission occurs in a freely expanding region of constant collimation with opening angle of 1.23 +/- 0.06 deg. The blue shifts of lines from low temperature gas are the same as those of high temperature gas within our uncertainties, again indicating that the hottest gas we observe to emit emission lines is already at terminal velocity. Fits to the emission line fluxes give a range of temperatures in the jet from 5e6 to 1e8 K. We derive the emission measure as a function of temperature for a four component model that fits the line flux data. Using the density sensitive Si XIII triplet, the characteristic electron density is 1e14 cm^{-3}, where the gas temperature is about 1.3e7 K. Based on an adiabatic expansion model of the jet, the electron densities drop from ~2e15 to 4e13 cm^{-3} at distances of 2e10 to 2e11 cm from the apex of the jet cone. The jet mass outflow rate is 1.5e-7 Msun / yr. The kinetic power is 3.2e38 erg/s, which is x1000 larger than the unabsorbed 2-10 keV X-ray luminosity. The bremsstrahlung emission associated with the lines can account for the entire continuum; we see no direct evidence for an accretion disk. The image from zeroth order shows extended emission at a scale of ~2", aligned in the general direction of the radio jets.Comment: 28 pages, 12 figures (1, 4, 5, and 6 are color), to appear in the Astrophysical Journa

Self-folding with shape memory composites

Origami-inspired manufacturing can produce complex structures and machines by folding two-dimensional composites into three-dimensional structures. This fabrication technique is potentially less expensive, faster, and easier to transport than more traditional machining methods, including 3-D printing. Self-folding enhances this method by minimizing the manual labor involved in folding, allowing for complex geometries and enabling remote or automated assembly. This paper demonstrates a novel method of self-folding hinges using shape memory polymers (SMPs), paper, and resistive circuits to achieve localized and individually addressable folding at low cost. A model for the torque exerted by these composites was developed and validated against experimental data, in order to determine design rules for selecting materials and designing hinges. Torque was shown to increase with SMP thickness, resistive circuit width, and supplied electrical current. This technique was shown to be capable of complex geometries, as well as locking assemblies with sequential folds. Its functionality and low cost make it an ideal basis for a new type of printable manufacturing based on two-dimensional fabrication techniques.National Science Foundation (U.S.) (award number CCF-1138967)National Science Foundation (U.S.) (award number EFRI-1240383

Immunomodulatory drugs in sepsis: a systematic review and meta-analysis

\ua9 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. Dysregulation of the host immune response has a central role in the pathophysiology of sepsis. There has been much interest in immunomodulatory drugs as potential therapeutic adjuncts in sepsis. We conducted a systematic review and meta-analysis of randomised controlled trials evaluating the safety and clinical effectiveness of immunomodulatory drugs as adjuncts to standard care in the treatment of adults with sepsis. Our primary outcomes were serious adverse events and all-cause mortality. Fifty-six unique, eligible randomised controlled trials were identified, assessing a range of interventions including cytokine inhibitors; anti-inflammatories; immune cell stimulators; platelet pathway inhibitors; and complement inhibitors. At 1-month follow-up, the use of cytokine inhibitors was associated with a decreased risk of serious adverse events, based on 11 studies involving 7138 patients (RR (95%CI) 0.95 (0.90–1.00), I2 = 0%). The only immunomodulatory drugs associated with an increased risk of serious adverse events were toll-like receptor 4 antagonists (RR (95%CI) 1.18 (1.04–1.34), I2 = 0% (two trials, 567 patients)). Based on 18 randomised controlled trials, involving 11,075 patients, cytokine inhibitors reduced 1-month mortality (RR (95%CI) 0.88 (0.78–0.98), I2 = 57%). Mortality reduction was also shown in the subgroup of 13 randomised controlled trials that evaluated anti-tumour necrosis factor α interventions (RR (95%CI) 0.93 (0.87–0.99), I2 = 0%). Anti-inflammatory drugs had the largest apparent effect on mortality at 2 months at any dose (two trials, 228 patients, RR (95%CI) 0.64 (0.51–0.80), I2 = 0%) and at 3 months at any dose (three trials involving 277 patients, RR (95%CI) 0.67 (0.55–0.81), I2 = 0%). These data indicate that, except for toll-like receptor 4 antagonists, there is no evidence of safety concerns for the use of immunomodulatory drugs in sepsis, and they may show some short-term mortality benefit for selected drugs

Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients

Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OH-efavirenz) have not been robustly evaluated in older HIV-infected persons

Self-folding shape memory laminates for automated fabrication

Nature regularly uses self-folding as an efficient approach to automated fabrication. In engineered systems, however, the use of self-folding has been primarily restricted to the assembly of small structures using exotic materials and/or complex infrastructures. In this paper we present three approaches to the self-folding of structures using low-cost, rapid-prototyped shape memory laminates. These structures require minimal deployment infrastructure, and are activated by light, heat, or electricity. We compare the fabrication of a fundamental structure (a cube) using each approach, and test ways to control fold angles in each case. Finally, for each self-folding approach we present a unique structure that the approach is particularly suited to fold, and discuss the advantages and disadvantages of each approach.National Science Foundation (U.S.) (Award CCF-1138967)National Science Foundation (U.S.) (Award EFRI-1240383