Antibiotic Cycling and Antibiotic Mixing: which one best mitigates antibiotic resistance?

Published onlineJournal ArticleThis is the final version of the article. Available from Oxford University Press via the DOI in this record.Can we exploit our burgeoning understanding of molecular evolution to slow the progress of drug resistance? One role of an infection clinician is exactly that: to foresee trajectories to resistance during antibiotic treatment and to hinder that evolutionary course. But can this be done at a hospital-wide scale? Clinicians and theoreticians tried to when they proposed two conicting behavioural strategies that are expected to curb resistance evolution in the clinic, these are known as 'antibiotic cycling' and 'antibiotic mixing'. However, the accumulated data from clinical trials, now approaching 4 million patient days of treatment, is too variable for cycling or mixing to be deemed successful. The former implements the restriction and prioritisation of di_erent antibiotics at di_erent times in hospitals in a manner said to 'cycle' between them. In antibiotic mixing, appropriate antibiotics are allocated to patients but randomly.Mixing results in no correlation, in time or across patients, in the drugs used for treatment which is why theorists saw this as an optimal behavioural strategy. So while cycling and mixing were proposed as ways of controlling evolution, we show there is good reason why clinical datasets cannot choose between them: by re-examining the theoretical literature we show prior support for the theoretical optimality of mixing was misplaced. Our analysis is consistent with a pattern emerging in data: neither cycling or mixing is a priori better than the other at mitigating selection for antibiotic resistance in the clinic.REB was funded during this work by an MRC Discipline Hopping Fellowship G0802611, RPM was funded by a Conacyt PhD award, all authors were supported by EPSRC grant EP/I00503X/1 (grant holder REB)

Evaluating the Microsoft HoloLens through an augmented reality assembly application

Industry and academia have repeatedly demonstrated the transformative potential of Augmented Reality (AR) guided assembly instructions. In the past, however, computational and hardware limitations often dictated that these systems were deployed on tablets or other cumbersome devices. Often, tablets impede worker progress by diverting a user\u27s hands and attention, forcing them to alternate between the instructions and the assembly process. Head Mounted Displays (HMDs) overcome those diversions by allowing users to view the instructions in a hands-free manner while simultaneously performing an assembly operation. Thanks to rapid technological advances, wireless commodity AR HMDs are becoming commercially available. Specifically, the pioneering Microsoft HoloLens, provides an opportunity to explore a hands-free HMD’s ability to deliver AR assembly instructions and what a user interface looks like for such an application. Such an exploration is necessary because it is not certain how previous research on user interfaces will transfer to the HoloLens or other new commodity HMDs. In addition, while new HMD technology is promising, its ability to deliver a robust AR assembly experience is still unknown. To assess the HoloLens’ potential for delivering AR assembly instructions, the cross-platform Unity 3D game engine was used to build a proof of concept application. Features focused upon when building the prototype were: user interfaces, dynamic 3D assembly instructions, and spatially registered content placement. The research showed that while the HoloLens is a promising system, there are still areas that require improvement, such as tracking accuracy, before the device is ready for deployment in a factory assembly setting

Thickness dependent magnetic anisotropy of ultrathin LCMO epitaxial thin films

The magnetic properties of La0.7Ca0.3MnO3 (LCMO) manganite thin films were studied with magnetometry and ferromagnetic resonance as a function of film thickness. They maintain the colossal magnetoresistance behavior with a pronounced metal-insulator transition around 150-200 K, except for the very thinnest films studied (3 nm). Nevertheless, LCMO films as thin as 3 nm remain ferromagnetic, without a decrease in saturation magnetization, indicating an absence of dead-layers, although below approx. 6 nm the films remain insulating at low temperature. Magnetization hysteresis loops reveal that the magnetic easy axes lie in the plane of the film for thicknesses in the range of 4-15 nm. Ferromagnetic resonance studies confirm that the easy axes are in-plane, and find a biaxial symmetry in-plane with two, perpendicular easy axes. The directions of the easy axes with respect to the crystallographic directions of the cubic SrTiO3 substrate differ by 45 degrees in 4 nm and 15 nm thick LCMO films.Comment: Presented at Intermag conference (Madrid, 2008). Accepted for publication in IEEE Transactions on Magnetic

When the most potent combination of antibiotics selects for the greatest bacterial load: the Smile-Frown transition

Final published PDF version of article deposited in accordance with SHERPA RoMEO guidelinesConventional wisdom holds that the best way to treat infection with antibiotics is to ‘hit early and hit hard’. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathematical modelling, evolution experiments, whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution experiments. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly-aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region containing four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution experiment repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concentrations

Voltage based current compensation converter control for power electronic interfaced distribution networks in future aircraft

Superconductors have a potential application in future turboelectric distributed propulsion (TeDP) aircraft and present significant new challenges for protection system design. Electrical faults and cooling system failures can lead to temperature rises within a superconducting distribution network, which necessitates a reduction or temporary curtailment of current to loads to prevent thermal runaway occurring within the cables. This scenario is undesirable in TeDP aircraft applications where the loads may be flight-critical propulsion motors. This article proposes a power management and control method that exploits the fast-acting measurement and response capabilities of the power electronic interfaces within the distribution network to maximize current supply to critical loads, reducing the impact of a temperature rise event in the superconducting distribution network. This new algorithm uses the detection of a resistive voltage in combination with a model-based controller that estimates the operating temperature of the affected superconducting cable to adapt the output current limit of the associated power electronic converter. To demonstrate the effectiveness of this method and its impact on wider system stability, the algorithm is applied to a simulated voltage-source converter supplied aircraft dc superconducting distribution network with representative propulsion motor loads

To Bt or Not to Bt? Balancing Spatial Genetic Heterogeneity to Control the Evolution of Ostrinia nubilalis

24 pages, 1 article*To Bt or Not to Bt? Balancing Spatial Genetic Heterogeneity to Control the Evolution of Ostrinia nubilalis* (Miller, Conrad; Munoz, Andres; Pena, Fernando; Rael, Rosalyn; Yakubu, Abdul-Aziz) 24 page

Evaluation of Wing Load Calibration and Sensing Methods Using Conventional Strain Gages and a Fiber Optic Sensing System Installed on a Straight Tapered Wing

This presentation presents the results from a wing load test in the FLL (Flight Loads Lab). Load calibration techniques for strain gages and fiber optics were compared and contrasted. This presentation has the potential to lead to more research testing at NASA Armstrong in the areas of load calibration technology