Macro- and micronutrient disposition in an ex vivo model of extracorporeal membrane oxygenation

Background Extracorporeal membrane oxygenation (ECMO) circuits have been shown to sequester circulating blood compounds such as drugs based on their physicochemical properties. This study aimed to describe the disposition of macro- and micronutrients in simulated ECMO circuits. Methods Following baseline sampling, known quantities of macro- and micronutrients were injected post oxygenator into ex vivo ECMO circuits primed with the fresh human whole blood and maintained under standard physiologic conditions. Serial blood samples were then obtained at 1, 30 and 60 min and at 6, 12 and 24 h after the addition of nutrients, to measure the concentrations of study compounds using validated assays. Results Twenty-one samples were tested for thirty-one nutrient compounds. There were significant reductions (p < 0.05) in circuit concentrations of some amino acids [alanine (10%), arginine (95%), cysteine (14%), glutamine (25%) and isoleucine (7%)], vitamins [A (42%) and E (6%)] and glucose (42%) over 24 h. Significant increases in circuit concentrations (p < 0.05) were observed over time for many amino acids, zinc and vitamin C. There were no significant reductions in total proteins, triglycerides, total cholesterol, selenium, copper, manganese and vitamin D concentrations within the ECMO circuit over a 24-h period. No clear correlation could be established between physicochemical properties and circuit behaviour of tested nutrients. Conclusions Significant alterations in macro- and micronutrient concentrations were observed in this single-dose ex vivo circuit study. Most significantly, there is potential for circuit loss of essential amino acid isoleucine and lipid soluble vitamins (A and E) in the ECMO circuit, and the mechanisms for this need further exploration. While the reductions in glucose concentrations and an increase in other macro- and micronutrient concentrations probably reflect cellular metabolism and breakdown, the decrement in arginine and glutamine concentrations may be attributed to their enzymatic conversion to ornithine and glutamate, respectively. While the results are generally reassuring from a macronutrient perspective, prospective studies in clinical subjects are indicated to further evaluate the influence of ECMO circuit on micronutrient concentrations and clinical outcomes.

Understanding PK/PD

Pharmacology is the science underpinning dosing, mechanisms of action and effectiveness of drugs. Central to pharmacology, are the studies of pharmacokinetics (PK) and pharmacodynamics (PD). On one hand, PK defines the time-course of drug concentrations in the body and incorporates the broad concepts of drug absorption, distribution, metabolism and elimination. On the other hand, PD describes the relationship between drug concentrations and pharmacological effects. In practice, PK is often referred as “what the body does to the drug” whilst PD as “what the drug does to the body”. Thus, PK/PD describes the relationship between drug dose and pharmacological effects with changes in drug concentrations leading to different pharmacological effects.

Experimental Infection of Culex Annulirostris, Culex Gelidus, and Aedes Vigilax With a Yellow Fever/Japanese Encephalitis Virus Vaccine Chimera (Chimerivax TM-JE)

Australian mosquitoes from which Japanese encephalitis virus (JEV) has been recovered (Culex annulirostris, Culex gelidus, and Aedes vigilax) were assessed for their ability to be infected with the ChimeriVax-JE vaccine, with yellow fever vaccine virus 17D (YF 17D) from which the backbone of ChimeriVax-JE vaccine is derived and with JEV-Nakayama. None of the mosquitoes became infected after being fed orally with 6.1 log(10) plaque-forming units (PFU)/mL of ChimeriVax-JE vaccine, which is greater than the peak viremia in vaccinees (mean peak viremia = 4.8 PFU/mL, range = 0-30 PFU/mL of 0.9 days mean duration, range = 0-11 days). Some members of all three species of mosquito became infected when fed on JEV-Nakayama, but only Ae. vigilax was infected when fed on YF 17D. The results suggest that none of these three species of mosquito are likely to set up secondary cycles of transmission of ChimeriVax-JE in Australia after feeding on a viremic vaccinee.

Experimental and computer simulation validation of ultrasound phase interference created by lateral inhomogeneity of transit time in replica bone marrow composite models

Purpose: The measurement of broadband ultrasonic attenuation (BUA) in cancellous bone for the assessment of osteoporosis follows a parabolic-type dependence with bone volume fraction; having minima values corresponding to both entire bone and entire marrow. Langton has recently proposed that the primary BUA mechanism may be significant phase interference due to variations in propagation transit time through the test sample as detected over the phase-sensitive surface of the receive ultrasound transducer. This fundamentally simple concept assumes that the propagation of ultrasound through a complex solid : liquid composite sample such as cancellous bone may be considered by an array of parallel ‘sonic rays’. The transit time of each ray is defined by the proportion of bone and marrow propagated, being a minimum (tmin) solely through bone and a maximum (tmax) solely through marrow. A Transit Time Spectrum (TTS), ranging from tmin to tmax, may be defined describing the proportion of sonic rays having a particular transit time, effectively describing lateral inhomogeneity of transit time over the surface of the receive ultrasound transducer. Phase interference may result from interaction of ‘sonic rays’ of differing transit times. The aim of this study was to test the hypothesis that there is a dependence of phase interference upon the lateral inhomogenity of transit time by comparing experimental measurements and computer simulation predictions of ultrasound propagation through a range of relatively simplistic solid:liquid models exhibiting a range of lateral inhomogeneities. Methods: A range of test models was manufactured using acrylic and water as surrogates for bone and marrow respectively. The models varied in thickness in one dimension normal to the direction of propagation, hence exhibiting a range of transit time lateral inhomogeneities, ranging from minimal (single transit time) to maximal (wedge; ultimately the limiting case where each sonic ray has a unique transit time). For the experimental component of the study, two unfocused 1 MHz ¾” broadband diameter transducers were utilized in transmission mode; ultrasound signals were recorded for each of the models. The computer simulation was performed with Matlab, where the transit time and relative amplitude of each sonic ray was calculated. The transit time for each sonic ray was defined as the sum of transit times through acrylic and water components. The relative amplitude considered the reception area for each sonic ray along with absorption in the acrylic. To replicate phase-sensitive detection, all sonic rays were summed and the output signal plotted in comparison with the experimentally derived output signal. Results: From qualtitative and quantitative comparison of the experimental and computer simulation results, there is an extremely high degree of agreement of 94.2% to 99.0% between the two approaches, supporting the concept that propagation of an ultrasound wave, for the models considered, may be approximated by a parallel sonic ray model where the transit time of each ray is defined by the proportion of ‘bone’ and ‘marrow’. Conclusions: This combined experimental and computer simulation study has successfully demonstrated that lateral inhomogeneity of transit time has significant potential for phase interference to occur if a phase-sensitive ultrasound receive transducer is implemented as in most commercial ultrasound bone analysis devices.

An experimental approach to air gap optimisation for a correction-less small field diode

Aim A recent Monte Carlo based study has shown that it is possible to design a diode that measures small field output factors equivalent to that in water. This is accomplished by placing an appropriate sized air gap above the silicon chip (1) with experimental results subsequently confirming that a particular Monte Carlo design was accurate (2). The aim of this work was to test if a new correction-less diode could be designed using an entirely experimental methodology. Method: All measurements were performed on a Varian iX at a depth of 5 cm, SSD of 95 cm and field sizes of 5, 6, 8, 10, 20 and 30 mm. Firstly, the experimental transfer of kq,clin,kq,msr from a commonly used diode detector (IBA, stereotactic field diode (SFD)) to another diode detector (Sun Nuclear, unshielded diode, (EDGEe)) was tested. These results were compared to Monte Carlo calculated values of the EDGEe. Secondly, the air gap above the EDGEe silicon chip was optimised empirically. Nine different air gap “tops” were placed above the EDGEe (air depth = 0.3, 0.6, 0.9 mm; air width = 3.06, 4.59, 6.13 mm). The sensitivity of the EDGEe was plotted as a function of air gap thickness for the field sizes measured. Results: The transfer of kq,clin,kq,msr from the SFD to the EDGEe was correct to within the simulation and measurement uncertainties. The EDGEe detector can be made “correction-less” for field sizes of 5 and 6 mm, but was ∼2% from being “correction-less” at field sizes of 8 and 10 mm. Conclusion Different materials will perturb small fields in different ways. A detector is only “correction-less” if all these perturbations happen to cancel out. Designing a “correction-less” diode is a complicated process, thus it is reasonable to expect that Monte Carlo simulations should play an important role.

Design and experimental testing of air slab caps which convert commercial electron diodes into dual purpose, correction-free diodes for small field dosimetry

Purpose Two diodes which do not require correction factors for small field relative output measurements are designed and validated using experimental methodology. This was achieved by adding an air layer above the active volume of the diode detectors, which canceled out the increase in response of the diodes in small fields relative to standard field sizes. Methods Due to the increased density of silicon and other components within a diode, additional electrons are created. In very small fields, a very small air gap acts as an effective filter of electrons with a high angle of incidence. The aim was to design a diode that balanced these perturbations to give a response similar to a water-only geometry. Three thicknesses of air were placed at the proximal end of a PTW 60017 electron diode (PTWe) using an adjustable “air cap”. A set of output ratios (ORfclin Det ) for square field sizes of side length down to 5 mm was measured using each air thickness and compared to ORfclin Det measured using an IBA stereotactic field diode (SFD). k fclin, f msr Qclin,Qmsr was transferred from the SFD to the PTWe diode and plotted as a function of air gap thickness for each field size. This enabled the optimal air gap thickness to be obtained by observing which thickness of air was required such that k fclin, f msr Qclin,Qmsr was equal to 1.00 at all field sizes. A similar procedure was used to find the optimal air thickness required to make a modified Sun Nuclear EDGE detector (EDGEe) which s “correction-free” in small field relative dosimetry. In addition, the feasibility of experimentally transferring k fclin, f msr Qclin,Qmsr values from the SFD to unknown diodes was tested by comparing the experimentally transferred k fclin, f msr Qclin,Qmsr values for unmodified PTWe and EDGEe diodes to Monte Carlo simulated values. Results 1.0 mm of air was required to make the PTWe diode correction-free. This modified diode (PTWeair) produced output factors equivalent to those in water at all field sizes (5–50 mm). The optimal air thickness required for the EDGEe diode was found to be 0.6 mm. The modified diode (EDGEeair) produced output factors equivalent to those in water, except at field sizes of 8 and 10 mm where it measured approximately 2% greater than the relative dose to water. The experimentally calculated k fclin, f msr Qclin,Qmsr for both the PTWe and the EDGEe diodes (without air) matched Monte Carlo simulated results, thus proving that it is feasible to transfer k fclin, f msr Qclin,Qmsr from one commercially available detector to another using experimental methods and the recommended experimental setup. Conclusions It is possible to create a diode which does not require corrections for small field output factor measurements. This has been performed and verified experimentally. The ability of a detector to be “correction-free” depends strongly on its design and composition. A nonwater-equivalent detector can only be “correction-free” if competing perturbations of the beam cancel out at all field sizes. This should not be confused with true water equivalency of a detector.

Contributions to Bayesian experimental design

This thesis progresses Bayesian experimental design by developing novel methodologies and extensions to existing algorithms. Through these advancements, this thesis provides solutions to several important and complex experimental design problems, many of which have applications in biology and medicine. This thesis consists of a series of published and submitted papers. In the first paper, we provide a comprehensive literature review on Bayesian design. In the second paper, we discuss methods which may be used to solve design problems in which one is interested in finding a large number of (near) optimal design points. The third paper presents methods for finding fully Bayesian experimental designs for nonlinear mixed effects models, and the fourth paper investigates methods to rapidly approximate the posterior distribution for use in Bayesian utility functions.

Do we need a law to help people try experimental drugs?

People with life-threatening or incurable diseases may be willing to try experimental drugs and unproven treatments, but they face the risk of exploitation. Is the law the best avenue to ensure that they are protected while medical innovation is encouraged? Protection of vulnerable people is a thread running through many laws, in Australia and elsewhere. In medical law, for instance, children and people with impaired decision-making capacity warrant special attention. But what of the ordinary person diagnosed with a life-threatening disease? Such people are vulnerable to harm and potential exploitation when they seek access to innovative, experimental or unproven treatments that depart from the existing range of accepted medicine.

An experimental study on anisotropic mechanical properties of porcine thoracic aorta

Objective: To study the anisotropic mechanical properties of the thoracic aorta in porcine. Methods: Twenty-one porcine thoracic aortas were collected and categorized into three groups. The aortas were then cut through in their axial directions and expanded into two-dimensional planes. Then, by setting the length direction of the planar aortas (i.e., axial directions of the aortas) as 0°, each planar aorta was counterclockwisely cut into 8 samples with orientation of 30°, 45°, 60°, 90°, 120°, 135°, 150° and 180°, respectively. Finally, the uniaxial tensile tests were applied on three groups of samples at the loading rates of 1, 5 and 10 mm/min, respectively, to obtain the elastic modulus and ultimate stress of the aorta in different directions and at different loading rates. Results: The stress-strain curves exhibited different viscoelastic behaviors. With the increase of sample orientations, the elastic modulus gradually increased from 30°, reached the maximum value at 90°, and then gradually decreased till 180°. The variation trend of ultimate stress was similar to that of elastic modulus. Moreover, different loading rates showed a significant influence on the results of elastic modulus and ultimate stress, but a weak influence on the anisotropic degree. Conclusions: The porcine thoracic aorta is highly anisotropic. This research finding provides parameter references for assignment of material properties in finite element modeling, and is significant for understanding biomechanical properties of the arteries.

Pulse-echo ultrasound transit time spectroscopy: A comparison of experimental measurements and simulation prediction

Considering ultrasound propagation through complex composite media as an array of parallel sonic rays, a comparison of computer simulated prediction with experimental data has previously been reported for transmission mode (where one transducer serves as transmitter, the other as receiver) in a series of ten acrylic step-wedge samples, immersed in water, exhibiting varying degrees of transit time inhomogeneity. In this study, the same samples were used but in pulse-echo mode, where the same ultrasound transducer served as both transmitter and receiver, detecting both ‘primary’ (internal sample interface) and ‘secondary’ (external sample interface) echoes. A transit time spectrum (TTS) was derived, describing the proportion of sonic rays with a particular transit time. A computer simulation was performed to predict the transit time and amplitude of various echoes created, and compared with experimental data. Applying an amplitude-tolerance analysis, 91.7±3.7% of the simulated data was within ±1 standard deviation (STD) of the experimentally measured amplitude-time data. Correlation of predicted and experimental transit time spectra provided coefficients of determination (R2) ranging from 100.0% to 96.8% for the various samples tested. The results acquired from this study provide good evidence for the concept of parallel sonic rays. Further, deconvolution of experimental input and output signals has been shown to provide an effective method to identify echoes otherwise lost due to phase cancellation. Potential applications of pulse-echo ultrasound transit time spectroscopy (PE-UTTS) include improvement of ultrasound image fidelity by improving spatial resolution and reducing phase interference artefacts.