Combined population genomic screening for three high-risk conditions in Australia: a modelling study

BACKGROUND: No previous health-economic evaluation has assessed the impact and cost-effectiveness of offering combined adult population genomic screening for mutliple high-risk conditions in a national public healthcare system. METHODS: This modeling study assessed the impact of offering combined genomic screening for hereditary breast and ovarian cancer, Lynch syndrome and familial hypercholesterolaemia to all young adults in Australia, compared with the current practice of clinical criteria-based testing for each condition separately. The intervention of genomic screening, assumed as an up-front single cost in the first annual model cycle, would detect pathogenic variants in seven high-risk genes. The simulated population was 18–40 year-olds (8,324,242 individuals), modelling per-sample test costs ranging AU$100–$1200 (base-case AU$200) from the year 2023 onwards with testing uptake of 50 FINDINGS: Over the population lifetime (to age 80 years), the model estimated that genomic screening per-100,000 individuals would lead to 747 QALYs gained by preventing 63 cancers, 31 CHD cases and 97 deaths. In the total model population, this would translate to 31,094 QALYs gained by preventing 2612 cancers, 542 non-fatal CHD events and 4047 total deaths. At AU$200 per-test, genomic screening would require an investment of AU$832 million for screening of 50$23,926 (∼£12,050/€14,110/US$15,345) per QALY gained over the status quo. In scenario analysis with 3$4758/QALY was obtained. Sensitivity analysis for the base case indicated that combined genomic screening would be cost-effective under 70% of simulations, cost-saving under 25% and not cost-effective under 5%. Threshold analysis showed that genomic screening would be cost-effective under the AU$50,000/QALY willingness-to-pay threshold at per-test costs up to AU$325 (∼£164/€192/US$208). INTERPRETATION: Our findings suggest that offering combined genomic screening for high-risk conditions to young adults would be cost-effective in the Australian public healthcare system, at currently realistic testing costs. Other matters, including psychosocial impacts, ethical and societal issues, and implementation challenges, also need consideration. FUNDING: Australian Government, Department of Health, Medical Research Future Fund, Genomics Health Futures Mission (APP2009024). National Heart Foundation Future Leader Fellowship (102604)

Acoustic cavitation in dual frequency ultrasound fields

© 2010 Dr. Adam Robert BrotchieMultiple frequency ultrasonic systems have become of interest in recent years in the context of scaling up and improving the efficiency of sonochemical reactors, having been found to offer certain advantages over single frequency systems. This thesis investigates dual frequency sound fields over a broad parameter space, addressing a large range of aspects of acoustic cavitation and the factors that influence these systems. Three different transducer types were employed: a low frequency sonotrode, a high frequency standing wave type transducer and a high intensity focused ultrasound (HIFU) transducer. The combination of two 20 kHz horns was found to be synergetic, with respect to sonoluminescence emission and sonochemical yields, only when the respective sizes of the two horns differed significantly, and the larger of the two horns was operated at low power and in a pulsed mode. The combination of a low frequency sonotrode with a HIFU field was highly synergistic under appropriate pulse and acoustic power conditions. This was attributed to cavitation fragments from the low frequency field providing a new source nuclei for cavitation in the HIFU cavitation zone. These results corroborate and extend upon those of previous reports, and are of relevance to the field of ultrasound lithotripsy. When a standing wave emitter was used in combination with the HIFU transducer, the reverse situation was observed, whereby HIFU cavitation stimulated cavitation in the standing wave field. This was only possible when the two frequencies were closely matched. A similar requirement was found for a system comprising two geometrically opposing standing wave emitters. It was proposed that this was due to the similar bubble active sizes rendering the stimulating mechanism more effective or due to more favourable superposition of the two sound waves with respect to bubble dynamics. For the combination of a sonotrode and standing wave system, it was found that considerable synergy (sonochemical and sonophysical) could be attained through pulsed, low power operation, and that this was further extended at low temperature, high viscosity and in the presence of coalescence inhibiting solutes. High-speed photographic observations demonstrated that the presence of the high frequency source stimulated cavitation in the vicinity of the low frequency sonotrode surface. This effect was more dramatic in the presence of coalescence inhibiting solutes. This can be ascribed to the existence of a much greater high frequency bubble population, which may act as cavitation nuclei under the horn, where the radial dynamics are dictated by the low frequency field. A combination of higher bubble density and the bubbles being driven relatively more asymmetrically and non-linearly in the dual frequency field led to a higher degree of fragmentation. The fragments of cavitation were able to (in the solute solutions) in turn, stimulate cavitation in the high frequency field, which was confirmed through analysis of the acoustic emission spectra. Sonochemical and sonoluminescence studies demonstrated a large synergy in these systems. Modelling of the radial bubble dynamics indicated that only at very low acoustic power can the combination of a high and low frequency source bring about a significant enhancement in collapse temperature. Experimental temperature determination, however, which represents a spatially and temporally averaged ‘chemical’ temperature, revealed that the collapse temperature was significantly lower than that measured during single frequency irradiation. This is likely due, at least in part, to bubbles being driven in a more asymmetric environment. This was substantiated by sonoluminescence spectra measured in the presence of sodium salts, which exhibited a much more prominent sodium emission line in the dual frequency system. Further, single bubble growth measurements indicated that dual frequency operation did not increase the rate of rectified diffusion, and actually suppressed it at elevated acoustic power, presumably because the bubbles were translocated away from the low frequency antinode. The bubble lifetime in the dual frequency field was calculated to be longer than those in either of the single frequency fields. It is plausible that this is due to a large number of bubbles pre-existing in the high frequency field prior to nucleation near the low frequency horn, extending their lifetime relative to single, low frequency sonication. Despite the fact that growth was retarded in the single bubble system, it is unclear to what extent rectified diffusion is affected in the multi-bubble field. Irrespective of the mechanism, the longer lifetime in the dual frequency field is consistent with the lower collapse temperature measured and with SL quenching studies. Bubble size distributions were determined using a pulsed ultrasound method and were found to be affected strongly by the driving frequency, acoustic power, pulse width and dissolved gas concentration. The inverse dependence of the bubble size on the driving frequency is consistent with linear resonance theory and the main implication of the studies with power, pulse duration and gas concentration is that bubble-bubble coalescence is the major determinant of the bubble size at a given frequency. Another important outcome of this investigation is that the coalescence inhibitive effect of simple electrolytes, a highly contentious issue, can be completely attributed to their effect on the dissolved gas concentration

Sonochemiluminescence from a Single Cavitation Bubble in Water

International audienceSingle bubble feels the pressure: Sonochemical luminescence has been detected in a single‐cavitation bubble within a narrow pressure domain below the sonoluminescence threshold. The parameter space of single‐bubble sonochemistry is distinct from that of single‐bubble atomic and molecular line emissions

Micropatterning for the Control of Surface Cavitation: Visualization through High-Speed Imaging

For the first time, we apply a high-speed imaging technique to record the activity of acoustically driven cavitation bubbles (86 kHz) on micropatterned surfaces with hydrophobic and hydrophilic stripes. The width of the hydrophobic stripes lies between 3.5 and 115 μm. This work provides the first direct visualization of the preferential location of bubbles on the hydrophobic areas of the patterns. The results confirm our previous prediction that surface cavitation strongly depends on the surface energy of the irradiated substrate. The observations show a remarkable effect of the stripe width on the size, movement, growth, splitting, and multiplying of the bubbles. The high-speed imaging also reveals that there is a minimal width of the hydrophobic stripes that allows bubble attraction and formation. Our observations are supported by a theoretical approach based on the forces acting on the bubbles

Ultrasonic Modification of Aluminum Surfaces: Comparison between Thermal and Ultrasonic Effects.

Ultrasound has become an increasingly popular tool in the modification of metal surfaces, imbuing them with various desired characteristics and functionalities. The exact role played by ultrasound in such processes remains largely speculative and thus requires clarification. In this study, aluminum was taken as a model metal to probe the nature of the surface modification, focusing on both chemical and physical changes. Using metal plates as substrates, the formation of a characteristic porous surface structure was ascertained to arise from a purely thermal mechanism, with the ultrasound providing an inhibitory influence when compared with controlled experiments matching the thermal conditions of sonication. No beneficial effect was observed through sonication, with regards to surface texture, porosity, and electrochemistry. However, for metal powders, a pronounced change in the phase composition was observed following ultrasonic exposure, largely attributed to the growth of bayerite from the surface. The immobilization of the powder on a thin epoxy film nullified such effects. This suggests that the changes in phase composition are due to the effect of ultrasound-induced mechanical stirring and high speed particle motion on the dissolution and reprecipitation of the metal oxide and hydrated oxide species. This work is of significant value to researchers both in materials science and in sonochemistry

Optimal Balance of the Striatal Medium Spiny Neuron Network

<div><p>Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics – it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.</p> </div