Computation of ultrasound propagation in a population of nonlinearly oscillating microbubbles including multiple scattering.

In contrast-enhanced echography, the simulation of nonlinear propagation of ultrasound through a population of oscillating microbubbles imposes a computational challenge. Also, the numerical complexity increases because each scatterer has individual properties. To address these problems, the Iterative Nonlinear Contrast Source (INCS) method has been extended to include a large population of nonlinearly responding microbubbles. The original INCS method solves the Westervelt equation in a four-dimensional spatiotemporal domain by generating increasingly accurate field corrections to iteratively update the acoustic pressure. The field corrections are computed by the convolution of a nonlinear contrast source with the Green's function of the linear background medium. Because the convolution integral allows a coarse discretization, INCS can efficiently deal with large-scale problems. To include a population of microbubbles, these are considered as individual contrast point sources with their own nonlinear response. The field corrections are computed as before, but now, in each iteration, the temporal signature of each contrast point source is computed by solving the bubble's Marmottant equation. Physically, each iteration adds an order of multiple scattering. Here, the performance of the extended INCS method and the significance of multiple scattering is demonstrated through various results from different configurations.

A spatial and temporal characterisation of single proton acoustic waves in proton beam cancer therapy.

An in vivo range verification technology for proton beam cancer therapy, preferably in real-time and with submillimeter resolution, is desired to reduce the present uncertainty in dose localization. Acoustical imaging technologies exploiting possible local interactions between protons and microbubbles or nanodroplets might be an interesting option. Unfortunately, a theoretical model capable of characterising the acoustical field generated by an individual proton on nanometer and micrometer scales is still missing. In this work, such a model is presented. The proton acoustic field is generated by the adiabatic expansion of a region that is locally heated by a passing proton. To model the proton heat deposition, secondary electron production due to protons has been quantified using a semi-empirical model based on Rutherford's scattering theory, which reproduces experimentally obtained electronic stopping power values for protons in water within 10% over the full energy range. The electrons transfer energy into heat via electron-phonon coupling to atoms along the proton track. The resulting temperature increase is calculated using an inelastic thermal spike model. Heat deposition can be regarded as instantaneous, thus, stress confinement is ensured and acoustical initial conditions are set. The resulting thermoacoustic field in the nanometer and micrometer range from the single proton track is computed by solving the thermoacoustic wave equation using k-space Green's functions, yielding the characteristic amplitudes and frequencies present in the acoustic signal generated by a single proton in an aqueous medium. Wavefield expansion and asymptotic approximations are used to extend the spatial and temporal ranges of the proton acoustic field.

Error analysis and reliability of zero-order Lamb mode inversion for waveguide characterization.

In recent years, several fitting techniques have been presented to reconstruct the parameters of a plate from its Lamb wave dispersion curves. Published studies show that these techniques can yield high accuracy results and have the potential of reconstructing several parameters at once. The precision with which parameters can be reconstructed by inverting Lamb wave dispersion curves, however, remains an open question of fundamental importance to many applications. In this work, we introduce a method of analyzing dispersion curves that yields quantitative information on the precision with which the parameters can be extracted. In our method, rather than employing error minimization algorithms, we compare a target dispersion curve to a database of theoretical ones that covers a given parameter space. By calculating a measure of dissimilarity (error) for every point in the parameter space, we reconstruct the distribution of the error in that space, beside the location of its minimum. We then introduce dimensionless quantities that describe the distribution of this error, thus yielding information about the spread of similar curves in the parameter space. We demonstrate our approach by considering both idealized and realistic scenarios, analyzing the dispersion curves obtained numerically for a plate and experimentally for a pipe. Our results show that the precision with which each parameter is reconstructed depends on the mode used, as well as the frequency range in which it is considered.

Tapering of the interventricular septum can affect ultrasound shear wave elastography: An in vitro and in silico study.

Shear wave elastography (SWE) has the potential to determine cardiac tissue stiffness from non-invasive shear wave speed measurements, important, e.g., for predicting heart failure. Previous studies showed that waves traveling in the interventricular septum (IVS) may display Lamb-like dispersive behaviour, introducing a thickness-frequency dependency in the wave speed. However, the IVS tapers across its length, which complicates wave speed estimation by introducing an additional variable to account for. The goal of this work is to assess the impact of tapering thickness on SWE. The investigation is performed by combining in vitro experiments with acoustic radiation force (ARF) and 2D finite element simulations, to isolate the effect of the tapering curve on ARF-induced and natural waves in the heart. The experiments show a 11% deceleration during propagation from the thick to the thin end of an IVS-mimicking tapered phantom plate. The numerical analysis shows that neglecting the thickness variation in the wavenumber-frequency domain can introduce errors of more than 30% in the estimation of the shear modulus, and that the exact tapering curve, rather than the overall thickness reduction, determines the dispersive behaviour of the wave. These results suggest that septal geometry should be accounted for when deriving cardiac stiffness with SWE.

Fundamental modeling of wave propagation in temporally relaxing media with applications to cardiac shear wave elastography.

Shear wave elastography (SWE) might allow non-invasive assessment of cardiac stiffness by relating shear wave propagation speed to material properties. However, after aortic valve closure, when natural shear waves occur in the septal wall, the stiffness of the muscle decreases significantly, and the effects of such temporal variation of medium properties on shear wave propagation have not been investigated yet. The goal of this work is to fundamentally investigate these effects. To this aim, qualitative results were first obtained experimentally using a mechanical setup, and were then combined with quantitative results from finite difference simulations. The results show that the amplitude and period of the waves increase during propagation, proportional to the relaxation of the medium, and that reflected waves can originate from the temporal stiffness variation. These general results, applied to literature data on cardiac stiffness throughout the heart cycle, predict as a major effect a period increase of 20% in waves propagating during a healthy diastolic phase, whereas only a 10% increase would result from the impaired relaxation of an infarcted heart. Therefore, cardiac relaxation can affect the propagation of waves used for SWE measurements and might even provide direct information on the correct relaxation of a heart.

[Ethically responsible care for MDRO carriers]. / Ethisch verantwoorde zorg voor BRMO-dragers.

Dutch healthcare institutions are relatively successful in preventing outbreaks of antibiotic-resistant pathogens, thus protecting vulnerable patients. However, measures taken to prevent the introduction and spread of MDROs can be burdensome for asymptomatic carriers of such bacteria or for people who may have been exposed to them. This leads to ethical dilemmas. On the basis of a study of the impact of being a carrier and precautionary measures on carrier well-being, we present an ethical framework for responsible care for carriers. We argue that solidarity requires that the burden of prevention and control of resistance is to be shouldered by society as a whole. It is not right to see this problem primarily as a conflict between the protection of vulnerable patients on the one hand and carriers on the other.

Experiences of carriers of multidrug-resistant organisms: a systematic review.

OBJECTIVES: A comprehensive overview of the ways control measures directed at carriers of multidrug-resistant organisms (MDRO) affect daily life of carriers is lacking. In this systematic literature review, we sought to explore how carriers experience being a carrier and how they experience being subjected to control measures by looking at the impact on basic capabilities. METHODS: We searched Medline, Embase and PsychINFO until 26 May 2016 for studies addressing experiences of MDRO carriers. Twenty-seven studies were included, addressing experiences with methicillin-resistant Staphylococcus aureus (n = 21), ESBL (n = 1), multiple MDRO (n = 4) and other (n = 1, not specified). We categorized reported experiences according to Nussbaum's capability approach. RESULTS: Carriage and control measures were found to interfere with quality of care, cause negative emotions, limit interactions with loved ones, cause stigmatization, limit recreational activities and create financial and professional insecurity. Further, carriers have difficulties with full comprehension of the problem of antimicrobial resistance, thus affecting six out of ten basic capabilities. CONCLUSIONS: Applying Nussbaum's capability approach visualizes an array of unintended consequences of control measures. Carriers experience stigmatization, especially in healthcare settings, and have limited understanding of their situation and the complexities of antimicrobial resistance.

Multiline 3D beamforming using micro-beamformed datasets for pediatric transesophageal echocardiography.

Until now, no matrix transducer has been realized for 3D transesophageal echocardiography (TEE) in pediatric patients. In 3D TEE with a matrix transducer, the biggest challenges are to connect a large number of elements to a standard ultrasound system, and to achieve a high volume rate (>200 Hz). To address these issues, we have recently developed a prototype miniaturized matrix transducer for pediatric patients with micro-beamforming and a small central transmitter. In this paper we propose two multiline parallel 3D beamforming techniques (µBF25 and µBF169) using the micro-beamformed datasets from 25 and 169 transmit events to achieve volume rates of 300 Hz and 44 Hz, respectively. Both the realizations use angle-weighted combination of the neighboring overlapping sub-volumes to avoid artifacts due to sharp intensity changes introduced by parallel beamforming. In simulation, the image quality in terms of the width of the point spread function (PSF), lateral shift invariance and mean clutter level for volumes produced by µBF25 and µBF169 are similar to the idealized beamforming using a conventional single-line acquisition with a fully-sampled matrix transducer (FS4k, 4225 transmit events). For completeness, we also investigated a 9 transmit-scheme (3 × 3) that allows even higher frame rates but found worse B-mode image quality with our probe. The simulations were experimentally verified by acquiring the µBF datasets from the prototype using a Verasonics V1 research ultrasound system. For both µBF169 and µBF25, the experimental PSFs were similar to the simulated PSFs, but in the experimental PSFs, the clutter level was ~10 dB higher. Results indicate that the proposed multiline 3D beamforming techniques with the prototype matrix transducer are promising candidates for real-time pediatric 3D TEE.

Are there ethical differences between stopping and not starting blood safety measures?

BACKGROUND AND OBJECTIVES: Concern with the costs of blood safety is growing, which raises the question whether safety measures that reduce risk only marginally should be discontinued. Withdrawing such safety measures would allow reallocating resources to more efficient health care interventions, but it might raise moral objections. MATERIALS AND METHODS: This study evaluates two ethical arguments why discontinuing blood safety measures would be more objectionable than not implementing them. The first argument is that whereas withdrawing protective measures causes harm to patients, not starting protective measures 'merely' omits to prevent harm. The second argument is that patients who benefit from protective measures are historically entitled to the continuation of those protective measures. RESULTS: Both arguments are unconvincing. There is only a weak causal connection between removing blood safety measures and harms that transfusion recipients suffer. Moreover, patients are not entitled to the continuation of protective measures that prove very inefficient, unless applying these protective measures rectifies past injustice towards them. CONCLUSION: Unless stronger ethical objections can be found, blood system operators and regulators should be more willing to withdraw inefficient safety measures.

[Active anti-smoking policy is a moral duty of government; responsibility for reducing smoking lies with both the individual and society]. / Actief antirookbeleid is morele taak van overheid.

Tobacco discouragement, smoking cessation and tobacco endgame policies are sometimes criticised for being unduly paternalistic: governments should respect citizens' freedom and not take over their individual responsibility for healthy behaviour. In this commentary, I argue that very strict tobacco policies can be justified on multiple grounds, including the harm principle, the public good of maintaining a healthy society, and the reduction of health inequities. The moral reasons governments have to protect people against the harms of smoking do not limit or infringe upon the responsibility of each individual to take care of her own health: responsibility for healthy behaviour is not a zero-sum game.

Using typing techniques in a specific outbreak: the ethical reflection of public health professionals.

Typing techniques are laboratory methods used in outbreak management to investigate the degree to which microbes found within an outbreak are related. Knowledge about relational patterns between microbes benefits outbreak management, but inevitably also tells us something about the relational patterns of the people hosting them. Since the technique is often used without explicit consent of all individuals involved, this may raise ethical questions. The aim of this study was to unravel the complex ethical deliberation of professionals over the use of such techniques. We organised group discussions (n = 3) with Dutch outbreak managers (n = 23). The topic list was based on previously identified ethical issues and discussions were analysed for recurrent themes. We found that outbreak managers first and foremost reflect on the balance of individual harm with public health benefit. This key question was approached by way of discussing four more specific ethical themes: (1) justification of governmental intervention, (2) responsibility to prevent infections, (3) scientific uncertainty and (4) legal consequences. The themes found in this study, rephrased into accessible questions, represent the shared ethical understanding of professionals and can help to articulate the ethical dimensions of using molecular science in response to infectious disease outbreaks.

A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction.

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.

A sensitive optical micro-machined ultrasound sensor (OMUS) based on a silicon photonic ring resonator on an acoustical membrane.

With the increasing use of ultrasonography, especially in medical imaging, novel fabrication techniques together with novel sensor designs are needed to meet the requirements for future applications like three-dimensional intercardiac and intravascular imaging. These applications require arrays of many small elements to selectively record the sound waves coming from a certain direction. Here we present proof of concept of an optical micro-machined ultrasound sensor (OMUS) fabricated with a semi-industrial CMOS fabrication line. The sensor is based on integrated photonics, which allows for elements with small spatial footprint. We demonstrate that the first prototype is already capable of detecting pressures of 0.4 Pa, which matches the performance of the state of the art piezo-electric transducers while having a 65 times smaller spatial footprint. The sensor is compatible with MRI due to the lack of electronical wiring. Another important benefit of the use of integrated photonics is the easy interrogation of an array of elements. Hence, in future designs only two optical fibers are needed to interrogate an entire array, which minimizes the amount of connections of smart catheters. The demonstrated OMUS has potential applications in medical ultrasound imaging, non destructive testing as well as in flow sensing.

Single pulse frequency compounding protocol for superharmonic imaging.

Second harmonic imaging is currently accepted as the standard in commercial echographic systems. A new imaging technique, coined as superharmonic imaging (SHI), combines the third till the fifth harmonics, arising during nonlinear sound propagation. It could further enhance the resolution and quality of echographic images. To meet the bandwidth requirement for SHI a dedicated phased array has been developed: a low frequency subarray, intended for transmission, interleaved with a high frequency subarray, used in reception. As the bandwidth of the elements is limited, the spectral gaps in between the harmonics cause multiple (ghost) reflection artifacts. A dual-pulse frequency compounding method aims at suppressing those artifacts at a price of a reduced frame rate. In this study we explore a possibility of performing frequency compounding within a single transmission. The traditional frequency compounding method suppresses the ripples by consecutively emitting two short Gaussian bursts with a slightly different center frequency. In the newly proposed method, the transmit aperture is divided into two parts: the first half is used to send a pulse at the lower center frequency, while the other half simultaneously transmits at a slightly higher center frequency. The suitability of the protocol for medical imaging applications in terms of the steering capabilities was performed in a simulation study with INCS and the hydrophone measurements. Moreover, an experimental study was carried out to find the optimal parameters for the clinical imaging protocol. The latter was subsequently used to obtain the images of a tissue mimicking phantom containing strongly reflecting wires. Additionally, the images of a human heart in the parasternal projection were acquired. The scanning aperture with the developed protocol amounts to approximately 90°, which is sufficient to capture the cardiac structures in the standard anatomical projections. The theoretically estimated and experimentally measured grating lobe levels are equal to -28.3 dB and -35.9 dB, respectively. A considerable improvement in the axial resolution of the SHI component (0.73 mm) at -6 dB in comparison with the third harmonic (2.23 mm) was observed. A similar comparison in terms of the lateral resolution slightly favored the superharmonic component by 0.2 mm. Additionally, the images of the tissue mimicking phantom exhibited the absence of the multiple reflection artifacts. The in-vivo acquisition allows one to clearly observe the dynamic of the mitral valve leaflets. The new method is equally effective in eliminating the ripple artifacts associated with SHI as the dual-pulse technique, while the full frame rate is maintained.

The need for ethical reflection on the use of molecular microbial characterisation in outbreak management.

Current thinking on the development of molecular microbial characterisation techniques in public health focuses mainly on operational issues that need to be resolved before incorporation into daily practice can take place. Notwithstanding the importance of these operational challenges, it is also essential to formulate conditions under which such microbial characterisation methods can be used from an ethical perspective. The potential ability of molecular techniques to show relational patterns between individuals with more certainty brings a new sense of urgency to already difficult ethical issues associated with privacy, consent and a moral obligation to avoid spreading a disease. It is therefore important that professionals reflect on the ethical implications of using these techniques in outbreak management, in order to be able to formulate the conditions under which they may be applied in public health practice.

Hazelnut allergy: a multi-faced condition with demographic and geographic characteristics.

Hazelnut (Corylus avellana) allergy varies from rather mild oral allergy symptoms to potentially life-threatening anaphylaxis and exhibits geographic and age-related variations. Severity of symptoms depends on the sensitisation profile of the patient and can partially be predicted using 'component-resolved diagnosis'. In our region (young) children predominantly exhibit sensitisation to hazelnut storage proteins Cor a 9 and Cor a 11 that is unrelated to birch pollen allergy and is generally associated with a more severe clinical outcome on consumption on raw and processed hazelnut. In contrast, adults predominantly present with an oral allergy syndrome due to an extensive cross-reactivity between the labile Cor a 1.04 and Bet v 1, the major allergen from birch (Betula verrucosa) pollen. In the absence of a cure, avoidance remains the key measure of effective management, particularly in those patients presenting with a severe form.

Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region.

BACKGROUND: Hazelnut (Corylus avellana) allergy exhibits age and geographically distinct sensitization patterns that have not yet been fully resolved. OBJECTIVE: To study sensitization to Cor a 11 in different age groups of hazelnut-allergic patients and infants with atopic dermatitis (AD) sensitized to hazelnut in a birch-endemic region. METHODS: Sera from 80 hazelnut-allergic patients, 33 infants under 1 year of age with AD (24 sensitized and 9 not sensitized to hazelnut), 32 healthy control individuals, and 29 birch pollen-allergic but hazelnut-tolerant individuals were tested for immunoglobulin (Ig) E reactivity to Cor a 11 by ImmunoCAP. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 was studied by ISAC microarray. RESULTS: Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitized to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitized to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitization to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. CONCLUSION: Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy, a finding that is consistent with observations concerning sensitization to Cor a 9.

Hb Haaglanden: a new nonsickling ß7Glu>Val variant. Consequences for basic diagnostics, screening, and risk assessment when dealing with HbS-like variants.

INTRODUCTION: To report a new hemoglobin variant undistinguishable from the common HbS on HPLC. To show the efficiency of the simplest confirmation method for HbS and to discuss the implications that may occur if HbS-like variants are wrongly reported as HbS. METHODS: Basic hematology, separation and measurement of the Hb fractions, 'sickle test,' and molecular analysis. RESULTS: The abnormal Hb fractions were eluting in the HbS window on HPLC, sickle test was however negative, and DNA sequencing of the beta globin gene revealed an unclassified variant HBBc.23A>T, p.Glu8Val in heterozygous form. CONCLUSIONS: Although the amino acid substitution of this new variant is identical to that of HbS and shifted of a single amino acid position, no polymerization occurs in vitro. The sickle test is a valid method to confirm or exclude HbS trait in individual cases. Whenever the case is part of a possible couple at risk, then one has to use full DNA analysis in both partners not to miss hidden concomitant defects important for genetic risk predictions.

Human basophils: a unique biological instrument to detect the allergenicity of food.

BACKGROUND: Labeling of major food allergens is mandatory for the safety of allergic consumers. Although enzyme-linked immunosorbent assay, polymerase chain reaction, and mass spectrometry are sensitive and specific instruments to detect trace amounts of food proteins, they cannot measure the ability of food constituents to trigger activation of mast cells or basophils. AIM: We evaluated the basophil activation test as an instrument to determine the allergenic potential of trace amounts of food allergens in complex matrices. Peanut (Arachis hypogaea) allergy was selected as a proof-of-concept model. METHODS: The study population comprised 5 severely peanut-allergic patients (3 males/2 females; median age, 12 years) all sensitized to 3 major peanut allergens (Ara h 1, Ara h 2, and Ara h 3) and 5 peanut-tolerant individuals (2 males/3 females; median age, 8 years). Basophils from patients and controls were stimulated with pure peanut extract and blank and peanut-spiked (0.1, 0.01, and 0.001 ppm) biscuits (baking time 11, 16, 21, 26 minutes) and chocolate extracts. RESULTS: Blank biscuits and chocolate did not induce cell activation in patients or controls. A comparison between patients and controls showed significantly higher activation of basophils after stimulation with 0.1 and 0.01 ppm of peanut-spiked biscuit at all baking times and peanut-spiked chocolate (P < .05). CONCLUSIONS: The basophil activation test is a highly sensitive and specific tool to detect traces of functionally active food allergens. For biscuits, its accuracy seems independent of baking time. Furthermore, it allows even the most sensitive patients to be included in study protocols.