A fast all-optical 3D photoacoustic scanner for clinical vascular imaging.

The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry-Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.

Variation in care and outcome for fragile hip fracture patients: a European multicentre study benchmarking fulfilment of established quality indicators.

PURPOSE: Despite the availability of clinical guidelines for hip fracture patients, adherence to these guidelines is challenging, potentially resulting in suboptimal patient care. The goal of this study was (1) to evaluate and benchmark the adherence to recently established quality indicators (QIs), and (2) to study clinical outcomes, in fragile hip fracture patients from different European countries. METHODS: This observational, cross-sectional multicenter study was performed in 10 hospitals from 9 European countries including data of 298 consecutive patients. RESULTS: A large variation both within and between hospitals were seen regarding adherence to the individual QIs. QIs with the lowest overall adherence rates were the administration of systemic steroids (5.4%) and tranexamic acid (20.1%). Indicators with the highest adherence rates (above 95%) were pre-operative (99.3%) and post-operative haemoglobin level assessment (100%). The overall median time to surgery was 22.6 h (range 15.7-42.5 h). The median LOS was 9.0 days (range 5.0-19.0 days). The most common complications were delirium (23.2%) and postsurgical constipation (25.2%). CONCLUSION: The present study shows large variation in the care for fragile patients with hip fractures indicating room for improvement. Therefore, hospitals should invest in benchmarking and knowledge-sharing. Large quality improvement initiatives with longitudinal follow up of both process and outcome indicators should be initiated.

AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABAA receptor (GABAAR)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

A review of the microtremor horizontal-to-vertical spectral ratio (MHVSR) method.

The single-station microtremor horizontal-to-vertical spectral ratio (MHVSR) method was initially proposed to retrieve the site amplification function and its resonance frequencies produced by unconsolidated sediments overlying high-velocity bedrock. Presently, MHVSR measurements are predominantly conducted to obtain an estimate of the fundamental site frequency at sites where a strong subsurface impedance contrast exists. Of the earthquake site characterization methods presented in this special issue, the MHVSR method is the furthest behind in terms of consensus towards standardized guidelines and commercial use. The greatest challenges to an international standardization of MHVSR acquisition and analysis are (1) the what - the underlying composition of the microtremor wavefield is site-dependent, and thus, the appropriate theoretical (forward) model for inversion is still debated; and (2) the how - many factors and options are involved in the data acquisition, processing, and interpretation stages. This paper reviews briefly a historical development of the MHVSR technique and the physical basis of an MHVSR (the what). We then summarize recommendations for MHVSR acquisition and analysis (the how). Specific sections address MHVSR interpretation and uncertainty assessment.

Longitudinal evaluation of laboratory-based serological assays for SARS-CoV-2 antibody detection.

Serological assays for SARS-CoV-2 infection are now widely available for use in diagnostic laboratories. Limited data are available on the performance characteristics in different settings, and at time periods remote from the initial infection. Validation of the Abbott (Architect SARS-CoV-2 IgG), DiaSorin (Liaison SARS-CoV-2 S1/S2 IgG) and Roche (Cobas Elecsys Anti-SARS-CoV-2) assays was undertaken utilising 217 serum samples from 131 participants up to 7 months following COVID-19 infection. The Abbott and DiaSorin assays were implemented into routine laboratory workflow, with outcomes reported for 2764 clinical specimens. Sensitivity and specificity were concordant with the range reported by the manufacturers for all assays. Sensitivity across the convalescent period was highest for the Roche at 95.2-100% (95% CI 81.0-100%), then the DiaSorin at 88.1-100% (95% CI 76.0-100%), followed by the Abbott 68.2-100% (95% CI 53.4-100%). Sensitivity of the Abbott assay fell from approximately 5 months; on this assay paired serum samples for 45 participants showed a significant drop in the signal-to-cut-off ratio and 10 sero-reversion events. When used in clinical practice, all samples testing positive by both DiaSorin and Abbott assays were confirmed as true positive results. In this low prevalence setting, despite high laboratory specificity, the positive predictive value of a single positive assay was low. Comprehensive validation of serological assays is necessary to determine the optimal assay for each diagnostic setting. In this low prevalence setting we found implementation of two assays with different antibody targets maximised sensitivity and specificity, with confirmatory testing necessary for any sample which was positive in only one assay.

Nonlinear ultrasound simulation in an axisymmetric coordinate system using a k-space pseudospectral method.

A full-wave model for nonlinear ultrasound propagation through a heterogeneous and absorbing medium in an axisymmetric coordinate system is developed. The model equations are solved using a nonstandard or k-space pseudospectral time domain method. Spatial gradients in the axial direction are calculated using the Fourier collocation spectral method, and spatial gradients in the radial direction are calculated using discrete trigonometric transforms. Time integration is performed using a k-space corrected finite difference scheme. This scheme is exact for plane waves propagating linearly in the axial direction in a homogeneous and lossless medium and significantly reduces numerical dispersion in the more general case. The implementation of the model is described, and performance benchmarks are given for a range of grid sizes. The model is validated by comparison with several analytical solutions. This includes one-dimensional absorption and nonlinearity, the pressure field generated by plane-piston and bowl transducers, and the scattering of a plane wave by a sphere. The general utility of the model is then demonstrated by simulating nonlinear transcranial ultrasound using a simplified head model.

Do low-fat foods alter risk of colorectal cancer from processed meat?

OBJECTIVES: We investigated potential causes of the high incidence rate of colorectal cancer (CRC) in New Zealand. STUDY DESIGN: A national population-based case-control study of 806 cases and 1025 controls was conducted to determine the risk factors for CRC in this population. METHODS: Information about family history of CRC, ethnicity, diet, school milk consumption, exercise, and height and weight at age 20 years were collected by a self-administered questionnaire from cases and controls. RESULTS: Response rates were 84% for cases and 65% for controls. Increasing preference for low-fat food alternatives was associated with reducing odds ratios (OR) for CRC (Ptrend<0.001) with a considerably reduced OR of always versus never choosing low-fat food alternatives (OR = 0.39, 95% confidence interval = 0.26, 0.58). Increased consumption of dairy products or milk was associated with reduced risk of CRC. Belonging to the male gender, having a first degree relative with CRC, and increasing consumption of processed meat, lamb, pork, and bread were associated with elevated risks of CRC. The increased risk from consumption of processed meat was not evident in subjects who regularly or always preferred low-fat food. CONCLUSIONS: A preference for low-fat food may ameliorate an increased risk of CRC from the consumption of processed meat.

Breast cancer and cytomegalovirus.

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

Enhancing bowel screening: Preventing colorectal cancer by flexible sigmoidoscopy in New Zealand.

OBJECTIVES: The prevention of colorectal cancer (CRC) attainable from introducing once-in-a-lifetime flexible sigmoidoscopy (FSIG) screening was assessed. STUDY DESIGN: This is a review of relevant available information for the assessment of the impact and resource demands of FSIG in New Zealand. METHODS: The reduction in bowel cancer incidence achievable by one-off FSIG screening from 50 to 59 years of age, an age group for which bowel screening is not currently offered, was reviewed. The prevention of CRC attainable from an offer of screening at 55 years of age in New Zealand was also estimated. The number and cost of the FSIG screening procedures required and referrals for colonoscopies and the savings in treatment were calculated. RESULTS: Annually, about 27,500 FSIG screening procedures would be required if 50% of those turning 55 years of age accepted an offer of once-in-a-lifetime FSIG screening. This would result in three-four-fold fewer people being referred for colonoscopy than in the national 2-yearly faecal immunochemical test (FIT) screening programme and subsequently reduce demand for colonoscopy from a false-positive FIT. The number of CRC cases prevented would increase over 17 years to more than 300 per year by 2033. After 10-15 years of screening, the annual savings in health service costs, primarily from CRC prevented, were sufficient to completely fund the FSIG screening. CONCLUSIONS: Inclusion of FSIG screening in the national bowel screening programme would significantly reduce both the incidence and mortality of CRC in New Zealand, reduce the colonoscopy demand of current bowel screening and reduce long-term health service costs.

Representing arbitrary acoustic source and sensor distributions in Fourier collocation methods.

Accurately representing acoustic source distributions is an important part of ultrasound simulation. This is challenging for grid-based collocation methods when such distributions do not coincide with the grid points, for instance when the source is a curved, two-dimensional surface embedded in a three-dimensional domain. Typically, grid points close to the source surface are defined as source points, but this can result in "staircasing" and substantial errors in the resulting acoustic fields. This paper describes a technique for accurately representing arbitrary source distributions within Fourier collocation methods. The method works by applying a discrete, band-limiting convolution operator to the continuous source distribution, after which source grid weights can be generated. This allows arbitrarily shaped sources, for example, focused bowls and circular pistons, to be defined on the grid without staircasing errors. The technique is examined through simulations of a range of ultrasound sources, and comparisons with analytical solutions show excellent accuracy and convergence rates. Extensions of the technique are also discussed, including application to initial value problems, distributed sensors, and moving sources.