Experimental and Numerical Investigation of Therapeutic Ultrasound Angioplasty

Therapeutic ultrasound angioplasty is an emerging minimally invasive cardiovascular surgical procedure that involves the delivery of ultrasonic displacements to the distal-tip of small diameter wire waveguides. The ultrasonic distal-tip displacements affect atherosclerotic plaque and thrombus by direct contact ablation, pressure wave components and cavitation, in addition to an acoustic streaming event around the distal-tip. This study uses experimental and numerical methods to investigate ultrasonic displacements in wire waveguides and the effect the distal-tip displacements have on the surrounding fluid. An experimental therapeutic ultrasound wire waveguide apparatus is described that delivers displacements to the distal-tip of 1.0 mm and tapered 0.35 mm diameter nickel-titanium (NiTi) waveguides. The operating frequency of the apparatus has been experimentally determined to be 23.5 kHz and for the power settings tested delivers displacements of up to 85 µm peak-to-peak (p-p) to the distal-tip of 1.0 mm diameter waveguides. The apparatus has been shown to directly ablate calcified materials with a stiffer response when compared with atherosclerotic plaques and to generate cavitation and acoustic streaming. A coupled fluid-structure numerical model of the waveguide and fluid surrounding the distal-tip has been developed that predicts the waveguide displacements and stresses along the entire length of the wire waveguide. The structural results of the model have been validated against experimental measurements of the displacements of the waveguide with the inclusion of a constant damping value of 4.5%. The fluid results of the model predict the pressure amplitudes developed in the surrounding fluid and compare closely with values reported in literature. The model predicts the distal-tip displacements required to cause cavitation, a major disruptive event, and has been compared with experimental observations made with the ultrasonic wire waveguide apparatus. The waveguide numerical model will prove a valuable design tool in the further development and improvement of this emerging cardiovascular technology

A Numerical Acoustic Fluid-structure Model of a Therapeutic Ultrasound Angioplasty Device

Ultrasonic angioplasty involves the use of ultrasonic vibrations delivered to the distal-tip of small diameter wire waveguides and is an emerging technology the may have potential use in the treatment of complicated atherosclerotic plaques during cardiovascular surgery. Complicated plaques, including chronic total occlusions and calcified lesions, seriously reduce success rates during standard intervention involving guidewire access, followed by balloon dilation or stent delivery. The large amplitude (0-150 μm) wire waveguide distal-tip displacements in the low-frequency ultrasonic (18-45 kHz) range have been shown to disrupt plaque material by direct contact ablation and cavitation, acoustic streaming and pressure wave components in adjacent fluid 1. The effects on this surrounding fluid are complex and are related to the distal-tip geometry, frequency of operation, vibration amplitude, as well as the operating environment, including, fluid properties and boundary conditions. While the majority of work to date on ultrasound angioplasty has focused on experimental and clinical studies 2, 3, further understanding of distal-tip effects is necessary. This work describes a numerical fluid-structure model of the wire waveguide distal-tip and is used to predict the pressures developed in the fluid region near the tip wall, the acoustic pressure field and, with the inclusion of appropriate threshold intensity, when cavitation will occur. The model has been validated against experimental acoustic pressure field results reported in the literature. The model can be further used to predict the effects of parameters such as distal-tip geometry, displacement amplitude and frequency of operation and will prove a valuable design aid in the choice of optimum powers to disrupt various biological materials

Performance evaluation of digital pulse position modulation for wavelength division multiplexing FSO systems impaired by interchannel crosstalk

Wavelength division multiplexing (WDM) has been proposed for fibre, intersatellite, free space and indoor optical communication systems. Digital pulse position modulation (DPPM) is a more power efficient modulation format than on-off keying (OOK) and a strong contender for the modulation of free-space systems. Although DPPM obtains this advantage in exchange for a bandwidth expansion, WDM systems using it are still potentially attractive, particularly for moderate coding levels. However, WDM systems are susceptible to interchannel crosstalk and modelling this in a WDM DPPM system is necessary. Models of varying complexity, based on simplifying assumptions, are presented and evaluated for the case of a single crosstalk wavelength. For a single crosstalk, results can be straightforwardly obtained by artificially imposing the computationally convenient constraint that frames (and thus slots also) align. Multiple crosstalk effects are additionally investigated, for the most practically relevant cases of modest coding level, and using both simulation and analytical methods. In general, DPPM maintains its sensitivity advantage over OOK even in the presence of crosstalk while predicting lower power penalty at low coding level in WDM systems

Effect of Divalproex on Brain Morphometry, Chemistry, and Function in Youth at High-Risk for Bipolar Disorder: A Pilot Study

Abstract Objective: Divalproex has been found efficacious in treating adolescents with and at high risk for bipolar disorder (BD), but little is known about the effects of mood stabilizers on the brain itself. We sought to examine the effects of divalproex on the structure, chemistry, and function of specific brain regions in children at high-risk for BD. Methods: A total of 24 children with mood dysregulation but not full BD, all offspring of a parent with BD, were treated with divalproex monotherapy for 12 weeks. A subset of 11 subjects and 6 healthy controls were scanned with magnetic resonance imaging (MRI, magnetic resonance spectroscopy [MRS], and functional MRI [fMRI]) at baseline and after 12 weeks. Results: There were no significant changes in amygdalar or cortical volume found over 12 weeks. Furthermore, no changes in neurometabolite ratios were found. However, we found the degree of decrease in prefrontal brain activation to correlate with degree of decrease in depressive symptom severity. Conclusions: Bipolar offspring at high risk for BD did not show gross morphometric, neurometabolite, or functional changes after 12 weeks of treatment with divalproex. Potential reasons include small sample size, short exposure to medications, or lack of significant neurobiological impact of divalproex in this particular population

Subluminal to superluminal propagation in a left-handed medium

In this paper we report large group delays in the propagation of narrow-band pulses through a dispersive medium with both dielectric function and magnetic permeability negative. We show how the numerical results can be understood in terms of the phase time as calculated from the complex transmission amplitude. We also demonstrate superluminal passage and saturation of phase time in the same material albeit in a different spectral region.Peer reviewedPhysic

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes