Confirmatory DPYD Testing in Patients Receiving Fluoropyrimidines Who are Suspected DPYD Variant Carriers Based on a Genetic Data Repository.

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx-relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx-informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research-only genetic data repositories to expand the number of patients who benefit from PGx-informed treatment while we continue to work toward wide-scale adoption of PGx testing and implementation.

Annual HIV screening rates for HIV-negative men who have sex with men in primary care.

BACKGROUND: Men who have sex with men (MSM) account for most new HIV diagnoses in the US. Annual HIV testing is recommended for sexually active MSM if HIV status is negative or unknown. Our primary study aim was to determine annual HIV screening rates in primary care across multiple years for HIV-negative MSM to estimate compliance with guidelines. A secondary exploratory endpoint was to document rates for non-MSM in primary care. METHODS: We conducted a three-year retrospective cohort study, analyzing data from electronic medical records of HIV-negative men aged 18 to 45 years in primary care at a large academic health system using inferential and logistic regression modeling. RESULTS: Of 17,841 men, 730 (4.1%) indicated that they had a male partner during the study period. MSM were screened at higher rates annually than non-MSM (about 38% vs. 9%, p<0.001). Younger patients (p-value<0.001) and patients with an internal medicine primary care provider (p-value<0.001) were more likely to have an HIV test ordered in both groups. For all categories of race and self-reported illegal drug use, MSM patients had higher odds of HIV test orders than non-MSM patients. Race and drug use did not have a significant effect on HIV orders in the MSM group. Among non-MSM, Black patients had higher odds of being tested than both White and Asian patients regardless of drug use. CONCLUSIONS: While MSM are screened for HIV at higher rates than non-MSM, overall screening rates remain lower than desired, particularly for older patients and patients with a family medicine or pediatric PCP. Targeted interventions to improve HIV screening rates for MSM in primary care are discussed.

Microfluidic particle sorting utilizing inertial lift force.

A simple passive microfluidic device that continuously separates microparticles is presented. Its development is motivated by the need for specific size micro perfluorocarbon (PFC) droplets to be used for a novel gas embolotherapy method. The device consists of a rectangular channel in which inertial lift forces are utilized to separate particles in lateral distance. At the entrance of the channel, particles are introduced at the center by focusing the flow from a center channel with flow from two side channels. Downstream, large particles will occupy a lateral equilibrium position in shorter axial distance than small particles. At the exit of the channel, flow containing large particles is separated from flow containing small particles. It is shown that 10.2-µm diameter microspheres can be separated from 3.0-µm diameter microspheres with a separation efficiency of 69-78% and a throughput in the order of 2 ·104 particles per minute. Computational Fluid Dynamics (CFD) calculations were done to calculate flow fields and verify theoretical particle trajectories. Theory underlying this research shows that higher separation efficiencies for very specific diameter cut-off are possible. This microfluidic channel design has a simple structure and can operate without external forces which makes it feasible for lab-on-a-chip (LOC) applications.

Minimally invasive gas embolization using acoustic droplet vaporization in a rodent model of hepatocellular carcinoma.

Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. Many patients are not eligible for curative therapies, such as surgical resection of the tumor or a liver transplant. Transarterial embolization is one therapy clinically used in these cases; however, this requires a long procedure and careful placement of an intraarterial catheter. Gas embolization has been proposed as a fast, easily administered, more spatially selective, and less invasive alternative. Here, we demonstrate the feasibility and efficacy of using acoustic droplet vaporization to noninvasively generate gas emboli within vasculature. Intravital microscopy experiments were performed using the rat cremaster muscle to visually observe the formation of occlusions. Large gas emboli were produced within the vasculature in the rat cremaster, effectively occluding blood flow. Following these experiments, the therapeutic efficacy of gas embolization was investigated in an ectopic xenograft model of hepatocellular carcinoma in mice. The treatment group exhibited a significantly lower final tumor volume (ANOVA, p = 0.008) and growth rate than control groups - tumor growth was completely halted. Additionally, treated tumors exhibited significant necrosis as determined by histological analysis. To our knowledge, this study is the first to demonstrate the therapeutic efficacy of gas embolotherapy in a tumor model.

Gas Embolization in a Rodent Model of Hepatocellular Carcinoma Using Acoustic Droplet Vaporization.

Trans-arterial embolization is a commonly used therapy in unresectable hepatocellular carcinoma. Current methods involve the careful placement of an intraarterial catheter and the deposition of embolizing particles. Gas embolotherapy has been proposed as an embolization method with the potential for high spatial resolution without the need for a catheter. This method involves vaporizing intravenouslyadministered droplets into gas bubbles using focused ultrasound - a process termed acoustic droplet vaporization. The bubbles can become lodged in the vasculature, thereby creating an embolus. Here, we initially demonstrate the feasibility of achieving significant targeted embolization with this method in the rat cremaster using intravital microscopy. The therapy was then tested in an ectopic xenograft mouse model of hepatocellular carcinoma. Gas embolotherapy was shown to maintain the tumor volume at baseline over a twoweek treatment course while control groups showed significant tumor growth. These preliminary results demonstrate thatgas embolotherapy could serve as an effective noninvasive method for the management of unresectable hepatocellular carcinoma.

Characterization of Bioeffects on Endothelial Cells under Acoustic Droplet Vaporization.

Gas embolotherapy is achieved by locally vaporizing microdroplets through acoustic droplet vaporization, which results in bubbles that are large enough to occlude blood flow directed to tumors. Endothelial cells, lining blood vessels, can be affected by these vaporization events, resulting in cell injury and cell death. An idealized monolayer of endothelial cells was subjected to acoustic droplet vaporization using a 3.5-MHz transducer and dodecafluoropentane droplets. Treatments included insonation pressures that varied from 2 to 8 MPa (rarefactional) and pulse lengths that varied from 4 to 16 input cycles. The bubble cloud generated was directly dependent on pressure, but not on pulse length. Cellular damage increased with increasing bubble cloud size, but was limited to the bubble cloud area. These results suggest that vaporization near the endothelium may impact the vessel wall, an effect that could be either deleterious or beneficial depending on the intended overall therapeutic application.

Pulsatile flow past an oscillating cylinder.

A fundamental study to characterize the flow around an oscillating cylinder in a pulsatile flow environment is investigated. This work is motivated by a new proposed design of the total artificial lung (TAL), which is envisioned to provide better gas exchange. The Navier-Stokes computations in a moving frame of reference were performed to compute the dynamic flow field surrounding the cylinder. Cylinder oscillations and pulsatile free-stream velocity were represented by two sinusoidal waves with amplitudes A and B and frequencies ω(c) and ω, respectively. The Keulegan-Carpenter number (K(c)=U(o)∕Dω(c)) was used to describe the frequency of the oscillating cylinder while the pulsatile free-stream velocity was fixed by imposing ω∕K(c)=1 for all cases investigated. The parameters of interest and their values were amplitude (0.5D