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Objective The Liver Imaging Reporting and Data System (LI-RADS) has been widely applied to CT and MR liver observations in patients at high-risk for hepatocellular carcinoma (HCC). We investigated the impact of CT vs MR in upgrading LI-RADS 3 to LI-RADS 5 observations using a large cohort of high-risk patients. Methods We performed a retrospective, longitudinal study of CT and MR radiographic reports (June 2013 - February 2017) with an assigned LI-RADS category. A final population of 757 individual scans and 212 high-risk patients had at least one LI-RADS 3 observation. Differences in observation time to progression between modalities were determined using uni- and multivariable analysis. Results Of the 212 patients with a LI-RADS 3 observation, 52 (25%) had progression to LI-RADS 5. Tp ranged from 64 - 818 days (median: 196 days). One hundred and three patients (49%) had MR and 109 patients (51%) had CT as their index study. Twenty-four patients with an MR index exam progressed to LI-RADS 5 during the follow-up interval, with progression rates of 22% (CI:13%-30%) at 1 year and 29% (CI:17%-40%) at 2 years. Twenty-eight patients with a CT index exam progressed to LI-RADS 5 during follow-up, with progression rates of 26% (CI:16%-35%) at 1 year and 31% (CI:19%-41%) at 2 years. Progression rates were not significantly different between patients whose LI-RADS 3 observation was initially diagnosed on MR vs CT (HR: 0.81, P = 0.44). Discussion MR and CT modalities are comparable for demonstrating progression from LI-RADS 3 to 5 for high risk patients.

Radiology reports often contain follow-up imaging recommendations, but failure to comply with them in a timely manner can lead to delayed treatment, poor patient outcomes, complications, and legal liability. Using a dataset containing 2,972,164 exams for over 7 years, in this study we explored the association between recommendation specificity on follow-up rates. Our results suggest that explicitly mentioning the follow-up interval as part of a follow-up imaging recommendation has a significant impact on adherence making these recommendations 3 times more likely (95% CI: 2.95 – 3.05) to be followed-up, while explicit mentioning of the follow-up modality did not have a significant impact. Our findings can be incorporated into routine dictation macros so that the follow-up duration is explicitly mentioned whenever clinically applicable, and/or used as the basis for a quality improvement project focussed on improving adherence to follow-up imaging recommendations.

Critical results reporting guidelines demand that certain critical findings are communicated to the responsible provider within a specific period of time. In this paper, we discuss a generic report processing pipeline to extract critical findings within the dictated report to allow for automation of quality and compliance oversight using a production dataset containing 1,210,858 radiology exams. Algorithm accuracy on an annotated dataset having 327 sentences was 91.4% (95% CI 87.6–94.2%). Our results show that most critical findings are diagnosed on CT and MR exams and that intracranial hemorrhage and fluid collection are the most prevalent at our institution. 1.6% of the exams were found to have at least one of the ten critical findings we focused on. This methodology can enable detailed analysis of critical results reporting for research, workflow management, compliance, and quality assurance.

BACKGROUND AND PURPOSE: Motion artifacts are a frequent source of image degradation in the clinical application of MR imaging (MRI). Here we implement and validate an MRI motion-artifact correction method using a multiscale fully convolutional neural network. MATERIALS AND METHODS: The network was trained to identify motion artifacts in axial T2-weighted spin-echo images of the brain. Using an extensive data augmentation scheme and a motion artifact simulation pipeline, we created a synthetic training dataset of 93,600 images based on only 16 artifact-free clinical MRI cases. A blinded reader study using a unique test dataset of 28 additional clinical MRI cases with real patient motion was conducted to evaluate the performance of the network. RESULTS: Application of the network resulted in notably improved image quality without the loss of morphologic information. For synthetic test data, the average reduction in mean squared error was 41.84%. The blinded reader study on the real-world test data resulted in significant reduction in mean artifact scores across all cases (P

Purpose To evaluate the impact of environmental and socioeconomic factors on outpatient cancellations and “no-show visits” (NSVs) in radiology. Materials and Methods We conducted a retrospective analysis by collecting environmental factor data related to outpatient radiology visits occurring between 2000 and 2015 at our multihospital academic institution. Appointment attendance records were joined with daily weather observations from the National Oceanic and Atmospheric Administration and estimated median income from the US Census American Community Survey. A multivariate logistic regression model was built to examine relationships between NSV rate and median income, commute distance, maximum daily temperature, and daily snowfall. Results There were 270,574 (8.0%) cancellations and 87,407 (2.6%) NSVs among 3,379,947 scheduled outpatient radiology appointments and 575,206 unique patients from 2000 to 2015. Overall cancellation rates decreased from 14% to 8%, and NSV rates decreased from 6% to 1% as median income increased from $20,000 to $120,000 per year. In a multivariate model, the odds of NSV decreased 10.7% per $10,000 increase in median income (95% confidence interval [CI]: 10.3%-11.1%) and 2.0% per 10°F increase in maximum daily temperature (95% CI: 1.3%-1.6%). The odds of NSV increased 1.4% per 10-mile increase in commute distance (95% CI: 1.3%-1.6%) and 4.5% per 1-inch increase in daily snowfall (95% CI: 3.6%-5.3%). Commute distance was more strongly associated with NSV for those in the two lower tertiles of income than the highest tertile (P Conclusion Environmental factors are strongly associated with patients’ attendance at scheduled outpatient radiology examinations. Modeling of appointment failure risk based on environmental features can help increase the attendance of outpatient radiology appointments.

In this paper, we model the statistical properties of imaging exam durations using parametric probability distributions such as the Gaussian, Gamma, Weibull, lognormal, and log-logistic. We establish that in a majority of radiology procedures, the underlying distribution of exam durations is best modeled by a log-logistic distribution, while the Gaussian has the poorest fit among the candidates. Further, through illustrative examples, we show how business insights and workflow analytics can be significantly impacted by making the correct (log-logistic) versus incorrect (Gaussian) model choices.

Identifying areas for workflow improvement and growth is essential for an interventional radiology (IR) department to stay competitive. Deployment of traditional methods such as Lean and Six Sigma helped in reducing the waste in workflows at a strategic level. However, achieving efficient workflow needs both strategic and tactical approaches. Uncertainties about patient arrivals, staff availability, and variability in procedure durations pose hindrances to efficient workflow and lead to delayed patient care and staff overtime. We present an alternative approach to address both tactical and strategic needs using discrete event simulation (DES) and simulation based optimization methods. A comprehensive digital model of the patient workflow in a hospital-based IR department was modeled based on expert interviews with the incumbent personnel and analysis of 192 days’ worth of electronic medical record (EMR) data. Patient arrival patterns and process times were derived from 4393 individual patient appointments. Exactly 196 unique procedures were modeled, each with its own process time distribution and rule-based procedure-room mapping. Dynamic staff schedules for interventional radiologists, technologists, and nurses were incorporated in the model. Stochastic model simulation runs revealed the resource “computed tomography (CT) suite” as the major workflow bottleneck during the morning hours. This insight compelled the radiology department leadership to re-assign time blocks on a diagnostic CT scanner to the IR group. Moreover, this approach helped identify opportunities for additional appointments at times of lower diagnostic scanner utilization. Demand for interventional service from Outpatients during late hours of the day required the facility to extend hours of operations. Simulation-based optimization methods were used to model a new staff schedule, stretching the existing pool of resources to support the additional 2.5 h of daily operation. In conclusion, this study illustrates that the combination of workflow modeling, stochastic simulations, and optimization techniques is a viable and effective approach for identifying workflow inefficiencies and discovering and validating improvement options through what-if scenario testing.

Objective Across the United States, there is a growing number of patients in Accountable Care Organizations and under risk contracts with commercial insurance. This is due to proliferation of new value-based payment models and care delivery reform efforts. In this context, the business model of radiology within a hospital or health system context is shifting from a primary profit-center to a cost-center with a goal of cost savings. Radiology departments need to increasingly understand how the transactional nature of the business relates to financial rewards. The main challenge with current reporting systems is that the information is presented only at an aggregated level, and often not broken down further, for instance, by type of exam. As such, the primary objective of this research is to provide better visibility into payments associated with individual radiology procedures in order to better calibrate expense/capital structure of the imaging enterprise to the actual revenue or value-add to the organization it belongs to. Materials and methods We propose a methodology that can be used to determine technical payments at a procedure level. We use a proportion based model to allocate payments to individual radiology procedures based on total charges (which also includes non-radiology related charges). Results Using a production dataset containing 424,250 radiology exams we calculated the overall average technical charge for Radiology to be $873.08 per procedure and the corresponding average payment to be $326.43 (range: $48.27 for XR and $2750.11 for PET/CT) resulting in an average payment percentage of 37.39% across all exams. Discussion We describe how charges associated with a procedure can be used to approximate technical payments at a more granular level with a focus on Radiology. The methodology is generalizable to approximate payment for other services as well. Understanding payments associated with each procedure can be useful during strategic practice planning. Conclusions Charge-to-total charge ratio can be used to approximate radiology payments at a procedure level.

Radiology reports often contain follow-up imaging recommendations. Failure to comply with these recommendations in a timely manner can lead to delayed treatment, poor patient outcomes, complications, unnecessary testing, lost revenue, and legal liability. The objective of this study was to develop a scalable approach to automatically identify the completion of a follow-up imaging study recommended by a radiologist in a preceding report. We selected imaging-reports containing 559 follow-up imaging recommendations and all subsequent reports from a multi-hospital academic practice. Three radiologists identified appropriate follow-up examinations among the subsequent reports for the same patient, if any, to establish a ground-truth dataset. We then trained an Extremely Randomized Trees that uses recommendation attributes, study meta-data and text similarity of the radiology reports to determine the most likely follow-up examination for a preceding recommendation. Pairwise inter-annotator F-score ranged from 0.853 to 0.868; the corresponding F-score of the classifier in identifying follow-up exams was 0.807. Our study describes a methodology to automatically determine the most likely follow-up exam after a follow-up imaging recommendation. The accuracy of the algorithm suggests that automated methods can be integrated into a follow-up management application to improve adherence to follow-up imaging recommendations. Radiology administrators could use such a system to monitor follow-up compliance rates and proactively send reminders to primary care providers and/or patients to improve adherence.

Persons living with HIV (PLWH) are living longer, remaining sexually active, and may continue risky sexual behaviors. As such, it is crucial for providers to ask all HIV-positive patients about behaviors related to HIV transmission and STD acquisition. The “Ask, Screen, Intervene” (ASI) curriculum was developed to increase provider knowledge, skills, and motivation to incorporate risk assessment and prevention services into the care of PLWH. The ASI curriculum was delivered to 2558 HIV-care providers at 137 sites between September 30, 2007 and December 31, 2010. Immediately post-training, participants self-reported significant gains in perceived confidence to demonstrate ASI knowledge and skills (p

With ongoing healthcare payment reforms in the USA, radiology is moving from its current state of a revenue generating department to a new reality of a cost-center. Under bundled payment methods, radiology does not get reimbursed for each and every inpatient procedure, but rather, the hospital gets reimbursed for the entire hospital stay under an applicable diagnosis-related group code. The hospital case mix index (CMI) metric, as defined by the Centers for Medicare and Medicaid Services, has a significant impact on how much hospitals get reimbursed for an inpatient stay. Oftentimes, patients with the highest disease acuity are treated in tertiary care radiology departments. Therefore, the average hospital CMI based on the entire inpatient population may not be adequate to determine department-level resource utilization, such as the number of technologists and nurses, as case length and staffing intensity gets quite high for sicker patients. In this study, we determine CMI for the overall radiology department in a tertiary care setting based on inpatients undergoing radiology procedures. Between April and September 2015, CMI for radiology was 1.93. With an average of 2.81, interventional neuroradiology had the highest CMI out of the ten radiology sections. CMI was consistently higher across seven of the radiology sections than the average hospital CMI of 1.81. Our results suggest that inpatients undergoing radiology procedures were on average more complex in this hospital setting during the time period considered. This finding is relevant for accurate calculation of labor analytics and other predictive resource utilization tools.

Liver disease is a leading cause of mortality for HIV-infected individuals in the antiretroviral therapy era, and hepatitis C virus (HCV) coinfection is a major factor [1, 2]. The prevalence of HCV coinfection is estimated to be 15%–40% among HIV-infected individuals [3–5]. However, higher rates of HCV coinfection have been reported in specific groups, including injection drug users [6]. Given the clinical significance of HCV coinfection, national guidelines recommend HCV antibody screening for all HIV-infected patients [7, 8]. However, false-negative results of serologic tests for HCV can occur in persons with acute HCV infection(during the period from exposure to HCV antibody seroconversion) and in those with chronic HCV infection. Chronic HCV viremia, or having detectable HCV RNA in serum (HCV RNA positivity) in the absence of detectable HCV antibodies (anti-HCV negativity), has been reported in HIV-uninfected [9–12] and HIV-infected individuals [13–17]. Experimental HCV infection of chimpanzees has also resulted in chronic HCV viremia without the development of HCV antibodies [18]. HIV-infected individuals may be at particular risk for seronegative HCV infection, possibly as a result of immunosuppression, with resultant failure to mount or maintain HCV antibody titers for detection by standard serodiagnostic tests [14, 17, 19]. The reported prevalence of chronic seronegative HCV infection among anti-HCV–negative, HIV-infected patients has varied between 0% and 13.2% [13, 15, 16, 20], depending upon the population studied and the HCV EIA used. Because the total reported number of HIV-infected patients with seronegative HCV infection is small, it has been difficult to establish the risk factors for seronegative HCV infection. We determined the prevalence of chronic seronegative HCV infection in a large, multicenter, nationally representative cohort of HIV-infected men and women. Using data combined from that cohort and data from 3 previously described cohorts, we analyzed the predictors of HCV RNA positivity among anti-HCV–negative, HIV-infected subjects to determine which groups of anti-HCV–negative subjects are at risk for having HCV RNA positivity.

Purpose: To characterize the group of providers delivering medical care to HIV and hepatitis C (HCV) co-infected homeless and marginally housed individuals in San Francisco and to assess factors affecting provider decisions to initiate HCV treatment in this population. Subjects and methods: The Research in Access to Care for the Homeless (REACH) cohort is a representative sample of HIV-infected homeless and marginally housed individuals identified from single room occupancy hotels, homeless shelters and free lunch programs in San Francisco. Primary care providers (PCP) for active, HIV/HCV co-infected REACH cohort participants were administered face-to-face, semi-structured interviews. REACH participants were administered quarterly face-to-face structured interviews. Results: 52/62 (83.9%) providers were interviewed regarding 133/155 (85.8%) active, HIV/HCV co-infected patients. Providers classified 94/133 (70.7%) patients as ineligible for HCV treatment. The mean number of reasons for ineligibility was 3.2. Most frequent reasons for provider determination of ineligibility included likelihood of poor medication adherence, depression, active injection drug use and patient disinterest in treatment. In addition, structural barriers to treatment included poor access to testing, delays in evaluation by a gastroenterologist and exclusion from treatment of patients with comorbidities. Conclusions: While HCV infection is common, HCV treatment is rare in the HIV/HCV coinfected urban poor. On average, the PCP in this study are experienced and are familiar with this patient population. There are many reasons for providers classifying patients as ineligible for HCV treatment. While these reasons indicate that treatment is difficult given chaotic lifestyle and concurrent medical conditions of this population, they are not insurmountable barriers. New treatments and strategies are necessary to treat this population with high rates of hepatitis C infection.

We describe characterization of digital signals using analogs of thermodynamic quantities: the topological entropy, Shannon entropy, thermodynamic energy, partition function, specific heat at constant volume, and an idealized version of Shannon entropy in the limit of digitizing with infinite dynamic range and sampling rate. We show that analysis based on these quantities is capable of detecting differences between digital signals that are undetectable by conventional methods of characterization based on peak-to-peak amplitude or signal energy. We report the results of applying thermodynamic quantities to a problem from nondestructive materials evaluation: detection of foreign objects (FO) embedded near the surface of thin graphite/epoxy laminates using backscattered waveforms obtained by C-scanning the laminate. The characterization problem was to distinguish waveforms acquired from the region containing the FO from those acquired outside. In all cases the thermodynamic analogs exhibit significant increases (up to 20-fold) in contrast and for certain types of FO materials permit detection when energy or amplitude methods fail altogether.

Objective As are the attenuation coefficient and sound speed, the backscatter coefficient is a fundamental ultrasonic property that has been used to characterize many tissues. Unfortunately, there is currently far less standardization for the ultrasonic backscatter measurement than for the other two, as evidenced by a previous American Institute of Ultrasound in Medicine (AIUM)-sponsored interlaboratory comparison of ultrasonic backscatter, attenuation, and speed measurements (J Ultrasound Med 1999; 18:615-631). To explore reasons for these disparities, the AIUM Endowment for Education and Research recently supported this second interlaboratory comparison, which extends the upper limit of the frequency range from 7 to 9 MHz. Methods Eleven laboratories were provided with standard test objects designed and manufactured at the University of Wisconsin (Madison, WI). Each laboratory was asked to perform ultrasonic measurements of sound speed, attenuation coefficients, and backscatter coefficients. Each laboratory was blinded to the values of the ultrasonic properties of the test objects at the time the measurements were performed. Results Eight of the 11 laboratories submitted results. The range of variation of absolute magnitude of backscatter coefficient measurements was about 2 orders of magnitude. If the results of 1 outlier laboratory are excluded, then the range is reduced to about 1 order of magnitude. Agreement regarding frequency dependence of backscatter was better than reported in the previous interlaboratory comparison. For example, when scatterers were small compared with the ultrasonic wavelength, experimental frequency-dependent backscatter coefficient data obtained by the participating laboratories were usually consistent with the expected Rayleigh scattering behavior (proportional to frequency to the fourth power). Conclusions Greater standardization of backscatter measurement methods is needed. Measurements of frequency dependence of backscatter are more consistent than measurements of absolute magnitude.

To measure Hepatitis C Virus (HCV) prevalence, incidence, and initiation of HCV therapy in a representative HIV-infected cohort of the urban poor.Cohort analysis.The Research and Access to Care for the Homeless (REACH) Cohort is a systematic sample of HIV-infected marginally housed individuals identified from single-room occupancy hotels, homeless shelters, and free lunch programs in San Francisco.Two hundred forty-nine participants with 28.9 months (median) of follow-up were studied. Mean age was 44 (range 24 to 75, standard deviation 8.4) years. Eighty-two percent were male, 43% were African-American, 64% were lifetime injection drug users, and 24% had been on the street or in a shelter in the prior month.We measured HCV testing and treatment history with structured interviews; additionally, participants were tested for HCV antibodies (EIA-2) with RNA viral load confirmation.At baseline, 172 (69.1%) were HCV-positive and 182 (73.1%) were HCV-positive at follow-up, including 155 (62.2%) with viremia. HCV-positive status was associated with having injected drugs, elevated serum alanine aminotransferase, homelessness in the last 1 year, and more severe depressive symptoms. The incidence of new HCV infection was 4.63% per person-year (ppy; 95% confidence interval, 2.31 to 8.13) in the entire cohort and 16.77% ppy among injection drug users. The prevalence of HCV antibody-negative HCV-viremia was 13.2% (10/76). Nonwhites were less likely to receive HCV testing and subspecialty referral, controlled for drug use and other confounders. Sixty-eight percent (123/182) were aware treatment was available; however, only 3.8% (7/182) or 1.16% ppy received HCV treatment.While HCV infection is common, HCV treatment is rare in the HIV-HCV coinfected urban poor. Urban poor, nonwhite individuals are less likely to receive HCV testing and subspecialty referral than their white counterparts. Antibody-negative infection may complicate screening and diagnosis in HIV-infected persons. J

Recent studies by our group have demonstrated the efficacy of perfluorocarbon liquid nanoparticles for enhancing the reflectivity of tissuelike surfaces to which they are bound. The magnitude of this enhancement depends in large part on the difference in impedances of the perfluorocarbon, the bound substrate, and the propagating medium. The impedance varies directly with temperature because both the speed of sound and the mass density of perfluorocarbon liquids are highly temperature dependent. However, there are relatively little data in the literature pertaining to the temperature dependence of the acoustic impedance of these compounds. In this study, the speed of sound and density of seven different fluorocarbon liquids were measured at specific temperatures between 20 degrees C and 45 degrees C. All of the samples demonstrated negative, linear dependencies on temperature for both speed of sound and density and, consequently, for the acoustic impedance. The slope of sound speed was greatest for perfluorohexane (-278 +/- 1.5 cm/s-degrees C) and lowest for perfluorodichlorooctane (-222 +/- 0.9 cm/s-degrees C). Of the compounds measured, perfluorohexane exhibited the lowest acoustic impedance at all temperatures, and perfluorodecalin the highest at all temperatures. Computations from a simple transmission-line model used to predict reflectivity enhancement from surface-bound nanoparticles are discussed in light of these results.

In this work, the Kramers-Kronig (K-K) relations are applied to experimental data of resonant nature by limiting the interval of integration to the measurement spectrum. The data are from suspensions of encapsulated microbubbles (Albunex) and have the characteristics of an ultrasonic notch filter. The goal is to test the consistency of this dispersion and attenuation data with the Kramers-Kronig relations in a strict manner, without any parameters from outside the experimental bandwidth entering in to the calculations. In the course of reaching the goal, the artifacts associated with the truncation of the integrals are identified and it is shown how their impacts on the results can be minimized. The problem is first approached analytically by performing the Kramers-Kronig calculations over a restricted spectral band on a specific Hilbert transform pair (Lorentzian curves). The resulting closed-form solutions illustrate the type of artifacts that can occur due to truncation and also show that accurate results can be achieved. Next, both twice-subtracted and lower-order Kramers-Kronig relations are applied directly to the attenuation and dispersion data from the encapsulated microbubbles. Only parameters from within the experimental attenuation coefficient and phase velocity data sets are used. The twice-subtracted K-K relations produced accurate estimates for both the attenuation coefficient and dispersion across all 12 data sets. Lower-order Kramers-Kronig relations also produced good results over the finite spectrum for most of the data. In 2 of the 12 cases, the twice-subtracted relations tracked the data markedly better than the lower-order predictions. These calculations demonstrate that truncation artifacts do not overwhelm the causal link between the phase velocity and the attenuation coefficient for finite bandwidth calculations. This work provides experimental evidence supporting the validity of the subtracted forms of the acoustic K-K relations between the phase velocity and attenuation coefficient.

In this study, the sensitivity of a novel fibrin-targeted contrast agent for fibrin detection was defined in vitro on human thrombus. The contrast agent was a lipid-encapsulated perfluorocarbon nanoparticle with numerous Gd-DTPA complexes incorporated into the outer surface. After binding to fibrin clots, scanning electron microscopy of treated clots revealed dense accumulation of nanoparticles on the clot surfaces. Fibrin clots with sizes ranging from 0.5‐7.0 mm were imaged at 4.7 T with or without treatment with the targeted contrast agent. Regardless of sizes, untreated clots were not detectable by T1-weighted MRI, while targeted contrast agent dramatically improved the detectability of all clots. Decreases in T1 and T2 relaxation times (20 ‐ 40%) were measured relative to the surrounding media and the control clots. These results suggest the potential for sensitive and specific detection of microthrombi that form on the intimal surfaces of unstable atherosclerotic plaque. Magn Reson Med 44:867‐ 872, 2000. © 2000 Wiley-Liss, Inc.

Ultrasound tissue characterization with measurement of backscatter has been employed in numerous experimental and clinical studies of cardiac pathology, yet the cellular components responsible for scattering from cardiac tissues have not been unequivocally identified. This laboratory has proposed a mathematical model for myocardial backscatter that postulates the fibrous extracellular matrix (ECM) as a significant determinant of backscatter. To demonstrate the importance of ECM, this group sought to determine whether measurements of backscatter from the isolated ECM could reproduce the known directional dependence, or anisotropy of backscatter, from intact cardiac tissues in vitro. Segments of left ventricular free wall from ten formalin fixed porcine hearts were insonified at 50 MHz, traversing the heart wall from endo- to epicardium to measure the anisotropy of myocardial backscatter, defined as the difference between peak (perpendicular to fibers) and trough (parallel to fibers) backscatter amplitude. The tissue segments were then treated with 10% NaOH to dissolve all of the cellular components, leaving only the intact ECM. Scanning electron micrographs (SEM) were obtained of tissue sections to reveal complete digestion of the cellular elements. The dimensions of the residual voids resulting from cell digestion were approximately the diameter of the intact myocytes (10-30 microm). These samples were reinsonified after seven days of treatment to compare the anisotropy of integrated backscatter. The magnitude of anisotropy of backscatter changed from 15.4 +/- 0.8 to 12.6 +/- 1.1dB for intact as compared with digested specimens. Because digestion of the myocardium leaves only extracellular sources of ultrasonic scattering, and because the isolated ECM exhibits similar ultrasonic anisotropy as does the intact myocardium, it is concluded that there is a direct association between the ECM and the anisotropy of backscatter within intact tissue. Thus, it is suggested that ultrasonic tissue characterization represents a potentially clinically applicable method for delineating the structure and function of the ECM.

The phase velocities and attenuation coefficients for suspensions of narrowly sized polymer microspheres are reported over a broadband spectrum from 3 to 30 MHz. The six suspensions used in this work contain microspheres with respective average diameters near 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, and 100 μm. The results of these measurements are compared with theoretical expressions for the phase velocity and attenuation coefficient derived from the scattering properties of an elastic sphere in water using the weak scattering limit of the Waterman and Truell dispersion relation [J. Math. Phys. 2, 512–537 (1961)]. This single-scattering limit of the theory is found to be sufficient for predicting the ultrasonic transport properties of these suspensions to a considerable degree of accuracy.

Objective: To assess the efficacy of salvage therapy containing ritonavir and saquinavir after failure of indinavir- or nelfinavir-containing regimens, and to determine correlates of success or failure. Design: Retrospective chart review. Setting. The Moore Clinic - the HIV clinic of Johns Hopkins Hospital. Patients: Forty-one HIV-infected patients were identified through physician contacts, referrals from other providers, and review of a comprehensive clinical database. Main outcome measures: To determine response to salvage therapy, HIV-1 viral RNA (absolute and log 10 -transformed) was measured using the Roche Amplicor quantitative HIV-1 RNA assay after initiation of the salvage regimen. Potential correlates of response included: viral RNA at the time of switch; viral RNA at the time of switch as a percentage of baseline viral RNA; magnitude of decline in viral RNA; and the interval between virologic failure of single protease inhibitor therapy and switch to the salvage regimen. Results: Thirteen (56.5%) of 23 patients failing indinavir responded to salvage therapy (HIV RNA < 400 copies/ml) with persistence throughout the follow-up period (median of 37 weeks; range 18-67 weeks). Mean absolute viral RNA at the time of switch was 20 238 copies/ml (median, 9281) compared with 42 953 copies/ml (median, 24 650) for the 10 non-responders. Mean log 10 viral RNA at switch was 3.804 for responders versus 4.405 for non-responders (P = 0.040). Among four responders who had failed nelfinavir, mean viral RNA was 9634 copies/ml and mean log 10 viral RNA was 3.749 at the time of switch. Two non-responders had a mean viral RNA of 21 551 and a mean log 10 viral RNA of 4.037 at switch. Conclusions: In contrast with previous reports, salvage regimens containing ritonavir and/or saquinavir can be effective and durable following the failure of combination regimens containing either indinavir or nelfinavir. Salvage therapy may be more likely to succeed when it is initiated early in failure at low viral loads.

To the Editor: Streptococcus suis, commensal and opportunistic pathogens of swine, and prevalent zoonotic agents worldwide, are α-hemolytic gram-positive cocci with 35 different serotypes (1). In humans, S. suis infection has been associated with bacterial meningitis, septic shock, arthritis, pneumonia, endocarditis, endophthalmitis, and spontaneous bacterial peritonitis (2,3). Most at risk are those who handle or eat undercooked pork, e.g., farm workers, butchers, and slaughterhouse workers (4). Most cases have been reported in Europe or Southeast Asia (2,3). Meningitis, first recognized in 1968 in Denmark (1), is the most common clinical manifestation of human infection with S. suis. A case of S. suis meningitis in a pig farmer was reported in the United States (5). Here, we describe another case in a 60-year-old man from San Francisco who had consumed raw pork while traveling in the Philippines. In June 2003, this man became ill with fever, diaphoresis, headache, nausea, and anorexia. He had just returned from a 7-month vacation in the Philippines. Three days after symptoms onset, his physician prescribed doxycycline. Symptoms continued and he was admitted to a local hospital 5 days later with a fever of 38.9°C, nuchal rigidity, headache, and general malaise. The patient described no recent contact with sick persons; past medical history was unremarkable. On physical examination, he was somnolent but fully oriented, with no focal findings on neurologic examination and only slight nuchal rigidity. He had a leukocyte count of 21,000/mm3, including 16,400/mm3 neutrophils. Cerebrospinal fluid (CSF) showed leukocyte count of 487/μL with 80% polymorphonuclear cells and 18% lymphocytes, and glucose and protein levels

Targeted ultrasonic contrast systems are designed to enhance the reflectivity of selected tissues in vivo [Lanza et al., Circulation 94, 3334 (1996)]. In particular, these agents hold promise for the minimally invasive diagnosis and treatment of a wide array of pathologies, most notably tumors, thromboses, and inflamed tissues. In the present study, acoustic microscopy was used to assess the efficacy of a novel, perfluorocarbon based contrast agent to enhance the inherent acoustic reflectivity of biological and synthetic substrates. Data from these experiments were used to postulate a simple model describing the observed enhancements. Frequency averaged reflectivity (30-55 MHz) was shown to increase 7.0 +/- 1.1 dB for nitrocellulose membranes with targeted contrast. Enhancements of 36.0 +/- 2.3 dB and 8.5 +/- 0.9 dB for plasma and whole blood clots, respectively, were measured between 20 and 35 MHz. A proposed acoustic transmission line model predicted the targeted contrast system would increase the acoustic reflectivity of the nitrocellulose membrane, whole blood clot, and fibrin plasma clot by 2.6, 8.0, and 31.8 dB, respectively. These predictions were in reasonable agreement with the experimental results of this paper. In conclusion, acoustic microscopy provides a rapid and sensitive approach for in vitro chracterization, development, and testing of mathematical models of targeted contrast systems. Given the current demand for targeted contrast systems for medical diagnostic and therapeutic use, the use of acoustic microscopy may provide a useful tool in the development of these agents.

A broadband ultrasonic measurement system has been utilized to characterize the concentration and frequency dependence of in vitro suspensions of Albunex® microspheres at concentrations ranging from 1.7×105 to 2.1×107 microspheres/mL and over a bandwidth of 1–16 MHz. The apparent backscattered power (not compensated for effects due to attenuation) was shown to increase with dose for lower concentrations of microspheres, but then to decrease rapidly with increasing concentration where attenuation effects become significant. Measurements of signal loss demonstrated that the attenuation grew exponentially with increasing concentration, so that a doubling of the number of microspheres led to a doubling of the value of the attenuation coefficient measured in dB/cm. This relationship was demonstrated over the entire system bandwidth. Compensation of the apparent backscattered power for the attenuation yielded the backscatter transfer function. This quantity was shown to be linearly proportional to concentration, so that a doubling of the number of microspheres led to a 3-dB increase in the backscatter transfer function. A broadband data reduction technique was used to further reduce the data to backscatter coefficient, an absolute parameter describing the intrinsic scattering efficiency of the Albunex® microsphere suspensions. The backscatter coefficient was shown to be linearly proportional to microsphere concentration at all concentrations investigated and over all the usable bandwidth. This suggests that, with appropriate compensation for attenuation and equipment parameters, perfusion or flow quantification techniques which assume a linear dependence of backscatter with contrast agent concentration should be applicable. The backscatter coefficient exhibits a rapid rise with frequency below 3 MHz, and appears to approach a frequency independent limit above 3 MHz. The relationships of the attenuation coefficient and backscatter transfer function to concentration were generally consistent with predictions from a simple scattering model. These relationships appear to be valid within the usable bandwidth of our measurement system for all concentrations investigated.

The phase velocities in suspensions of Albunex, an ultrasound contrast agent, are determined using the technique of broadband phase spectroscopy. In these suspensions, phase velocities were measured as a function of Albunex concentration in Isoton II (buffered saline). The dispersion over the measurement bandwidth (1-15 MHz) grew with increasing Albunex concentration, exhibiting a 221-m/s change (17% increase) in phase velocity between 1.0 and 3.8 MHz at the highest concentration reported (32 microL Albunex/8 mL Isoton). The dispersion behavior of the Albunex suspensions is described using a model of encapsulated gas bubbles. The influence of the dispersion in Albunex on broadband pulses is discussed, as well as the potential impact this dispersion may have on the formation of ultrasonic images of the heart.

Tissue characterization would be facilitated by improved methods of calibration with which to make absolute measurements of the backscatter and attenuation of tissue or contrast agents. In this paper, the use of polystyrene microspheres is examined as a potential broadband in vitro calibration tool by employing an experimental system designed to characterize ultrasonic contrast agents. The frequency-dependent attenuation coefficient and backscatter coefficient were measured for a series of microsphere size distributions with a broadband ultrasound system using a custom-built specimen chamber and a novel suspension mixing technique. The measurements were used in a broadband reduction method to yield the backscatter coefficient. The range of ka spanned in this study is from ka=0.5 to ka=12. The broadband nature of the pulses permitted simultaneous measurement of different regimes of scattering of the microspheres (specifically, the transition region from Rayleigh to short-wavelength asymptotic scattering). ...

Broadband normalized signal loss of commercially available Albunex®, an ultrasonic contrast agent, was measured in vitro at concentrations approaching those which may be found in vivo for clinical doses. The measurements were made using a novel specimen chamber, careful material handling procedures, and a broadband square wave pulser system. Results were obtained over the full bandwidth of the experimental system (1 to 20 MHz) at concentrations up to 1.9×106 microspheres/mL. Further results were obtained over a partial bandwidth of the experimental system at concentrations up to 1.5×107 microspheres/mL. The frequency-dependent signal loss exhibited a peak for all concentrations investigated. In the meaningful bandwidth of the system, the signal loss (expressed in dB) was directly proportional to microsphere concentration. The experimental results for normalized signal loss were compared with predictions from a linear single-scattering model for encapsulated bubbles. The experimental data was used to estimate values for the two adjustable parameters in the model: microsphere shell elasticity (4200±1000 dyn/cm) and friction (0.0054±0.0015 dyn s/cm).

Anisotropy of ultrasonic scattering and attenuation in heart tissue depends on the specific orientation of myofibers with respect to angle of insonification. The present study was designed to delineate the effect of the angle of insonification with respect to the alignment of myofibers on measurements of integrated backscatter. A transmural cube of myocardium was cut from the anterior wall of the left ventricles from 5 normal canine hearts and their transmural scattering behavior was studied with the use of reflection acoustic microscopy at 50 MHz. A theoretical model for scattering based on the Born approximation (weak scattering) was employed to predict the relationship between backscatter and angle of insonification. Insonification of the basal face (basal view) demonstrated a wide transmural variation in integrated backscatter (/spl sim/15 dB), while insonification of the lateral face (lateral view) had much reduced variation (/spl sim/4 dB), despite an equivalent overall shift in transmural fiber angle of /spl sim/85/spl deg/ across the ventricular wall. Integrated backscatter was greatest in the midmyocardium when the basal face was viewed and least in the midmyocardium when the lateral face was viewed. The backscatter in the subepicardial and subendocardial regions was similar for both views. The maximum difference in backscatter from basal and lateral views at the midmyocardial level was approximately 18 dB, which represents a 64-fold change in the intensity of ultrasonic backscatter. The mathematical model developed for scattering based on the Born approximation (weak scattering) predicted the observed relationship between backscatter and angle of insonification. The rapid angular variation of integrated backscatter perpendicular to the fiber direction and the slow variation at parallel incidence observed experimentally were predicted by the model. This angular variation is due to the specific shape and elastic properties assumed for the predominant myocardial scatterer. There was a strong relationship between backscatter and fiber orientation, indicating that the view chosen for insonification of myocardium in clinical imaging may influence the estimation of scattering behavior. The mathematical model utilized here predicts the anisotropic behavior of scattering and suggests that the principal scattering structure in normal myocardium may be a stiff collagen shell surrounding a more compliant myocyte. This model might provide a valid approach for the study of material properties of the heart with the use of ultrasound. >

The physical structures responsible for ultrasonic scattering from myocardial tissue have not yet been conclusively defined. It is hypothesized in this paper that the backscatter from myocardium is primarily due to inhomogeneities approximately the size of the myocytes. In particular, it is proposed that the acoustic contrast responsible for the scattering is that between the extracellular collagen network that surrounds each myocyte (or myocyte bundle) and the rest of the tissue (the myocytes' intracellular contents). To test this hypothesis, a simple elastic wave scattering model for myocardium was developed. An elementary scatterer is modeled as an ellipsoidal shell, having the material properties of wet collagen, imbedded in a host medium having the average properties of myocardium. The first Born approximation to elastic scattering is used to calculate the frequency-dependent scattering from a single scatterer. To scale up from a single scatterer to a distribution of scatterers, it is assumed that the power received at the transducer is simply the sum of the power scattered in the direction of the transducer by each individual scatterer located in the active volume of the beam (an independent-scatterer approximation). Calculations are restricted to the backscattering direction (pulse-echo), although the theory can accommodate pitch-catch scattering at all angles. With the aid of a computer program, the acoustic backscatter coefficient is calculated using the Born formalism and then measurement effects (frequency-dependent beam width and attenuation correction factors) are incorporated to arrive at calculated integrated (frequency-averaged) backscatter. Both the backscatter coefficient and integrated backscatter are calculated for angles of incidence that range from parallel to the long axis of the scatterer to perpendicular to this fiber direction. For the low MHz frequencies typically used in clinical echocardiography, the calculated absolute magnitude of the acoustic backscatter coefficient lies within a range from 0.0001 to 0.001 cm-1 sr-1. For selected fiber geometries, the anisotropy in integrated backscatter as the angle of incidence is varied with respect to the fiber orientation is about 10 dB. The predicted frequency dependence of the acoustic backscatter coefficient is calculated to be about f3.9 in the low MHz frequency range. These calculated results are reasonably consistent with published experimental measurements and provide a successful preliminary test of the hypothesis.

BACKGROUND Although angiotensin-converting enzyme (ACE) inhibitors have become a mainstay of treatment for chronic congestive heart failure (CHF), it is not known whether the cardiac remodeling effects are a secondary phenomenon, resulting from ACE inhibitors' hemodynamic actions of afterload reduction, or occur through an independent mechanism. METHODS AND RESULTS We used ultrasonic tissue characterization to define potentially salutary effects of treatment with ACE inhibitors on the material properties of the heart and its potential influence on cardiac remodeling at the cellular level. Ten 1-month-old, cardiomyopathic (CM) Syrian hamsters and 6 normal (NL) hamsters were treated with captopril (2 g/L water ad libitum), and 10 CM hamsters and 10 NL hamsters were maintained untreated for 3 months. Hearts were excised, and backscattered radiofrequency data were acquired from 1200 independent sites from each specimen with a high-resolution 50-MHz acoustic microscope for calculation of integrated backscatter (IB). Treatment with captopril reduced left ventricular mass, calcium concentration, and IB in CM hearts without affecting myofiber size or collagen concentration. The IB from grossly normal regions of myocardium in NL hamsters, treated CM hamsters, and untreated CM hamsters was not significantly different. The IB from the microscopic regions of scar tissue in treated CM hamsters was significantly less (P = .0004) than that from scar tissue in untreated CM hamsters. CONCLUSIONS The reduced IB from treated scar tissue components reflects specific alterations in the material properties (elastic stiffness, density) of fibrous regions in CM hearts induced by captopril. This is the first report that defines specific cellular effects of ACE inhibitors on the material properties of isolated components of cardiac tissue in experimental cardiomyopathy. These alterations in material properties of scar tissue components represent a potential mechanism for the salutary actions of ACE inhibitors in heart failure.

Ultrasound-mediated delivery (USMD) is an active research topic, as researchers develop applications for therapeutic ultrasound in addition to thermal ablation. In USMD, ultrasound is used in conjunction with microbubbles and drugs, nanoparticles, siRNA, pDNA, stem cells, etc., to facilitate their cellular delivery and uptake using pressure and temperature-mediated mechanisms to bring about a desired therapeutic effect. To investigate the potential of targeted USMD of nanoparticles, pDNA, and stem cells for cardiovascular and other applications, a general-purpose preclinical research tool, therapy imaging probe system (TIPS) was designed. It consists of a wideband annular array, a small-animal acoustic coupler, a motorized positioning system, integrated control software for ultrasound image-guided treatment planning and execution, and triggering electronics that allow ECG and respiration-gated ultrasound exposures. TIPS was then used to enhance delivery of nanoparticles into the murine myocardium and heart vessel walls to demonstrate the feasibility of the technology, pave the way for additional basic research in cardiovascular USMD, and begin to explore the requirements that USMD devices will have to meet to be useful in a clinical setting.

The progressive increase in stiffening of the myocardium associated with the aging process and abetted by comorbid conditions such as diabetes may be linked to an excessive number of collagen cross links within the myocardial extra-cellular matrix. To determine whether ultrasound can delineate changes in the physical properties of heart tissue undergoing cross linking, the authors employed a model in which increased cross linking was induced by treating rat myocardial tissue with specific chemical fixatives. Rat hearts (n=5 each group) were arrested at end-diastole, insonified (30 to 50 MHz) fresh within a few minutes of excision in a phosphate buffered solution, placed in a fixative (10% formalin or 2.5% glutaraldehyde) and insonified at 30-minute intervals thereafter for 24 hours. Ultrasonic attenuation increased in tissues cross linked with formalin (maximal change: 27.2/spl plusmn/3.4 dB/cm) and glutaraldehyde (maximal change: 40.2/spl plusmn/5.6 dB/cm) over a 24-hour period. The frequency dependence of the attenuation coefficient increased as a function of the extent of collagen cross links in formalin (maximal change: 0.8/spl plusmn/0.3 dB/cm-MHz) and glutaraldehyde (maximal change: 0.9/spl plusmn/0.6 dB/cm-MHz). This study represents the first time that the precise time course of myocardial protein cross linking in situ has been characterized by using real time monitoring, and the physiologic effect has been delineated on microscopic material properties.

Targeted acoustic contrast agents are designed to enhance the sensitivity and specificity of ultrasonic diagnoses. The authors have previously developed a ligand targeted ultrasonic contrast system which is a liquid, lipid encapsulated perfluorocarbon emulsion. The emulsion particles are small (250 nm) and have inherently low echogenicity unless bound to a surface by a pretargeted ligand through avidin-biotin interactions. The authors have recently proposed a simple acoustic transmission line model that treats the emulsion particles as a thin layer over the targeted surface. The acoustic reflectivity of the contrast layer is related to the longitudinal velocity and density of the perfluorocarbon. Improvement of the contrast effect may be achieved by using perfluorocarbons with slower longitudinal velocities and/or lower densities. The authors report the longitudinal velocities as a function of frequency of 20 perfluorocarbons using a broadband phase spectroscopic approach for estimating phase velocities. Experimentally determined velocities ranged from 520/spl plusmn/2 m/sec (perfluorohexane) to 705/spl plusmn/5 m/sec (perfluorodecalin). No measurable dispersion was observed over the useful bandwidth of 2 to 22 MHz. Increasing carbon backbone chain length and fluorine substitution with halogens of greater atomic weight increased the measured speed of sound. The authors' experimental data were consistent (R=0.87) with a published empirical model that predicts velocity as a function of molecular structure. These data provide a rational basis for optimizing targeted perfluorocarbon-based contrast agents and offer further insight into the physical mechanisms responsible for the observed enhancement of the acoustic scattering.

The ability to enhance specific molecular markers of pathology with ultrasound has been previously demonstrated by our group employing a nanoparticle contrast agent [Lanza et al., Invest. Radiol. 35, 227–234 (2000); Ultrasound Med. Biol. 23, 863–870 (1997)]. One of the advantages of this agent is very low echogenicity in the blood pool that allows increased contrast between the blood pool and the bound, site-targeted agent. We measured acoustic backscatter and attenuation coefficient as a function of the contrast agent concentration, ambient pressure, peak acoustic pressure, and as an effect of duty cycle and wave form shape. Measurements were performed while the nanoparticles were suspended in either whole porcine blood or plasma. The nanoparticles were only detectable when insonified within plasma devoid of red blood cells and were shown to exhibit backscatter levels more than 30 dB below the backscatter from whole blood. Attenuation of nanoparticles in whole porcine blood was not measurably different from that of whole blood alone over a range of concentrations up to eight times the maximum in vivo dose. The resulting data provide upper bounds on blood pool attenuation coefficient and backscatter and will be needed to more precisely define levels of molecular contrast enhancement that may be obtained in vivo.

Specific ultrasonic tissue characterization parameters were correlated with the three-dimensional architecture and material properties (density, compressibility, size, and orientation) of aortic elastic elements at the microscopic level. The medial layer of 10 samples of normal canine aorta were insonified in vitro utilizing acoustic microscopy from 30 to 44 MHz. The following quantitative indexes exhibited substantial anisotropic elastic behavior in radial (R), circumferential (C), and longitudinal (L) directions: backscatter coefficient (R:0.9/spl plusmn/0.2; C:0.008/spl plusmn/0.0008; L:0.0077/spl plusmn/0.0008 sr/sup -1/ cm/sup -1/); frequency dependence of backscatter (R:3.3; C:1.4; L:1.5); attenuation coefficients (R:105/spl plusmn/22; L:135/spl plusmn/13; C:131/spl plusmn/14 dB/cm). Thus, the ultrasonic indexes are anisotropic: equivalent in the C and L directions, but markedly different in the R direction. These data are indicative of an aortic microstructure that interacts with ultrasonic waves as thin sheet-like elastic layers instead of independent elastin fibers. This specific sheet-like organization of elastin microfibers may function to limit shear injury to concentric aortic lamellae and prevent aortic dissection. The marked anisotropic behavior of normal aortas suggests that ultrasound may be useful for nondestructive characterization of vascular integrity.

Modern ultrasound contrast agents primarily comprise microbubble formulations that circulate in the intravascular compartment and are designed to enhance acoustic signals reflected from the blood pool. A variety of shell materials have been utilized to stabilize gas bubbles of the order of 1–10 microns in diameter. Reflectivity from microbubbles is enhanced by resonance and non-linear physical effects. However, the overall efficacy of bubbles as contrast agents must be considered in light of their marked instability to insonification pressures, marked attenuation artifacts, “blooming” effects, and their short circulatory half-life. Low molecular weight gaseous perfluorocarbon formulations have been utilized in vivo because they may offer advantages in formulation and reflectivity. In contrast, higher molecular weight perfluorocarbon emulsions that are liquid at body temperature have been formulated as nongaseous nanoparticle preparations (diameters 100– 300 nanometers), originally for use as blood substitutes. Unfortunately they exhibit low inherent echogenicity and are poor blood pool contrast agents under conditions of conventional 2-D echocardiography or harmonic imaging, or when imaged with color flow or spectral Doppler. Nevertheless, these nanoparticle formulations are chemically inert, manifest long circulatory half-lives, are not destroyed by ultrasonic imaging, and they possess low acoustic attenuation. Such features might still render them of interest as blood pool contrast agents if properly formulated and imaged. Recently, a new ultrasonic imaging modality, Power Doppler Harmonic Imaging (PDHI), has been introduced (4). This technique color-encodes changes in acoustic signal amplitude and motion of ultrasonic scatterers between insonifying pulses. PDHI has been used in a number of clinical studies to assess coronary artery bypass graft patency, tumor blood flow, and myocardial perfusion. In view of the exquisite sensitivity of Doppler for detecting the presence of small scatterers with limited scattering cross-sections as compared to microbubbles (e.g., red blood cells), and the enhanced ability of PDHI to register backscatter power, we hypothesized that certain liquid perfluorocarbon nanoparticle emulsions (5) might be more efficiently detected with this new imaging modality. Furthermore, although we have demonstrated previously that the liquid nanoparticle emulsions do not manifest any appreciable resonance behavior at clinically relevant imaging frequencies, they have performed well as targeted imaging agents in vitro and in vivo over a very broad range of frequencies (5–50 MHz)(6–8). Thus we anticipated that the PDHI method might permit imaging of these nanoparticles in the blood pool without reliance on any intrinsic resonance behavior.

Targeted acoustic contrast agents offer the potential for sensitive ultrasonic detection of pathologic tissues. We have previously reported the development of a ligand-targeted, lipid-encapsulated, liquid perfluorodichlorooctane ultrasonic contrast system with a small nominal particle size (approximately 250-nm diameter)Perfluorocarbon nanoparticles substantially increase reflectivity when bound to targeted surfaces, and we propose that this system can be approximated physically as a simple, thin layer, acoustic transmission line. In this study, we evaluate this model and compare the ultrasonic reflectivity of different perfluorocarbon formulations with widely varying acoustic impedances targeted to either nitrocellulose membranes or plasma thrombi in vitro. Five perfluorocarbons were investigated: perfluorohexane (PFH), perfluorooctane (PFO), perfluorooctyl bromide (PFOB), perfluorodichlorooctane (PFDCO), and perfluorodecalin (PFD). Ultrasonic reflection was measured by acoustic microscopy (17 to 35 MHz). Acoustic reflectivity was increased (P < 0.05) by all targeted perfluorocarbon formulations, and the magnitude of the contrast effect was inversely correlated with the perfluorocarbon acoustic impedance. PFH nanoparticles exhibited the greatest enhancement, and PFD nanoparticles showed the least. The acoustic transmission line model predicted well the relative differences in acoustic reflectivity and frequency dependence among the perfluorocarbon formulations. For future clinical applications, PFO nanoparticles may provide the best combination of acoustic enhancement, in vivo physical stability, and safety.

Molecular imaging contrast agents specifically detect the biochemical "signatures" of disease before anatomical manifestations are apparent. Sensitive and specific localization of fibrin both in vivo and in vitro has been demonstrated with the use of a ligand-directed liquid perfluorocarbon nanoparticle. Since the acoustic properties of perfluorocarbons are known to vary with temperature, it was hypothesized that temperature could be used to augment the magnitude of enhancement imparted by targeted nanoparticles. Accordingly, the acoustic backscatter of two different substrates, nitrocellulose membrane and human plasma clot, targeted by the nanoparticles was measured at temperatures ranging from 27 degrees to 47 degrees C in 5 degrees C increments. Classic avidin-biotin interactions were utilized to couple biotinylated nanoparticles to avidin-conjugated nitrocellulose membranes. Ultrasonic contrast enhancement of the nitrocellulose membrane at 25 MHz, measured by acoustic microscopy, increased from 2.0+/-0.3 dB at 27 degrees C to 3.7+/-0.4 at 47 degrees C. In a similar experiment, antifibrin nanoparticles bound to human plasma clots also exhibited temperature-dependent ultrasonic signal enhancement ranging from 13.9+/-1.5 dB at 27 degrees C to 18.1+/-1.5 dB at 47 degrees C. The increase in ultrasonic contrast enhancement measured was well described by a simple, acoustic transmission line model with temperature-dependent impedance. These results suggest that temperature-dependent changes in acoustic backscatter may be used to further differentiate tissues targeted with site-specific nanoparticles from surrounding normal soft tissues.

Complex molecular signaling heralds the early stages of pathologies such as angiogenesis, inflammation, unstable atherosclerotic plaques, and areas of remote thrombi. In previous studies, acoustic enhancement of blood clot morphology was demonstrated with the use of a nongaseous, fibrin-targeted acoustic nanoparticle emulsion delivered to areas of thrombosis both in vitro and in vivo. In this study, a system was designed and constructed that allows visualization of the evolution of acoustic contrast enhancement. To evaluate the system, two targets were examined: avidin-complexed nitrocellulose membrane and human plasma clots. The time evolution of enhancement was visualized in 10-min increments for 1 h. A monotonic increase was observed in ultrasonic reflection enhancement from specially treated nitrocellulose membranes for targeted emulsions containing perfluorooctylbromide (1.30+/-0.3 dB) and for perfluorooctane (2.64+/-0.5 dB) within the first 60 min of imaging. In comparison, the inherently nonechogenic plasma clots showed a substantial increase of 12.0+/-0.9 dB when targeted with a perfluoro-octane emulsion. This study demonstrates the concept of molecular imaging and provides the first quantifiable time-evolution report of the binding of a site-targeted ultrasonic contrast agent. Moreover, with the incorporation of specific drug treatments into the nanoparticulate contrast agent, ultrasonic molecular imaging may yield reliable detection and quantification of nascent pathologies and facilitate targeted drug therapy.

Our overall goal is to develop clinically applicable tissue characterization methods, based on quantitative analyses of backscattered ultrasound, which can differentiate normal from diseased heart segments. In implementing these methods there is a need to compensate for the inherent anisotropic properties of the heart that are exhibited in echocardiographic images. [1–4] Furthermore, quantitative tissue characterization methods may be able to exploit the inherent anisotropy of the myocardium to achieve assessment of cardiac properties.[5–9] The specific aims of this investigation were to measure the spectral properties of backscattered ultrasound using a clinical imaging system and to determine effects of inherent tissue anisotropy on measured spectral properties of backscattered ultrasound.

Measurements of the frequency dependence of ultrasonic backscatter are presented for specific angles of insonification for regions of infarcted and noninfarcted human myocardium. A 5-MHz transducer was used to insonify cylindrical cores taken from 7 noninfarcted regions and 12 infarcted regions of the left ventricular free wall of 6 formalin-fixed human hearts explanted because of ischemic cardiomyopathy. The dependence of apparent (uncompensated for diffraction effects and attenuation) backscatter on frequency was approximated by a power-law dependence, magnitude of B(f)2 = afn. Under ideal conditions in a lossless medium, the effect of not compensating for the effects of diffraction and attenuation leads to the value of n to be 2.0 for Rayleigh scatterers while the frequency dependence of the fully compensated backscatter coefficient would be f4. The value of n was determined over the frequency range, 3-7 MHz. Both nonifarcted and infarcted myocardium exhibited anisotropy of the frequency dependence of backscatter, with maxima occurring at angles that were perpendicular to the predominant myofiber direction and minima when parallel to the fibers. Perpendicular insonification yielded results for n of 1.8 +/- 0.1 for noninfarcted myocardium and 1.2 +/- 0.1 for infarcted myocardium while parallel insonification yielded results of 0.4 +/- 0.1 for noninfarcted and 0.0 +/- 0.1 for infarcted myocardium. The functional form of the angle-dependent backscatter is similar for both noninfarcted and infarcted myocardium, although the frequency dependence is clearly different for both tissue states for all angles of insonification. The results of this study indicate that the anisotropy of the frequency dependence of backscatter may play a significant role in ultrasonic imaging and is an important consideration for ultrasonic tissue characterization in myocardium.