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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.

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.

Purpose Radiology reports often contain follow-up imaging recommendations. However, these recommendations are not always followed up by referring physicians and patients. Failure to comply in a timely manner can lead to delayed treatment, poor patient outcomes, unnecessary testing, lost revenue, and legal liability. Therefore, the primary objective of this research was to determine adherence rates to follow-up recommendations. Methods We extracted radiology examination–related data, including report text, for examinations performed between January 1, 2010, and February 28, 2017, from the radiology information system at an academic institution. The data set contained 2,972,164 examinations. The first 6 years were used as the period during which a follow-up recommendation was to be detected, allowing for a maximum of 14 months for a follow-up examination to be performed. Results At least one recommendation for follow-up imaging was present in 10.6% of radiology reports. Overall, the follow-up imaging adherence rate was 58.14%. Mammography had the highest follow-up adherence rate at 69.03%, followed by MRI at 67.54%. Of the modalities, nuclear medicine had the lowest adherence rate at 37.93%. Conclusions This study confirms that follow-up imaging adherence rates are inherently low and vary by modality and that appropriate interventions may be needed to improve compliance to follow-up imaging recommendations.

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.

Radiology reports often contain follow-up imaging recommendations. Failure to comply with these recommendations in a timely manner can lead to poor patient outcomes, complications, and legal liability. As such, the primary objective of this research was to determine adherence rates to follow-up recommendations.Radiology-related examination data, including report text, for examinations performed between June 1, 2015, and July 31, 2017, were extracted from the radiology departments at the University of Washington (UW) and Lahey Hospital and Medical Center (LHMC). The UW dataset contained 923,885 examinations, and the LHMC dataset contained 763,059 examinations. A 1-year period was used for detection of imaging recommendations and up to 14-months for the follow-up examination to be performed.On the basis of an algorithm with 97.9% detection accuracy, the follow-up imaging recommendation rate was 11.4% at UW and 20.9% at LHMC. Excluding mammography examinations, the overall follow-up imaging adherence rate was 51.9% at UW (range, 44.4% for nuclear medicine to 63.0% for MRI) and 52.0% at LHMC (range, 30.1% for fluoroscopy to 63.2% for ultrasound) using a matcher algorithm with 76.5% accuracy.This study suggests that follow-up imaging adherence rates vary by modality and between sites. Adherence rates can be influenced by various legitimate factors. Having the capability to identify patients who can benefit from patient engagement initiatives is important to improve overall adherence rates. Monitoring of follow-up adherence rates over time and critical evaluation of variation in recommendation patterns across the practice can inform measures to standardize and help mitigate risk.

To understand why patients "no-show" for imaging appointments, and to provide new insights for improving resource utilization.We conducted a retrospective analysis of nearly 2.9 million outpatient examinations in our radiology information system from 2000 to 2015 at our multihospital academic institution. No-show visits were identified by the "reason code" entry "NOSHOW" in our radiology information system. We restricted data to radiography, CT, mammography, MRI, ultrasound, and nuclear medicine examinations that included all studied variables. These variables included modality, patient age, appointment time, day of week, and scheduling lead time. Multivariate logistic regression was used to identify factors associated with no-show visits.Out of 2,893,626 patient visits that met our inclusion criteria, there were 94,096 no-shows during the 16-year period. Rates of no-show visits varied from 3.36% in 2000 to 2.26% in 2015. The effect size for no-shows was strongest for modality and scheduling lead time. Mammography had the highest modality no-show visit rate of 6.99% (odds ratio [OR] 5.38, P.001) compared with the lowest modality rate of 1.25% in radiography. Scheduling lead time greater than 6 months was associated with more no-show visits than scheduling within 1 week (OR 3.18, P.001). Patients 60 years and older were less likely to miss imaging appointments than patients under 40 (OR 0.70, P.001). Mondays and Saturdays had significantly higher rates of no-show than Sundays (OR 1.52 and 1.51, P .001).Modality type and scheduling lead time were the most predictive factors of no-show. This may be used to guide new interventions such as targeted reminders and flexible scheduling.

No-show appointments are a troublesome, but frequent, occurrence in radiology hospital departments and private practice. Prior work in medical appointment no-show prediction has focused on general practice and has not considered features specific to the radiology environment. We collect data from 16 years of outpatient examinations in a multi-site hospital radiology department. Data from the radiology information system (RIS) are fused with patient income estimated from U.S. Census data. Features were categorized into three groups: Patient, Exam, and Scheduling. Models based on the total feature set and separately on each feature group were developed using logistic regression to assess the per-appointment likelihood of no-show. After five-fold cross-validation, no-show prediction using the total feature set from 554,611 appointments yielded an area under the curve (AUC) of 0.770 ± 0.003. Feature groups that were most informative in the prediction of no-show appointments were those based on the type of exam and on scheduling attributes such as the lead time of scheduling the appointment. A data-driven no-show prediction model like the one presented here could be useful to schedulers in the implementation of an automated scheduling policy or the assignment of examinations with a high risk of no-show to lower impact appointment slots.

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.

The use of ultrasound contrast agents as local drug delivery systems Continues to grow. Current limitations are the amount of drug that can be incorporated as well as the efficiency of drug release Upon insonification. This Study focuses oil the synthesis and characterisation of novel polymeric microcapsules for ultrasound-triggered delivery of lipophilic drugs. Microcapsules with a shell Of fluorinated end-capped poly(L-lactic acid) were made through pre-mix membrane emulsification and contained, apart from a gaseous phase, different amounts of hexadecane oil as a drug-carrier reservoir. Mean number weighted diameters were between 1.22 mu m and 1.31 mu m. High-speed imaging at similar to 10 million fames per second showed that for low acoustic pressures (1 MHz, 0.24 MPa) microcapsules compressed but remained intact. At higher diagnostic pressures of 0.51 MPa, microcapsules cracked, thereby releasing the encapsulated gas and model lipophilic drug, U-Sing conventional ultrasound B-mode imaging at a frequency of 2.5 MHz, a marked enhancement of scatter intensity over a tissue-mimicking phantom was observed for all differently loaded microcapsules. The partially oil-filled microcapsules with high drug loads and well-defined acoustic activation thresholds have great potential for ultrasound-triggered local delivery of lipophilic drugs under ultrasound image-guidance. (C) 2008 Elsevier B.V. All rights reserved.

Intravascular transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is a promising therapeutic approach after acute myocardial infarction. Efficacy and targeting of myocardial cell engraftment are crucial variables determining the therapeutic value of MSC transplantation. Highly focused ultrasound-mediated stimulation of microbubbles (hf-UMS) allows locoregional pre-treatment of target tissue. In a "proof of concept" study, we investigated augmentation of site-targeted MSC engraftment with hf-UMS. We further evaluated the ability of transplanted MSCs to transmigrate across the endothelial barrier into non-ischemic and post-ischemic myocardium in vivo. After acute myocardial ischemia and reperfusion, rats received hf-UMS focused on the anterior left-ventricular wall followed by intravascular transplantation of MSCs. Global and regional myocardial engraftment of MSCs was quantified by means of confocal laser-scanning microscopy; endothelial adhesion, transendothelial migration and invasion of basement membrane were distinguished. Targeted myocardium exhibited higher amount of transplanted MSCs vs. non-targeted tissue. The rate of transendothelial migration was lowest in non-ischemic (41.2+/-2%) compared to post-ischemic myocardium (53+/-5.7%, p

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.

The increasing uptake of information technology in the healthcare domain has resulted in a large volume of digital health data being generated on a regular basis. Most of the health information systems exchange information using HL7 messages making HL7 a good source for data collection. Despite the large volume of data that is generated within the treatment facilities, sharing this data for research and development purposes is not straightforward due to patient privacy protection legislation. In this paper we present an HL7 data processing pipeline that extracts information from complex HL7 data structures, de-identifies fields containing identifiable patient information, and reconstructs HL7 messages using the de-identified data, while providing a secure mechanism for re-identification. Using a dataset of 149,647 production HL7 messages, we demonstrate how the system has over 99% accuracy, suggesting that this is a feasible approach to de-identify patient data.

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

Syphilis has re-emerged in the United States and elsewhere, and clinicians caring for HIV-infected patients are challenged with syphilis diagnosis and management decisions. HIV alters the natural history of syphilis to an extent that is poorly understood, and initial presentation may be more varied in coinfected patients. Although commonly available diagnostic assays for syphilis should be interpreted as usual, such tests rely on antibody measurement and may be an imperfect indicator of active infection. Assessment of all available clinical and risk behavior data remains critically important in the diagnosis of syphilis in coinfected patients. Treatment of syphilis in such patients requires stage-appropriate therapy, with careful serologic monitoring to assess response. Clinicians must have heightened appreciation of the role of frequent risk assessment, serologic screening, symptom recognition, and follow-up of treated patients, as well as an understanding of public health functions such as sex partner treatment and communicable disease reporting.

To define the impact of age on microscopic structural remodeling after myocardial infarction, the physical properties of infarct scar tissue and viable remote zone tissues in young (3 months) and older adult (18 months) Fischer rats were quantified with the use of high-frequency (50 MHz) high-resolution acoustic microscopy 3 months after coronary artery occlusion. We observed that integrated backscatter increased by 100% in the viable zones of old animals after infarction, but remained relatively unaffected in the same regions of younger animals. Mathematical models of myocardial scattering behavior indicated that a 25% increase in stiffness of the extracellular matrix materials in viable zones likely occurred in the older animals. Alterations in gross tissue collagen content were not responsible for this increased stiffness. These observations are compatible with the hypothesis that progressive age-related changes in the quality of the collagen (e.g., excessive age-related crosslinking) rather than its amount per se may have altered the stiffness of the extracellular matrix of remodeled viable tissue in older animals.

Breast cancer is the fastest growing cancer, accounting for 29%, of new cases in 2012, and second leading cause of cancer death among women in the United States and worldwide. Ultrasound (US) has been used as an indispensable tool for breast cancer detection/diagnosis and treatment. In computer-aided assistance, lesion segmentation is a preliminary but vital step, but the task is quite challenging in US images, due to imaging artifacts that complicate detection and measurement of the suspect lesions. The lesions usually present with poor boundary features and vary significantly in size, shape, and intensity distribution between cases. Automatic methods are highly application dependent while manual tracing methods are extremely time consuming and have a great deal of intra- and inter- observer variability. Semi-automatic approaches are designed to counterbalance the advantage and drawbacks of the automatic and manual methods. However, considerable user interaction might be necessary to ensure reasonable segmentation for a wide range of lesions. This work proposes an automatic enhancement approach to improve the boundary searching ability of the live wire method to reduce necessary user interaction while keeping the segmentation performance. Based on the results of segmentation of 50 2D breast lesions in US images, less user interaction is required to achieve desired accuracy, i.e. < 80%, when auto-enhancement is applied for live-wire segmentation.

The cardiac aging process is accompanied by global mechanical dysfunction that reflects increased myocardial stiffness. Accordingly, age-related changes in microscopic material properties of myocardium were delineated with high-frequency ultrasound (US) (30 to 44 MHz) tissue characterization methods for aging Fischer 344 rats at 6 (adult), 18 (aged), and 24 (senescent) months of age. The excised lateral wall of the left ventricle of rats (n = 10 per group) was insonified with a 50-MHz acoustic microscope for determination of integrated backscatter, backscatter coefficient and attenuation coefficient. Histological and biochemical analyses for collagen content and cardiac myocyte diameter were performed. Collagen concentration increased progressively with age, with the greatest increments occurring from 6 to 18 months (38.0 ± 6.3 to 53.0 ± 7.1 mg/g dry wt), and leveling off at 24 months (60.0 ± 7.4 mg/g dry wt). Tissue microscopic material properties also changed progressively from 6 to 24 months of age, as determined by US methods: integrated backscatter increased (−44.7 ± 1.8 vs. –40.8 ± 1.9 dB, p < 0.05), attenuation increased (47.1 ± 5.9 to 65.3 ± 7.8 dB/cm, p < 0.05), and the backscatter coefficient increased (0.73 ± 0.16 × 10−5 to 3.76 ± 1.6 × 10−5 cm-1, p < 0.05), from 6 to 24 months of age in each case. Age-related alterations in indices of cardiac microscopic material properties were closely correlated with the changes in cardiac microstructure. Ultrasonic tissue characterization may prove to be a sensitive tool to monitor changes in the cardiac microstructure, such as increased collagen deposition, that occur within age-related diastolic dysfunction. (E-mail: saw@howdy.wustl.edu)

RATIONALE AND OBJECTIVES Molecular imaging with targeted contrast agents enables tissues to be distinguished by detecting specific cell-surface receptors. In the present study, a ligand-targeted acoustic nanoparticle system is used to identify angioplasty-induced expression of tissue factor by smooth muscle cells within carotid arteries. METHODS Pig carotid arteries were overstretched with balloon catheters, treated with tissue factor-targeted or a control nanoparticle system, and imaged with intravascular ultrasound before and after treatment. RESULTS Tissue factor-targeted emulsions bound and increased the echogenicity and gray-scale levels of overstretched smooth muscle cells within the tunica media, versus no change in contralateral control arteries. Expression of stretch-induced tissue factor in carotid artery media was confirmed by immunohistochemistry. CONCLUSIONS The potential for abnormal thrombogenicity of balloon-injured arteries, as reflected by smooth muscle expression of tissue factor, was imaged using a novel, targeted, nanoparticulate ultrasonic contrast agent.

Myocardial edema has been associated with impaired ventricular compliance and diastolic filling. To determine the sensitivity of high-frequency (40 MHz) ultrasound to myocardial edema, we employed a model in which myocardial edema was induced by immersion of tissue in isotonic saline. The effect of freezing tissue on edema formation was also evaluated. Rat hearts were arrested at end-diastole and insonified fresh within 15 min of excision (n = 5) or following being frozen for 24 h and thawed (n = 4). Measurements of attenuation, backscatter, tissue thickness and speed of sound were performed at baseline and hourly for 4 h, and compared with direct measurements of myocardial edema. Fresh tissue demonstrated a greater propensity for the development of edema than frozen tissue. Integrated backscatter increased in both tissues, whereas the magnitude and slope of attenuation decreased as edema evolved. We conclude that high-frequency ultrasound sensitively detects myocardial edema, and we propose that the extension of these methods to clinical frequencies may prove useful for monitoring and treatment of cardiac edematous disease states.

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.

In this paper, we report the effects of inherent tissue anisotropy on the spectral properties of backscattered ultrasound when measured with a commercially-available imaging system. We insonified five specimens of bovine tendon immersed in a water tank and rotated in 10° increments while being imaged with a Hewlett-Packard Sonos 1500 system. The backscattered RF signals corresponding to each angle of insonification were digitized and the spectral characteristics of the backscattered ultrasound were determined. The mean anisotropy, defined as the average difference between values at perpendicular and parallel insonification, for band-limited estimates of backscattered power, centroid frequency, upper-band to lower-band power ratio, and upper-band to total-band power ratio were found to be 24.6 ± 1.1 dB, 142 ± 27 kHz, 32 ± 13%, and 22 ± 5%, respectively (mean ± SE). The magnitude of each of these backscatter spectral parameters was larger at perpendicular insonification compared with the corresponding values at parallel insonification, consistent with previous measurements of the inherent anisotropy of ultrasonic attenuation and backscatter in tissue.

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.

Diagnostic ultrasonic characterization of the heart is designed to assess the state of the myocardium with ultrasonic parameters that relate to structural or functional components of cardiac muscle. The potential cross fertilization of ideas and methods between those borne out of research in quantitative nondestructive evaluation of materials and those borne out of research in diagnostic medical applications in the area of ultrasonics represents an attractive goal. In this paper we describe our approach to tissue characterization of the heart based on quantitative ultrasonic imaging. We discuss methods of ultrasonic tissue characterization applied in laboratory and clinical investigations. Specific examples of the application of clinical quantitative tissue characterization include measurements of the hearts of patients with remote myocardial infarction, dilated cardiomyopathy, acute myocardial ischemia, and hearts of patients with diabetes. The role of anisotropy in quantitative tissue characterization a...

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). ...

This study delineates the role of angiotensin II type I (AT1) receptor in the remodeling of Syrian cardiomyopathic hamsters. Twelve cardiomyopathic (T0-2) hamsters received L-158,809 treatment ad libitum in their drinking water (27 µg/ml) and 9 cardiomyopathic and 9 normal F1-B hamsters received tap water from 1 to 4 months of age. Although pharmacologically effective with regard to complete suppression of the blood pressure response to angiotensin II infusion, L-158,809 did not diminish the progression or severity of cardiomyopathy. Heart weight/100 g body weight and left ventricular wall thickness adjusted for body weight of both L-158,809 and cardiomyopathic control hamsters did not differ and exceeded those of F1-B controls (p < 0.05). Myocardial material properties (e.g., stiffness and density) of cardiomyopathic hamsters treated with L-158,809 were not affected. Thus, the progression of fibrosis, calcification, and necrosis in T0-2 cardiomyopathic hamsters was not sensitive to AT1 receptor blockade.

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) of drugs and genes, especially with the enhancement of microbubble or nanoparticle agents, has been demonstrated in various settings for some years. Translation to pre-clinical disease models faces many challenges. This paper reports on the development and characteristics of a device for preclinical translational research in USMD. Feasibility of short-haripin RNA (shRNA) delivery in vivo using this device was demonstrated.

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 integration of therapeutic interventions with diagnostic imaging has been recognized as one of the next technological developments that will have a major impact on medical treatments. Important advances in this field are based on a combination of progress in guiding and monitoring ultrasound energy, novel drug classes becoming available, the development of smart delivery vehicles, and more in depth understanding of the mechanisms of the cellular and molecular basis of diseases. Recent research demonstrates that both pressure sensitive and temperature sensitive delivery systems hold promise for local treatment. The use of ultrasound for the delivery of drugs has been demonstrated in particular the field of cardiology and oncology for a variety of therapeutics ranging from small drug molecules to biologics and nucleic acids.

Localized therapeutic effects of an experimental therapeutic agent on a mouse MC38 tumor model were evaluated using a combined ultrasound therapy and imaging probe system (TIPS). With ultrasound activated paclitaxel delivery, the tumor growth is substantially retarded for at least 3 days. The therapeutic effect of ultrasound is statistically significant (p=0.03) within one day after treatment but gradually decreases with time. Therefore, it is suggested that multiple treatments over a long period are required for cancer treatment. It is also demonstrated in this preclinical study that TIPS is an effective tool for imaging-guided, ultrasound-activated drug delivery.

Novel polymeric microcapsules, filled with a mixture of gas and oil, were produced and their potential as ultrasound contrast agent-based drug delivery system for lipophilic drugs was investigated. Microcapsules were synthesized that contained either no oil, were almost half-filled with oil, or were almost completely filled with oil. Mean number weighted diameters were between 1.22 and 1.31 μm. At a low MI (1 MHz, Place of 0.24 MPa), microcapsules typically compressed without cracking. At a high MI (1 MHz, Place of 0.51 MPa), microcapsules cracke, thereby releasing their content. Guidance and monitoring of therapy will be possible because the microcapsules were echogenic and stable at low MI. These microcapsules therefore have great potential as local drug delivery system for lipophilic drugs.

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.