Abstract:Background & Aims
Liver biopsy analysis is the standard method used to diagnose nonalcoholic fatty liver disease (NAFLD). Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis, but is expensive. Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity, specificity, and quantitative accuracy, and results vary among operators. A new quantitative ultrasound (QUS) technique can identify steatosis in animal models… Show more
“…This CAP technique is performed in conjunction with liver fibrosis assessment based on 1D Transient Elastography (Foucher et al 2006b, Sandrin et al 2002. Other recent studies have used ultrasound to detect steatosis (Lin et al 2015, Son et al 2015 but they are based on a single cutoff value. Beyond such binary below/above diagnosis, there is a real clinical unmet need for a non-expensive, widely available, and highly reliable technique to precisely grade hepatic steatosis as MRI does.…”
Hepatic steatosis is a common condition, the prevalence of which is increasing along with non-alcoholic fatty liver disease (NAFLD). Currently, the most accurate noninvasive imaging method for diagnosing and quantifying hepatic steatosis is MRI, which estimates the proton-density fat fraction (PDFF) as a measure of fractional fat content. However, MRI suffers several limitations including cost, contra-indications and poor availability. Although conventional ultrasound is widely used by radiologists for hepatic steatosis assessment, it remains qualitative and operator dependent. Interestingly, the speed of sound within soft tissues is known to vary slightly from muscle (1.575 mm • µs −1 ) to fat (1.450 mm • µs −1 ). Building upon this fact, steatosis could affect liver sound speed when the fat content increases. The main objectives of this study are to propose a robust method for sound speed estimation (SSE) locally in
Institute of Physics and Engineering in Medicine
“…This CAP technique is performed in conjunction with liver fibrosis assessment based on 1D Transient Elastography (Foucher et al 2006b, Sandrin et al 2002. Other recent studies have used ultrasound to detect steatosis (Lin et al 2015, Son et al 2015 but they are based on a single cutoff value. Beyond such binary below/above diagnosis, there is a real clinical unmet need for a non-expensive, widely available, and highly reliable technique to precisely grade hepatic steatosis as MRI does.…”
Hepatic steatosis is a common condition, the prevalence of which is increasing along with non-alcoholic fatty liver disease (NAFLD). Currently, the most accurate noninvasive imaging method for diagnosing and quantifying hepatic steatosis is MRI, which estimates the proton-density fat fraction (PDFF) as a measure of fractional fat content. However, MRI suffers several limitations including cost, contra-indications and poor availability. Although conventional ultrasound is widely used by radiologists for hepatic steatosis assessment, it remains qualitative and operator dependent. Interestingly, the speed of sound within soft tissues is known to vary slightly from muscle (1.575 mm • µs −1 ) to fat (1.450 mm • µs −1 ). Building upon this fact, steatosis could affect liver sound speed when the fat content increases. The main objectives of this study are to propose a robust method for sound speed estimation (SSE) locally in
Institute of Physics and Engineering in Medicine
“…To generate the BSC image, the FOI was divided into 75%-overlapped sub-regions of interest (sub-ROIs) with dimensions of 193 m by193 m (equivalent to 4 by 4 wavelengths at 32 MHz). For each sub-ROI, a BSC value was estimated using the reference phantom technique (77,78), yielding a BSC versus ultrasonic frequency curve. Each sub-ROI's BSC value was generated by averaging the BSC over the frequency range from 25 to 43 MHz, denoted BSC (25 to 43 MHz), with a color then assigned to each BSC (25 to 43 MHz) value.…”
All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-B antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-B in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8 ϩ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity.
IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-B activation among its other antagonistic functions.A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.
“…Furthermore, there may be a role for CAC scores in assessing long-term, longitudinal cardiovascular risk among patients with NASH [Kim et al 2012;Budoff et al 2013]. Other imaging modalities to assess cardiovascular risk, such as cardiac MRI or quantitative ultrasound [Lin et al 2014] to quantify hepatic steatosis, which has been associated with cardiovascular disease [Arulanandan et al 2015], may be utilized in future trials. Measures of vascular and endothelial dysfunction, such as the ankle-brachial index, measures of flow-mediated dilation and carotid intima-media thickness [Sookoian and Pirola, 2008;Kozakova et al 2012], may be potential cardiovascular endpoints in future NASH trials.…”
Section: Other Modalities Of Assessing Cardiovascular Risk In Nashmentioning
Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular risk and mortality. No US Food and Drug Administration (FDA) approved therapies for NASH are available; clinical trials to date have not yet systematically assessed for changes in cardiovascular risk. This study examines the prospective utility of cardiovascular risk assessments, the Framingham risk score (FRS) and coronary artery calcium (CAC) score, as endpoints in a NASH randomized clinical trial, and assesses whether histologic improvements lead to lower cardiovascular risk. Methods: Secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial (MOZART) in which 50 biopsy-proven NASH patients received oral ezetimibe 10 mg daily (n = 25) versus placebo (n = 25). Biochemical profiling, FRS, CAC scores, liver biopsies were obtained at baseline and endpoint. Results: Ezetimibe improved FRS whereas placebo did not (4.4 ± 6.2 to 2.9 ± 4.8, p = 0.038; 3.0 ± 4.4 to 2.9 ± 4.2, p = 0.794). CAC scores did not change with ezetimibe or placebo (180.4 ± 577.2 to 194.1 ± 623.9, p = 0.293; 151.4 ± 448.9 to 183.3 ± 555.7, p = 0.256). Ezetimibe improved FRS and CAC scores in more patients than placebo (48% versus 23%, p = 0.079, and 21% versus 0%, p = 0.090, respectively), though not significantly. No differences were noted in cardiovascular risk scores among histologic responders versus nonresponders. Conclusions: Ezetimibe improved FRS whereas placebo did not. FRS and CAC scores improved in a greater proportion of patients with ezetimibe; this trend did not reach significance. These findings indicate the utility and feasibility of monitoring cardiovascular risk in a NASH trial. The utility of CAC scores may be higher in trials of longer duration (⩾52 weeks) and with older patients (age ⩾45). ClinicalTrials.gov registration: NCT01766713.
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