Cost-effectiveness of cytomegalovirus vaccination for females in China: A decision-analytical Markov study.

BACKGROUND: The global burden of disease caused by congenital cytomegalovirus (CMV) infection is high. Previous modeling studies have suggested that CMV vaccination may be cost-effective in developed countries. Congenital CMV infection is more likely driven by maternal non-primary infection in China. We aimed to measure the effectiveness and cost-effectiveness of population-level CMV vaccination in Chinese females. METHODS: A decision tree Markov model was developed to simulate potential CMV vaccination strategies in a multi-cohort setting, with a population size of 1,000,000 each for the infant, adolescent (10-year-old) and young adult (20-year-old) cohorts. The hypothetical vaccines were assumed to have 50% efficacy, 20 years of protection, 70% coverage, at a price of US$120/dose for base-case analysis. Costs and disability-adjusted life years (DALYs) were discounted by 3% per year and the vaccination would be considered cost-effective if an incremental cost-effectiveness ratio (ICER) was lower than 2021 Chinese per capita GDP (US$12,500). FINDINGS: For the pre-infection (PRI) vaccine efficacy type, the adolescent strategy was the most cost-effective, with an ICER of US$12,213 (12,134 to 12,291) pre DALY averted, compared with the next best strategy (young adult strategy). For pre- and post-infection (P&PI) efficacy type, the young adult strategy was the most cost-effective as it was cost-saving. In one-way analysis varying the PRI vaccine price, the infant strategy, adolescent strategy and the young adult strategy would be a dominant strategy over others if the vaccine cost ≤US$60, US$61-121 and US$122-251 per dose respectively. In contrast, the young adult strategy continued to be the preferred strategy until the P&PI vaccine price exceeded US$226/dose. Our main results were robust under a wide variety of sensitivity analyses and scenario analyses. INTERPRETATION: CMV vaccination for females would be cost-effective and even cost-saving in China. Our findings had public health implications for control of CMV diseases.

MR Elastography-Based Shear Strain Mapping for Assessment of Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVES: To evaluate the potential of MR elastography (MRE)-based shear strain mapping to noninvasively predict the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: Fifty-nine histopathology-proven HCC patients with conventional 60-Hz MRE examinations (+/-MVI, n = 34/25) were enrolled retrospectively between December 2016 and October 2019, with one subgroup comprising 29/59 patients (+/-MVI, n = 16/13) who also underwent 40- and 30-Hz MRE examinations. Octahedral shear strain (OSS) maps were calculated, and the percentage of peritumoral interface length with low shear strain (i.e., a low-shear-strain length, pLSL, %) was recorded. For OSS-pLSL, differences between the MVI (+) and MVI (-) groups and diagnostic performance at different MRE frequencies were analyzed using the Mann-Whitney test and area under the receiver operating characteristic curve (AUC), respectively. RESULTS: The peritumor OSS-pLSL was significantly higher in the MVI (+) group than in the MVI (-) group at the three frequencies (all p < 0.01). The AUC of peritumor OSS-pLSL for predicting MVI was good/excellent in all frequency groups (60-Hz: 0.73 (n = 59)/0.80 (n = 29); 40-Hz: 0.84; 30-Hz: 0.90). On further analysis of the 29 cases with all frequencies, the AUCs were not significantly different. As the frequency decreased from 60-Hz, the specificity of OSS increased at 40-Hz (53.8-61.5%) and further increased at 30-Hz (53.8-76.9%), and the sensitivity remained high at lower frequencies (100.0-93.8%) (all p > 0.05). CONCLUSIONS: MRE-based shear strain mapping is a promising technique for noninvasively predicting the presence of MVI in patients with HCC, and the most recommended frequency for OSS is 30-Hz. KEY POINTS: • MR elastography (MRE)-based shear strain mapping has the potential to predict the presence of microvascular invasion (MVI) in hepatocellular carcinoma preoperatively. • The low interface shear strain identified at tumor-liver boundaries was highly correlated with the presence of MVI.

Quantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models.

OBJECTIVES: To determine the potential of bi-parametric dual-frequency hepatic MR elastography (MRE) for predicting portal pressure (PP) in mouse models of portal hypertension (PHTN) with the presence of varying hepatic fibrosis. METHODS: We studied 73 wild-type male mice, including 22 mice with hepatic congestion, 20 mice with cholestatic liver injury, and 31 age-matched sham mice. Hepatic shear stiffness (SS) and volumetric strain (VS) were calculated by 3D MRE acquired at 80 and 200 Hz. We measured PP immediately after MRE. Liver fibrosis was verified by hydroxyproline assay. We predicted PP by fitting generalized linear models with single- and dual-frequency SS and VS, respectively. The relationship between predicted and actual PP was evaluated by Spearman's correlation. We compared the prediction accuracy of portal hypertension for all models with DeLong tests at a significance level of 0.05. RESULTS: Animals with congestive or cholestatic liver disease developed significant PHTN and hepatic fibrosis to varying degrees. In both models, SS increased, while VS decreased significantly compared with shams. All bi-parametric models had high diagnostic accuracy for PHTN. The dual-frequency models (AUCs: 0.90 [81-95%], 0.91 [81-95%]) had substantially or significantly higher accuracy than single-frequency ones (AUCs: 0.83 [71-91%], and 0.78 [66-87%]). The predicted PP of dual-frequency models also showed stronger correlations with actual PP than single-frequency predictions. CONCLUSIONS: The bi-parametric dual-frequency model improved the diagnostic accuracy of liver MRE in diagnosing PHTN in preclinical models. This technical advance has the potential to monitor PHTN progression and treatment efficacy in the presence of varying fibrosis. KEY POINTS: • Bi-parametric hepatic MR elastography can predict portal pressure. • The prediction models of shear stiffness and volumetric strain with dual-frequency measurements demonstrate high diagnostic accuracy (AUCs > 0.9) in two different portal hypertension mouse models with varying fibrosis.

Assessment of advanced hepatic MR elastography methods for susceptibility artifact suppression in clinical patients.

PURPOSE: To assess the success rate, image quality, and the ability to stage liver fibrosis of a standard 2D gradient-recalled echo (GRE) and four different spin-echo (SE) magnetic resonance elastography (MRE) sequences in patients with different liver iron concentrations. MATERIALS AND METHODS: A total of 332 patients who underwent 3T MRE examinations that included liver fat and iron quantification were enrolled, including 136 patients with all five MRE techniques. Thirty-four patients had biopsy results for fibrosis staging. The liver stiffness, region of interest area, image quality, and success rate of the five sequences were compared in 115/136 patients. The area under the receiver operating characteristic curves (AUCs) and the accuracies for diagnosing early-stage fibrosis and advanced fibrosis were compared. The effect of BMI (body mass index), the R2* relaxation time, and fat fraction on the image quality and liver stiffness measurements were analyzed. RESULTS: The success rates were significantly higher in the four SE sequences (99.1-100%) compared with GRE MRE (85.3%) (all P < 0.001). There were significant differences of the mean ROI area between every pair of sequences (all P < 0.0001). There were no significant differences in the AUC of the five MRE sequences for discriminating advanced fibrosis (10 P-values ranging from 0.2410-0.9171). R2* had a significant effect on the success rate and image quality for the noniron 2D echo-planar imaging (EPI), 3D EPI and 2D GRE (all P < 0.001) sequences. BMI had a significant effect on the iron 2D EPI (P = 0.0230) and iron 2D SE (P = 0.0040) sequences. CONCLUSION: All five techniques showed good diagnostic performance in staging liver fibrosis. The SE MRE sequences had higher success rates and better image quality than GRE MRE in 3T clinical hepatic imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:976-987.

Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).

UNLABELLED: Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). CONCLUSIONS: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.

Assessment of stiffness changes in the ex vivo porcine aortic wall using magnetic resonance elastography.

Magnetic resonance elastography (MRE) is a noninvasive phase-contrast technique for estimating the mechanical properties of tissues by imaging propagating mechanical waves within the tissue. In this study, we hypothesize that changes in arterial wall stiffness, experimentally induced by formalin fixation, can be measured using MRE in ex vivo porcine aortas. In agreement with our hypothesis, the significant stiffness increase after sample fixation was clearly demonstrated by MRE and confirmed by mechanical testing. The results indicate that MRE can be used to examine the stiffness changes of the aorta. This study has provided evidence of the effectiveness of using MRE to directly assess the stiffness change in aortic wall. The results offer motivation to pursue MRE as a noninvasive method for the evaluation of arterial wall mechanical properties.

Test-retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C.

PURPOSE: To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis-C-infected subjects. MATERIALS AND METHODS: A biopsy-correlated repeatability study using four-slice MRE was conducted in five healthy and four HCV-infected subjects. Subjects were scanned twice on day 1 and after 7-14 days. Each slice was acquired during a 14-s breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare). Results were analyzed by two independent analysts. RESULTS: The intraclass correlation coefficient (ICC) was 0.85 (90% confidence interval [CI]: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects. CONCLUSION: MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for noninvasive assessment of liver fibrosis (CLINICALTRIALS.GOV IDENTIFIER: NCT00896233).

Noninvasive In vivo assessment of renal tissue elasticity during graded renal ischemia using MR elastography.

OBJECTIVES: : Magnetic resonance elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE. MATERIAL AND METHODS: : In 6 anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20%, 40%, 60%, 80%, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE 6 weeks after induction of chronic unilateral RAS (n = 6) or control (n = 3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining. RESULTS: : During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, P = 0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80% ± 5.4% stenosis) in which RBF was decreased by 60% ± 14% compared with controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, P = 0.3), despite histologic evidence of renal tissue fibrosis. CONCLUSION: : Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.

Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension.

OBJECTIVE: Liver stiffness is associated with portal hypertension in patients with chronic liver disease. However, the relation between spleen stiffness and clinically significant portal hypertension remains unknown. The purposes of this study were to determine the feasibility of measuring spleen stiffness with MR elastography and to prospectively test the technique in healthy volunteers and in patients with compensated liver disease. MATERIALS AND METHODS: Spleen stiffness was measured with MR elastography in 12 healthy volunteers (mean age, 37 years; range, 25-82 years) and 38 patients (mean age, 56 years; range, 36-60 years) with chronic liver disease of various causes. For patients with liver disease, laboratory findings, spleen size, presence and size of esophageal varices, and liver histologic results were recorded. Statistical analyses were performed to assess all measurements. RESULTS: MR elastography of the spleen was successfully performed on all volunteers and patients. The mean spleen stiffness was significantly lower in the volunteers (mean, 3.6 +/- 0.3 kPa) than in the patients with liver fibrosis (mean, 5.6 +/- 5.0 kPa; range, 2.7-19.2 kPa; p < 0.001). In addition, a significant correlation was observed between liver stiffness and spleen stiffness for the entire cohort (r(2) = 0.75; p < 0.001). Predictors of spleen stiffness were splenomegaly, spleen volume, and platelet count. A mean spleen stiffness of 10.5 kPa or greater was identified in all patients with esophageal varices. CONCLUSION: MR elastography of the spleen is feasible and shows promise as a quantitative method for predicting the presence of esophageal varices in patients with advanced hepatic fibrosis.

Assessment of hepatic fibrosis with magnetic resonance elastography.

BACKGROUND & AIMS: Accurate detection of hepatic fibrosis is crucial for assessing prognosis and candidacy for treatment in patients with chronic liver disease. Magnetic resonance (MR) elastography, a technique for quantitatively assessing the mechanical properties of soft tissues, has been shown previously to have potential for noninvasively detecting liver fibrosis. The goal of this work was to obtain preliminary estimates of the sensitivity and specificity of the technique in diagnosing liver fibrosis, and to assess its potential for identifying patients who potentially can avoid a biopsy procedure. METHODS: MR elastography was performed in 35 normal volunteers and 50 patients with chronic liver disease. MR imaging measurements of hepatic fat to water ratios were obtained to assess the potential for fat infiltration to affect stiffness-based detection of fibrosis. RESULTS: Liver stiffness increased systematically with fibrosis stage. Receiver operating curve analysis showed that, with a shear stiffness cut-off value of 2.93 kilopascals, the predicted sensitivity and specificity for detecting all grades of liver fibrosis is 98% and 99%, respectively. Receiver operating curve analysis also provided evidence that MR elastography can discriminate between patients with moderate and severe fibrosis (grades 2-4) and those with mild fibrosis (sensitivity, 86%; specificity, 85%). Hepatic stiffness does not appear to be influenced by the degree of steatosis. CONCLUSIONS: MR elastography is a safe, noninvasive technique with excellent diagnostic accuracy for assessing hepatic fibrosis. Based on the high negative predictive value of MR elastography, an initial clinical application may be to triage patients who are under consideration for biopsy examination to assess possible hepatic fibrosis.

Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography.

Chronic liver disease is a world-wide problem that causes progressive hepatic fibrosis as a hallmark of progressive injury. At present, the gold standard for diagnosing hepatic fibrosis is liver biopsy, which is an invasive method with many limitations, including questionable accuracy and risks of complications. MR elastography (MRE), a phase-contrast MRI technique for quantitatively assessing the mechanical properties of soft tissues, is a potential noninvasive diagnostic method to assess hepatic fibrosis. In this work, MRE was evaluated as a quantitative method to assess the in vivo mechanical properties of the liver tissues in a knockout animal model of liver fibrosis. This work demonstrates that the shear stiffness of liver tissue increases systematically with the extent of hepatic fibrosis, as measured by histology. A linear correlation between liver stiffness and fibrosis extent was well-defined in this animal model. An additional finding of the study was that fat infiltration, commonly present in chronic liver disease, does not significantly correlate with liver stiffness at each fibrosis stage and thus does not appear to interfere with the ability of MRE to assess fibrosis extent. In conclusion, MRE has the potential not only for assessing liver stiffness, but also for monitoring potential therapies for hepatic fibrosis.