The epidemiologic and economic impact of varicella and herpes zoster vaccination in South Korea: A mathematical modelling study.

BACKGROUND: In South Korea, the National Immunization Program has included one-dose varicella vaccination for 1-year-olds since 2005. This study examines the potential impact of introducing a two-dose varicella vaccination for children, along with zoster vaccination for adults, using either the zoster vaccine live (ZVL) or recombinant zoster vaccine (RZV). METHODS: The investigation considered four strategies in a base case scenario. The first involved introducing zoster vaccination for 60-year-olds, with a 60 % coverage. The second strategy combined zoster vaccination with a second-dose varicella vaccination for 4-year-olds, with a 90 % coverage. An age-structured model spanning 50 years was employed, assuming a zoster vaccine catch-up campaign over the initial 5 years. Cost-effectiveness analyses were conducted, assessing incremental cost-effectiveness ratios (ICERs), incremental net monetary benefits (INMBs), and net loss under different ages at zoster vaccination (50, 60, 65, and 70 years) and varying willingness-to-pay (WTP) levels from ₩40 million ($34,998) to ₩84 million ($74,000). RESULTS: All strategies were cost-effective and significantly reduced herpes zoster (HZ) incidence, preventing approximately 3,077,000 to 7,609,000 cases, depending on the chosen strategy. The combined strategy prevented around 4,950,000 varicella and 653,000 HZ cases additionally. RZV outperformed ZVL by preventing twice as many HZ cases and offering greater QALY gains. However, ZVL was more cost-effective due to its lower cost. Probabilistic sensitivity analyses revealed that RZV became more cost-effective at higher WTP thresholds, exceeding ₩60.9 million ($53,193) in terms of ICER and ₩62.5 million ($54,591) for INMBs and net loss. The optimal age for zoster vaccination was 60 years concerning ICER but 50 years regarding INMB. CONCLUSIONS: Combining RZV with a two-dose varicella vaccination strategy reduced the disease burden and improved QALY more effectively, though ZVL remained more cost-effective at lower WTP levels. Decisions regarding vaccination policies should be balanced between the public health needs and WTP levels.

Cost-Benefit Analysis of Tafenoquine for Radical Cure of Plasmodium vivax Malaria in Korea.

BACKGROUND: Plasmodium vivax malaria has a persistent liver stage that causes relapse, and introducing tafenoquine to suppress relapse could aid in disease eradication. Therefore, we assessed the impact of tafenoquine introduction on P. vivax malaria incidence and performed a cost-benefit analysis from the payer's perspective. METHODS: We expanded the previously developed P. vivax malaria dynamic transmission model and calibrated it to weekly civilian malaria incidences in 2014-2018. Primaquine and tafenoquine scenarios were considered by assuming different relapse probabilities, and relapse and total P. vivax malaria cases were predicted over the next decade for each scenario. We then estimated the number of cases prevented by replacing primaquine with tafenoquine. The cost and benefit of introducing tafenoquine were obtained using medical expenditure from a nationwide database, and a cost-benefit analysis was conducted. A probabilistic sensitivity analysis was performed to assess the economic feasibility robustness of tafenoquine introduction under uncertainties of model parameters, costs, and benefits. RESULTS: Under 0.04 primaquine relapse probability, the introduction of tafenoquine with relapse probability of 0.01 prevented 129 (12.27%) and 35 (77.78%) total and relapse cases, respectively, over the next decade. However, under the same relapse probability as primaquine, introducing tafenoquine had no additional preventative effect. The 14-day primaquine treatment cost was $3.71. The tafenoquine and the glucose-6-phosphate dehydrogenase rapid diagnostic testing cost $57.37 and $7.76, totaling $65.13. The average medical expenditure per malaria patient was estimated at $1444.79. The cost-benefit analysis results provided an incremental benefit-cost ratio (IBCR) from 0 to 3.21 as the tafenoquine relapse probability decreased from 0.04 to 0.01. The probabilistic sensitivity analysis showed an IBCR > 1, indicating that tafenoquine is beneficial, with a probability of 69.1%. CONCLUSION: Tafenoquine could reduce P. vivax malaria incidence and medical costs and bring greater benefits than primaquine.

Estimation of single-dose varicella vaccine effectiveness in South Korea using mathematical modeling.

In South Korea, despite the implementation of a universal single-dose vaccination program for children aged 12-15 months in 2005, the varicella incidence rate remains significant. Prior case-control studies have reported that currently used varicella vaccines are extremely inefficacious. We estimated vaccine effectiveness (VE) by fitting a dynamic transmission model to age-specific varicella incidence data from 2007 to 2015 and available vaccine coverage data. The initial vaccine efficacy and primary failure rates were estimated to be 61.1% and 38.9%, respectively. The average duration of protection was 21.4 years. The mean VE [(1-relative risk) %] for the simulated data of 2004-2014 birth cohorts decreased from 59.8% to 50.7% over 9 years. This mathematical modeling study demonstrated that the single-dose vaccine exhibits moderate effectiveness, and a high proportion of primary failure could be a main cause of breakthrough infections. Therefore, a two-dose vaccination strategy should be considered.

Hyperoxia-Induced ΔR1: MRI Biomarker of Histological Infarction in Acute Cerebral Stroke.

OBJECTIVE: To evaluate whether hyperoxia-induced ΔR1 (hyperO2ΔR1) can accurately identify histological infarction in an acute cerebral stroke model. MATERIALS AND METHODS: In 18 rats, MRI parameters, including hyperO2ΔR1, apparent diffusion coefficient (ADC), cerebral blood flow and volume, and 18F-fluorodeoxyglucose uptake on PET were measured 2.5, 4.5, and 6.5 hours after a 60-minutes occlusion of the right middle cerebral artery. Histological examination of the brain was performed immediately following the imaging studies. MRI and PET images were co-registered with digitized histological images. The ipsilateral hemisphere was divided into histological infarct (histological cell death), non-infarct ischemic (no cell death but ADC decrease), and non-ischemic (no cell death or ADC decrease) areas for comparisons of imaging parameters. The levels of hyperO2ΔR1 and ADC were measured voxel-wise from the infarct core to the non-ischemic region. The correlation between areas of hyperO2ΔR1-derived infarction and histological cell death was evaluated. RESULTS: HyperO2ΔR1 increased only in the infarct area (p ≤ 0.046) compared to the other areas. ADC decreased stepwise from non-ischemic to infarct areas (p = 0.002 at all time points). The other parameters did not show consistent differences among the three areas across the three time points. HyperO2ΔR1 sharply declined from the core to the border of the infarct areas, whereas there was no change within the non-infarct areas. A hyperO2ΔR1 value of 0.04 s-1 was considered the criterion to identify histological infarction. ADC increased gradually from the infarct core to the periphery, without a pronounced difference at the border between the infarct and non-infarct areas. Areas of hyperO2ΔR1 higher than 0.04 s-1 on MRI were strongly positively correlated with histological cell death (r = 0.862; p < 0.001). CONCLUSION: HyperO2ΔR1 may be used as an accurate and early (2.5 hours after onset) indicator of histological infarction in acute stroke.

Deterministic Tractography Analysis of Rat Brain Using SIGMA Atlas in 9.4T MRI.

Preclinical studies using rodents have been the choice for many neuroscience researchers due totheir close reflection of human biology. In particular, research involving rodents has utilized MRI to accurately identify brain regions and characteristics by acquiring high resolution cavity images with different contrasts non-invasively, and this has resulted in high reproducibility and throughput. In addition, tractographic analysis using diffusion tensor imaging to obtain information on the neural structure of white matter has emerged as a major methodology in the field of neuroscience due to its contribution in discovering significant correlations between altered neural connections and various neurological and psychiatric diseases. However, unlike image analysis studies with human subjects where a myriad of human image analysis programs and procedures have been thoroughly developed and validated, methods for analyzing rat image data using MRI in preclinical research settings have seen significantly less developed. Therefore, in this study, we present a deterministic tractographic analysis pipeline using the SIGMA atlas for a detailed structural segmentation and structural connectivity analysis of the rat brain's structural connectivity. In addition, the structural connectivity analysis pipeline presented in this study was preliminarily tested on normal and stroke rat models for initial observation.

Estimating the basic reproductive number of varicella in South Korea incorporating social contact patterns and seroprevalence.

Varicella, which is caused by the varicella zoster virus (VZV), is a common infectious disease affecting children. Varicella vaccines have been used for decades; however, vaccination policies vary across countries because of differences in VZV epidemiology. The basic reproductive number R0a transmissibility measure parameter, also differs from country to country. In this study R0 for varicella was estimated in South Korea using the contact rate matrix derived from averaged POLYMOD contact data, the Korean population, and proportionality factor fitted to the Korean VZV seroprevalence R0 for varicella in South Korea was estimated to be 5.67 (95% CI: 5.33, 6.33). Therefore, to reach the herd immunity threshold, the critical vaccine coverage should be greater than 82.4% with a perfect vaccine, or the primary vaccine failure proportion should be less than 17.6% with 100% coverage. Because of the relatively low seroconversion rate and rapidly waning immunity after one-dose vaccination in South Korea, the herd immunity threshold is difficult to attain with only a one-dose vaccine. Two doses of vaccination may be necessary to effectively interrupt varicella transmission and maintain herd immunity in South Korea. The study results can help guide the decision-making on an effective varicella vaccination policy in South Korea.

The impact of two-dose varicella vaccination on varicella and herpes zoster incidence in South Korea using a mathematical model with changing population demographics.

BACKGROUND: In South Korea, one-dose varicella vaccination was introduced to the National Immunization Program in 2005, but varicella outbreaks have continued to occur. Therefore, a two-dose vaccination strategy is considered. METHODS: We developed an age-structured deterministic compartment model using Korean population projection data. The impact of adding a second dose of varicella vaccine on varicella and herpes zoster (HZ) epidemiology was assessed under four different vaccine effectiveness (VE) scenarios (base, moderate, lowest, highest) and the optimal timing of the second vaccine dose (18 months, 4, 5, or 6 years of age) was examined over the period 2020-2065. RESULTS: A two-dose vaccination schedule reduced the cumulative varicella incidence by > 90% compared to no vaccination, regardless of the VE. The additional reduction attributable to a second dose compared to a single dose was greatest (82%) with the lowest VE scenario. A second dose at 6 years of age reduced the varicella incidence at a population level, whereas a second dose at 18 months of age reduced the varicella incidence primarily in the target birth cohorts. Routine vaccination at the age of 18 months with a catch-up vaccination of 6-year-olds was the optimal strategy for birth cohort and population-level control. HZ incidence continued to increase under no vaccination scenario, which represents the effect of aging population. Under a two-dose scenario, the additional increase in HZ incidence attributable to the reduced exogenous boosting was small relative to a one-dose scenario and a further reduction in HZ cases was observed. CONCLUSION: A two-dose varicella vaccination schedule would significantly reduce varicella and HZ incidence in the long term. A second dose at the age of 18 months with a catch-up vaccination of 6-year-olds would be optimal for controlling varicella in South Korea.

Modelling the impact of rapid diagnostic tests on Plasmodium vivax malaria in South Korea: a cost-benefit analysis.

BACKGROUND: Rapid diagnostic tests (RDTs) are widely used for diagnosing Plasmodium vivax malaria, especially in resource-limited countries. However, the impact of RDTs on P. vivax malaria incidence and national medical costs has not been evaluated. We assessed the impact of RDT implementation on P. vivax malaria incidence and overall medical expenditures in South Korea and performed a cost-benefit analysis from the payer's perspective. METHODS: We developed a dynamic compartmental model for P. vivax malaria transmission in South Korea using delay differential equations. Long latency and seasonality were incorporated into the model, which was calibrated to civilian malaria incidences during 2014-2018. We then estimated averted malaria cases and total medical costs from two diagnostic scenarios: microscopy only and both microscopy and RDTs. Medical costs were extracted based on data from a hospital in an at-risk area for P. vivax malaria and were validated using Health Insurance Review and Assessment Service data. We conducted a cost-benefit analysis of RDTs using the incremental benefit:cost ratio (IBCR) considering only medical costs and performed a probabilistic sensitivity analysis to reflect the uncertainties of model parameters, costs and benefits. RESULTS: The results showed that 55.3% of new P. vivax malaria cases were averted, and $696 214 in medical costs was saved over 10 years after RDT introduction. The estimated IBCR was 2.5, indicating that RDT implementation was beneficial, compared with microscopy alone. The IBCR was sensitive to the diagnosis time reduction, infectious period and short latency period, and provided beneficial results in a benefit over $10.6 or RDT cost under $39.7. CONCLUSIONS: The model simulation suggested that RDTs could significantly reduce P. vivax malaria incidence and medical costs. Moreover, cost-benefit analysis demonstrated that the introduction of RDTs was beneficial over microscopy alone. These results support the need for widespread adoption of RDTs.

Cost-effectiveness analysis of pre-exposure prophylaxis for the prevention of HIV in men who have sex with men in South Korea: a mathematical modelling study.

In February 2018, the Ministry of Food and Drug Safety in Korea approved tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) co-formulate for use in pre-exposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) infection. This study aimed to estimate the cost-effectiveness of PrEP in men who have sex with men (MSM), a major risk group emerging in Korea. A dynamic compartmental model was developed for HIV transmission and progression in MSM aged 15-64 years. With a combined model including economic analysis, we estimated averted HIV infections, changes in HIV prevalence, discounted costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). PrEP was evaluated in both the general MSM and high-risk MSM populations and was assumed to reduce infection risk by 80%. Implementing PrEP in all MSM would avert 75.2% HIV infections and facilitate a gain of 37,372 QALYs at a cost of $274,822 per QALY gained over 20 years relative to the status quo. Initiating PrEP in high-risk MSM with an average of eight partners per year (around 20% of MSM) would improve the cost-effectiveness, averting 78.0% HIV infections and add 29,242 QALYs at a cost of $51,597 per QALY gained, which is within the willingness-to-pay threshold for Korea of $56,000/QALY gained. This result was highly sensitive to annual PrEP costs, quality-of-life for people who are on PrEP, and initial HIV prevalence. Initiating PrEP in a larger proportion of MSM in Korea would prevent more HIV infections, but at an increasing cost per QALY gained. Focusing PrEP on higher risk MSM and any reduction in PrEP cost would improve cost-effectiveness.

Cerebral mapping of glutamate using chemical exchange saturation transfer imaging in a rat model of stress-induced sleep disturbance at 7.0T.

BACKGROUND: Glutamate chemical exchange saturation transfer (GluCEST) imaging has been widely used in brain psychiatric disorders. Glutamate signal changes may help to evaluate the sleep-related disorders, and could be useful in diagnosis. PURPOSE: To evaluate signal changes in the hippocampus and cortex of a rat model of stress-induced sleep disturbance using GluCEST. STUDY TYPE: Prospective animal study. ANIMAL MODEL: Fourteen male Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: 7.0T small bore MRI / fat-suppressed, turbo-rapid acquisition with relaxation enhancement (RARE) for CEST, and spin-echo, point-resolved proton MR spectroscopy (1 H MRS). ASSESSMENT: Rats were divided into two groups: the stress-induced sleep-disturbance group (SSD, n = 7) and the control group (CTRL, n = 7), to evaluate and compare the cerebral glutamate signal changes. GluCEST data were quantified using a conventional magnetization transfer ratio asymmetry in the left- and right-side hippocampus and cortex. The correlation between GluCEST signal and glutamate concentrations, derived from 1 H MRS, was evaluated. STATISTICAL ANALYSIS: Wilcoxon rank-sum test between CEST signals and multiparametric MR signals, Wilcoxon signed-rank test between CEST signals on the left and right hemispheres, and a correlation test between CEST signals and glutamate concentrations derived from 1 H MRS. RESULTS: Measured GluCEST signals showed significant differences between the two groups (left hippocampus; 4.23 ± 0.27% / 5.27 ± 0.42% [SSD / CTRL, P = 0.002], right hippocampus; 4.50 ± 0.44% / 5.04 ± 0.34% [P = 0.035], left cortex; 2.81 ± 0.38% / 3.56 ± 0.41% [P = 0.004], and right cortex; 2.95 ± 0.47% / 3.82 ± 0.26% [P = 0.003]). GluCEST signals showed positive correlation with glutamate concentrations (R2 = 0.312; P = 0.038). DATA CONCLUSION: GluCEST allowed the visualization of cerebral glutamate changes in rats subjected to sleep disturbance, and may yield valuable insights for interpreting alterations in cerebral biochemical information. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1866-1872.

Changes to gamma-aminobutyric acid levels during short-term epileptiform activity in a kainic acid-induced rat model of status epilepticus: A chemical exchange saturation transfer imaging study.

PURPOSE: To evaluate temporal changes in gamma-aminobutyric acid (GABA) signals in the hippocampus during epileptiform activity induced by kainic acid (KA) in a rat model of status epilepticus using chemical exchange saturation transfer (CEST) imaging technique. METHODS: CEST imaging and 1H magnetic resonance spectroscopy (1H MRS) were applied to a systemic KA-induced rat model to compare GABA signals. All data acquisition and analytical procedures were performed at three different time points (before KA injection, and 1 and 3 h after injection). The CEST signal was analyzed based on regions of interests (ROIs) in the hippocampus, while 1H MRS was analyzed within a 12.0 µL ROI in the left hippocampus. Signal correlations between the two methods were evaluated as a function of time change up to 3 h after KA injection. RESULTS: The measured GABA CEST-weighted signal intensities of the rat epileptic hippocampus before injection showed significant differences from those after (averaged signals from both hippocampi: 4.37% ±â€¯0.87% and 7.305 ±â€¯1.11%; P < 0.05), although the signal had increased slightly at both time points after KA injection, the differences were not significant (P > 0.05). In contrast, the correlation between the CEST imaging values and 1H MRS was significant (r ≥ 0.64; P < 0.05; in all cases). CONCLUSIONS: GABA signal changes during epileptiform activity in the rat hippocampus, as detected using CEST imaging, provided a significant contrast according to changes in metabolic activity. Our technical approach may serve as a potential supplemental option to provide biomarkers for brain disease.

Amide proton transfer-weighted MRI can detect tissue acidosis and monitor recovery in a transient middle cerebral artery occlusion model compared with a permanent occlusion model in rats.

OBJECTIVES: To assess whether increases in amide proton transfer (APT)-weighted signal reflect the effects of tissue recovery from acidosis using transient rat middle cerebral artery occlusion (MCAO) models, compared to permanent occlusion models. MATERIALS AND METHODS: Twenty-four rats with MCAO (17 transient and seven permanent occlusions) were prepared. APT-weighted signal (APTw), apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and MR spectroscopy were evaluated at three stages in each group (occlusion, reperfusion/1 h post-occlusion, and 3 h post-reperfusion/4 h post-occlusion). Deficit areas showing 30% reduction to the contralateral side were measured. Temporal changes were compared with repeated measures of analysis of variance. Relationship between APTw and lactate concentration was calculated. RESULTS: Both APTw and CBF values increased and APTw deficit area reduced at reperfusion (largest p = .002) in transient occlusion models, but this was not demonstrated in permanent occlusion. No significant temporal change was demonstrated with ADC at reperfusion. APTw deficit area was between ADC and CBF deficit areas in transient occlusion model. APTw correlated with lactate concentration at occlusion (r = - 0.49, p = .04) and reperfusion (r = - 0.32, p = .02). CONCLUSIONS: APTw values increased after reperfusion and correlated with lactate content, which suggests that APT-weighted MRI could become a useful imaging technique to reflect tissue acidosis and its reversal. KEY POINTS: • APT-weighted signal increases in the tissue reperfusion, while remains stable in the permanent occlusion. • APTw deficit area was between ADC and CBF deficit areas in transient occlusion model, possibly demonstrating metabolic penumbra. • APTw correlated with lactate concentration during ischemia and reperfusion, indicating tissue acidosis.

Hyperoxia-Induced ΔR1.

Background and Purpose- Acceleration of longitudinal relaxation under hyperoxic challenge (ie, hyperoxia-induced ΔR1) indicates oxygen accumulation and reflects baseline tissue oxygenation. We evaluated the feasibility of hyperoxia-induced ΔR1 for evaluating cerebral oxygenation status and degree of ischemic damage in stroke. Methods- In 24-hour transient stroke rat models (n=13), hyperoxia-induced ΔR1, ischemic severity (apparent diffusion coefficient [ADC]), vasogenic edema (R2), total and microvascular blood volume (superparamagnetic iron oxide-driven ΔR2* and ΔR2, respectively), and glucose metabolism activity (18F-fluorodeoxyglucose uptake on positron emission tomography) were measured. The distribution of these parameters according to hyperoxia-induced ΔR1 was analyzed. The partial pressure of tissue oxygen change during hyperoxic challenge was measured using fiberoptic tissue oximetry. In 4-hour stroke models (n=6), ADC and hyperoxia-induced ΔR1 was analyzed with 2,3,5-triphenyltetrazolium chloride staining being a criterion of infarction. Results- Ischemic hemisphere showed significantly higher hyperoxia-induced ΔR1 than nonischemic brain in a pattern depending on ADC. During hyperoxic challenge, ischemic hemisphere demonstrated uncontrolled increase of partial pressure of tissue oxygen, whereas contralateral hemisphere rapidly plateaued. Ischemic hemisphere also demonstrated significant correlation between hyperoxia-induced ΔR1 and R2. Hyperoxia-induced ΔR1 showed a significant negative correlation with 18F-fluorodeoxyglucose uptake. The ADC, R2, ΔR2, and 18F-fluorodeoxyglucose uptake showed a dichotomized distribution according to the hyperoxia-induced ΔR1 as their slopes and values were higher at low hyperoxia-induced ΔR1 (<50 ms-1) than at high ΔR1. In 4-hour stroke rats, the distribution of ADC according to the hyperoxia-induced ΔR1 was similar with 24-hour stroke rats. The hyperoxia-induced ΔR1 was greater in the infarct area (47±10 ms-1) than in peri-infarct area (16±4 ms-1; P<0.01). Conclusions- Hyperoxia-induced ΔR1 adequately indicates cerebral oxygenation and can be a feasible biomarker to classify the degree of ischemia-induced damage in neurovascular function and metabolism in stroke brain.

Reducing effects of dispersal on the bias of 2-sample mark-recapture estimators of stream fish abundance.

The 2-sample mark-recapture method with Chapman's estimator is often used by inland fishery managers to estimate the reach-scale abundance of stream fish. An important assumption of this method is that no dispersal into or out of the study reach occurs between the two samples. Violations of this assumption are probably common in practice, but their effect on bias (systematic error) of abundance estimates is poorly understood, especially in small populations. Estimation methods permitting dispersal exist but, for logistical reasons, often are infeasible for routine assessments in streams. The purpose of this paper is to extend available results regarding effects of dispersal on the bias of Chapman's estimator as applied to reach-scale studies of stream fish abundance. We examine for the first time the joint effects of dispersal and sampling variation on the bias of this estimator. To reduce the bias effects of dispersal, we propose a modified sampling scheme in which the original study reach is expanded, a central subreach is sampled during the mark session (sample 1), and the entire reach is sampled during the recapture session (sample 2). This modified sampling scheme can substantially reduce bias effects of dispersal without requiring unique marking of individual fish or additional site visits. Analytical and simulation results show that sampling variation tends to create negative bias with respect to study-reach abundance, while dispersal tends to create positive bias; the net effect can be positive, negative, or zero, depending on the true abundance, capture probabilities, and amount and nature of dispersal. In most cases, simply expanding the study reach is an effective way to reduce dispersal-related bias of Chapman's estimator, but expanding the study reach and employing the modified sampling scheme we propose is a better alternative for accurately estimating abundance with the same level of sampling effort.

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters.

Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic-contrast-enhanced MRI (DCE-MRI) using extravascular extracellular agent (Gd-DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region-dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment-induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α-caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

Influence of B1-Inhomogeneity on Pharmacokinetic Modeling of Dynamic Contrast-Enhanced MRI: A Simulation Study.

OBJECTIVE: To simulate the B1-inhomogeneity-induced variation of pharmacokinetic parameters on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: B1-inhomogeneity-induced flip angle (FA) variation was estimated in a phantom study. Monte Carlo simulation was performed to assess the FA-deviation-induced measurement error of the pre-contrast R1, contrast-enhancement ratio, Gd-concentration, and two-compartment pharmacokinetic parameters (Ktrans, ve, and vp). RESULTS: B1-inhomogeneity resulted in -23-5% fluctuations (95% confidence interval [CI] of % error) of FA. The 95% CIs of FA-dependent % errors in the gray matter and blood were as follows: -16.7-61.8% and -16.7-61.8% for the pre-contrast R1, -1.0-0.3% and -5.2-1.3% for the contrast-enhancement ratio, and -14.2-58.1% and -14.1-57.8% for the Gd-concentration, respectively. These resulted in -43.1-48.4% error for Ktrans, -32.3-48.6% error for the ve, and -43.2-48.6% error for vp. The pre-contrast R1 was more vulnerable to FA error than the contrast-enhancement ratio, and was therefore a significant cause of the Gd-concentration error. For example, a -10% FA error led to a 23.6% deviation in the pre-contrast R1, -0.4% in the contrast-enhancement ratio, and 23.6% in the Gd-concentration. In a simulated condition with a 3% FA error in a target lesion and a -10% FA error in a feeding vessel, the % errors of the pharmacokinetic parameters were -23.7% for Ktrans, -23.7% for ve, and -23.7% for vp. CONCLUSION: Even a small degree of B1-inhomogeneity can cause a significant error in the measurement of pharmacokinetic parameters on DCE-MRI, while the vulnerability of the pre-contrast R1 calculations to FA deviations is a significant cause of the miscalculation.

Difference in the intratumoral distributions of extracellular-fluid and intravascular MR contrast agents in glioblastoma growth.

Contrast enhancement by an extracellular-fluid contrast agent (CA) (Gd-DOTA) depends primarily on the blood-brain-barrier permeability (bp), and transverse-relaxation change caused by intravascular T2 CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single-CA-using dynamic contrast-enhanced MRI (DCE-MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd-DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2 mL). bp was quantified according to the non-PK parameters of Gd-DOTA-using DCE-MRI (wash-in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION-induced ΔR2 * and ΔR2 . With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual-contrast MRI demonstrated a different region-oriented distribution between Gd-DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR2 and ΔR2 ) as the tumor increased in size; (d) the tumor center showed greater bp-indicating parameters, i.e. wash-in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI-histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate-dextran signals and up-regulated immunoreactivity of CD31-VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular-fluid Gd chelates and intravascular SPION.

Enhanced Thalamic Functional Connectivity with No fMRI Responses to Affected Forelimb Stimulation in Stroke-Recovered Rats.

Neurological recovery after stroke has been extensively investigated to provide better understanding of neurobiological mechanism, therapy, and patient management. Recent advances in neuroimaging techniques, particularly functional MRI (fMRI), have widely contributed to unravel the relationship between the altered neural function and stroke-affected brain areas. As results of previous investigations, the plastic reorganization and/or gradual restoration of the hemodynamic fMRI responses to neural stimuli have been suggested as relevant mechanisms underlying the stroke recovery process. However, divergent study results and modality-dependent outcomes have clouded the proper interpretation of variable fMRI signals. Here, we performed both evoked and resting state fMRI (rs-fMRI) to clarify the link between the fMRI phenotypes and post-stroke functional recovery. The experiments were designed to examine the altered neural activity within the contra-lesional hemisphere and other undamaged brain regions using rat models with large unilateral stroke, which despite the severe injury, exhibited nearly full recovery at ∼6 months after stroke. Surprisingly, both blood oxygenation level-dependent and blood volume-weighted (CBVw) fMRI activities elicited by electrical stimulation of the stroke-affected forelimb were completely absent, failing to reveal the neural origin of the behavioral recovery. In contrast, the functional connectivity maps showed highly robust rs-fMRI activity concentrated in the contra-lesional ventromedial nucleus of thalamus (VM). The negative finding in the stimuli-induced fMRI study using the popular rat middle cerebral artery model denotes weak association between the fMRI hemodynamic responses and neurological improvement. The results strongly caution the indiscreet interpretation of stroke-affected fMRI signals and demonstrate rs-fMRI as a complementary tool for efficiently characterizing stroke recovery.

Simultaneous evaluation of vascular morphology, blood volume and transvascular permeability using SPION-based, dual-contrast MRI: imaging optimization and feasibility test.

Exploiting ultrashort-T(E) (UTE) MRI, T1-weighted positive contrast can be obtained from superparamagnetic iron oxide nanoparticles (SPIONs), which are widely used as a robust T2-weighted, negative contrast agent on conventional MR images. Our study was designed (a) to optimize the dual-contrast MRI method using SPIONs and (b) to validate the feasibility of simultaneously evaluating the vascular morphology, blood volume and transvascular permeability using the dual-contrast effect of SPIONs. All studies were conducted using 3 T MRI. According to numerical simulation, 0.15 mM was the optimal blood SPION concentration for visualizing the positive contrast effect using UTE MRI (T(E) = 0.09 ms), and a flip angle of 40° could provide sufficient SPION-induced enhancement and acceptable measurement noise for UTE MR angiography. A pharmacokinetic study showed that this concentration can be steadily maintained from 30 to 360 min after the injection of 29 mg/kg of SPIONs. An in vivo study using these settings displayed image quality and CNR of SPION-enhanced UTE MR angiography (image quality score 3.5; CNR 146) comparable to those of the conventional, Gd-enhanced method (image quality score 3.8; CNR 148) (p > 0.05). Using dual-contrast MR images obtained from SPION-enhanced UTE and conventional spin- and gradient-echo methods, the transvascular permeability (water exchange index 1.76-1.77), cerebral blood volume (2.58-2.60%) and vessel caliber index (3.06-3.10) could be consistently quantified (coefficient of variation less than 9.6%; Bland-Altman 95% limits of agreement 0.886-1.111) and were similar to the literature values. Therefore, using the optimized setting of combined SPION-based MRI techniques, the vascular morphology, blood volume and transvascular permeability can be comprehensively evaluated during a single session of MR examination.

Dual MRI T1 and T2(*) contrast with size-controlled iron oxide nanoparticles.

Contrast-enhancing magnetic resonance mechanism, employing either positive or negative signal changes, has contrast-specific signal characteristics. Although highly sensitive, negative contrast typically decreases the resolution and spatial specificity of MRI, whereas positive contrast lacks a high contrast-to-noise ratio but offers high spatial accuracy. To overcome these individual limitations, dual-contrast acquisitions were performed using iron oxide nanoparticles and a pair of MRI acquisitions. Specifically, vascular signals in MR angiography were positively enhanced using ultrashort echo (UTE) acquisition, which provided highly resolved vessel structures with increased vessel/tissue contrast. In addition, fast low angle shot (FLASH) acquisition yielded strong negative vessel contrast, resulting in the higher number of discernible vessel branches than those obtained from the UTE method. Taken together, the high sensitivity of the negative contrast delineated ambiguous vessel regions, whereas the positive contrast effectively eliminated the false negative contrast areas (e.g., airways and bones), demonstrating the benefits of the dual-contrast method. FROM THE CLINICAL EDITOR: In this study, the MRI properties of iron oxide nanoparticles were studied in an animal model. These contrast agents are typically considered negative contrast materials, leading to signal loss on T2* weighted images, but they also have known T1 effects as well, which is lower than that of standard positive contrast agents (like gadolinium or manganese) but is still detectable. This dual property was utilized in this study, demonstrating high sensitivity of the negative contrast in delineating ambiguous vessel regions, whereas the positive contrast eliminated false negative contrast areas (areas giving rise to susceptibility effects).