Imaging as a surrogate marker of drug efficacy in cardiovascular disease.
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ABSTRACT:
SUBMITTER: Tarkin JM
PROVIDER: S-EPMC6580750 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Imaging as a surrogate marker of drug efficacy in cardiovascular disease.
Tarkin Jason M JM Dweck Marc R MR Rudd James H F JHF
Heart (British Cardiac Society) 20181031 7
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Project description:ObjectiveRecognizing what physicians know and do not know about a particular disease is one of the keys to designing clinical decision support systems, since these systems can fulfill complementary role by recognizing this boundary. To our knowledge, however, no study has attempted to quantify how many diseases physicians actually know and thus the boundary is unclear. This study explores a method to solve this problem by investigating whether the vocabulary assessment techniques developed in the linguistics field can be applied to assess physicians' knowledge.MethodsThe test design required us to pay special attention to disease knowledge assessment. First, to avoid imposing unnecessary burdens on the physicians, we chose a self-assessment questionnaire that was straightforward to fill out. Second, to prevent overestimation, we used a "pseudo-word" approach: fictitious diseases were included in the questionnaire, and positive responses to them were penalized. Third, we used paper-based tests, rather than computer-based ones, to further prevent participants from cheating by using a search engine. Fourth, we selectively used borderline diseases, i.e., diseases that physicians might or might not know about, rather than well-known or little-known diseases, in the questionnaire.ResultsWe collected 102 valid answers from 109 physicians who attended the seminars we conducted. On the basis of these answers, we estimated that the average physician knew of 2008 diseases (95% confidence interval: (1939, 2071)). This preliminary estimation agrees with the guideline for the national license examination in Japan, suggesting that this vocabulary assessment was able to evaluate physicians' knowledge. The survey included physicians with various backgrounds, but there were no significant differences between subgroups. Other implication for researches on clinical decision support and limitation of the sampling method adopted in this study are also discussed, toward more rigorous estimation in future surveys.
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Project description:The risk prediction of future cardiovascular events is mainly based on conventional risk factor assessment by validated algorithms, such as the Framingham Risk Score, the Pooled Cohort Equations and the European SCORE Risk Charts. The identification of subclinical atherosclerosis has emerged as a promising tool to refine the individual cardiovascular risk identified by these models, to prognostic stratify asymptomatic individuals and to implement preventive strategies. Several imaging modalities have been proposed for the identification of subclinical organ damage, the main ones being coronary artery calcification scanning by cardiac computed tomography and the two-dimensional ultrasound evaluation of carotid arteries. In this context, echocardiography offers an assessment of cardiac calcifications at different sites, such as the mitral apparatus (including annulus, leaflets and papillary muscles), aortic valve and ascending aorta, findings that are associated with the clinical manifestation of atherosclerotic disease and are predictive of future cardiovascular events. The aim of this paper is to summarize the available evidence on clinical implications of cardiac calcification, review studies that propose semiquantitative ultrasound assessments of cardiac calcifications and evaluate the potential of ultrasound calcium scores for risk stratification and prevention of clinical events.
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Project description:Background and purposeThe development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-[(11)C]-verapamil PET/MR imaging with cyclosporin A, a p-glycoprotein inhibitor.Materials and methodsSix patients with drug-resistant epilepsy, 5 patients with drug-sensitive epilepsy, and 8 healthy controls underwent dynamic (R)-[(11)C]-verapamil PET/MR imaging with an intravenous infusion of cyclosporin A. Asymmetry indices [(Right Region - Left Region)/(Right Region + Left Region) × 200%] of the standard uptake values in each of the paired lobes were calculated.ResultsAll patients with drug-resistant epilepsy had significantly different asymmetry from the healthy controls, whereas all patients with drug-sensitive epilepsy had asymmetry similar to that in healthy controls. In the temporal lobe, the asymmetry indices of patients with left temporal lobe drug-resistant epilepsy were more positive than those of healthy controls (healthy controls: 4.0413 ± 1.7452; patients: 7.2184 ± 1.8237; P = .048), and those of patients with right temporal drug-resistant epilepsy were more negative (patients: -1.6496 ± 3.4136; P = .044). In addition, specific regions that had significant asymmetry were different between the lateral and medial temporal lobe epilepsy groups. In the frontal lobe, the asymmetry index of patients with right frontal lobe drug-resistant epilepsy was more negative than that in healthy controls.ConclusionsWe confirmed that statistical parametric mapping analysis by using asymmetry indices of (R)-[(11)C]-verapamil PET/MR imaging with cyclosporin A could be used as a surrogate marker for drug-resistant epilepsy, and this approach might be helpful for localizing or lateralizing the epileptic zone.
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Project description:Genome-wide Illumina InfiniumMethylation 450 K DNA methylation analysis was performed on blood samples from clinical atherosclerosis patients (n = 8) and healthy donors (n = 8) in the LVAD study (NCT02174133, NCT01799005). Multiple differentially methylated regions (DMR) could be identified in atherosclerosis patients, related to epigenetic control of cell adhesion, chemotaxis, cytoskeletal reorganisations, cell proliferation, cell death, estrogen receptor pathways and phagocytic immune responses. Furthermore, a subset of 34 DMRs related to impaired oxidative stress, DNA repair, and inflammatory pathways could be replicated in an independent cohort study of donor-matched healthy and atherosclerotic human aorta tissue (n = 15) and human carotid plaque samples (n = 19). Upon integrated network analysis, BRCA1 and CRISP2 DMRs were identified as most central disease-associated DNA methylation biomarkers. Differentially methylated BRCA1 and CRISP2 regions were verified by MassARRAY Epityper and pyrosequencing assays and could be further replicated in blood, aorta tissue and carotid plaque material of atherosclerosis patients. Moreover, methylation changes at BRCA1 and CRISP2 specific CpG sites were consistently associated with subclinical atherosclerosis measures (coronary calcium score and carotid intima media thickness) in an independent sample cohort of middle-aged men with subclinical cardiovascular disease in the Aragon Workers' Health Study (n = 24). Altogether, BRCA1 and CRISP2 DMRs hold promise as novel blood surrogate markers for early risk stratification and CVD prevention.
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Project description:The abnormal phosphorylation of tau is a necessary precursor to the formation of tau fibrils, a marker of Alzheimer's disease. We hypothesize that hyperphosphorylative conditions may result in unique cell surface markers. We identify and demonstrate the utility of such surrogate markers to identify the hyperphosphorylative state. Methods: Cell SELEX was used to identify novel thioaptamers specifically binding hyperphosphorylative cells. Cell surface vimentin was identified as a potential binding target of the aptamer. Novel molecular magnetic resonance imaging (M-MRI) probes using these aptamers and a small molecule ligand to vimentin were used for in vivo detection of this pre-pathological state. Results: In a mouse model of pathological tau, we demonstrated in vivo visualization of the hyperphosphorylative state by M-MRI, enabling the identification at a pre-pathological stage of mice that develop frank tau pathology several months later. In vivo visualization of the hyperphosphorylative state by M-MRI was further validated in a second mouse model (APP/PS1) of Alzheimer's disease again identifying the mutants at a pre-pathological stage. Conclusions: M-MRI of the hyperphosphorylative state identifies future tau pathology and could enable extremely early-stage diagnosis of Alzheimer's disease, at a pre-patholgical stage.
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Project description:Background and objectivesExperimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD.Design, setting, participants, & measurementsPlasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125I-iothalamate and 131I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry.ResultsIn these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R=0.47] and albuminuria [R=0.39] and negatively with GFR [R=-0.58] and effective renal blood flow [R=-0.52], all P<0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P<0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P=0.7, 0.9, and 0.3, respectively).ConclusionsOn cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents.
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