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Biomedical subjects

T S Hatsukami

Publications and source records attributed to T S Hatsukami.

At least 19 recordsLinked to original sources
PubMed2005

Carotid plaque composition differs between ethno-racial groups: an MRI pilot study comparing mainland Chinese and American Caucasian patients.

OBJECTIVE: Ethnicity-based research may identify new clues to the pathogenesis of atherosclerotic disease. Therefore, we sought to determine whether carotid lesions differ between 20 Chinese and 20 Caucasian Americans by MRI. METHODS AND RESULTS: Inclusion criteria were >50% stenosis as measured by duplex ultrasound and recent symptoms attributed to carotid artery disease. The patients were imaged in 2 centers (Beijing, China and Seattle, Wash) using a standardized protocol. Both carotid arteries were reviewed quantitatively (lumen, wall, outer wall, tissue components) and morphologically (lesion types, fibrous cap status). Significant differences between the Chinese and Americans were found for the mean size of the lipid/necrotic core (13.6 versus 7.8 mm2; P=0.002), percentage of slices with calcified type VII lesions (1.6 versus 12.4%; P=0.03), and percentage of slices with early type III lesions (19.3 versus 9.3%; P=0.02). Furthermore, the mean outer wall area in the common carotid artery was larger in the Chinese population (P=0.007). CONCLUSIONS: This pilot study suggests that composition and morphology of atherosclerotic lesions in symptomatic carotid disease differ between ethno-racial groups. Quantitative MRI-based review of carotid atherosclerosis comparing plaque morphology and composition between ethno-racial groups is feasible, and future MRI studies may improve our understanding of the pathophysiology of this disease.

Aged↗
PubMed2004

Differentiation of intraplaque versus juxtaluminal hemorrhage/thrombus in advanced human carotid atherosclerotic lesions by in vivo magnetic resonance imaging.

BACKGROUND: Intraplaque hemorrhage and juxtaluminal hemorrhage/thrombus may differ in cause and clinical implications. This study tested the hypothesis that MRI can distinguish between intraplaque hemorrhage and juxtaluminal hemorrhage/thrombus and investigated the association between hemorrhage and underlying lesion types. METHODS AND RESULTS: Twenty-six patients scheduled for carotid endarterectomy were imaged with a 1.5-T GE scanner by a multicontrast-weighted MRI technique. Hemorrhages were identified with previously established MRI criteria, and differentiations were made between intraplaque and juxtaluminal hemorrhage/thrombus. Corresponding histology was used to confirm the magnetic resonance findings. Tissues underlying areas of hemorrhage/thrombus were histologically categorized according to modified American Heart Association criteria. Of 190 matched sections, 140 contained areas of hemorrhage by histology, of which MRI correctly detected 134. The sensitivity and specificity for MRI to correctly identify cross sections that contained hemorrhage were 96% and 82%, respectively. Furthermore, MRI was able to distinguish juxtaluminal hemorrhage/thrombus from intraplaque hemorrhage with an accuracy of 96%. The distribution of lesion types underlying hemorrhages differed significantly (P=0.004). Intraplaque hemorrhage had an underlying lipid-rich type IV/V lesion in 55% of histological sections, whereas juxtaluminal hemorrhage/thrombus had an underlying calcified lesion type VII in 70% of sections. CONCLUSIONS: In vivo high-resolution MRI can detect and differentiate intraplaque hemorrhage from juxtaluminal hemorrhage/thrombus with good accuracy. The association of hemorrhage and lesion types suggests potential differences in origin. Noninvasive MRI therefore provides a possible tool for prospectively studying differences in origin of plaque hemorrhage and the association of plaque progression and instability.

Carotid Artery Diseases↗
PubMed2004

Quantitative evaluation of carotid plaque composition by in vivo MRI.

OBJECTIVE: This study evaluates the ability of MRI to quantify all major carotid atherosclerotic plaque components in vivo. METHODS AND RESULTS: Thirty-one subjects scheduled for carotid endarterectomy were imaged with a 1.5T scanner using time-of-flight-, T1-, proton density-, and T2-weighted images. A total of 214 MR imaging locations were matched to corresponding histology sections. For MRI and histology, area measurements of the major plaque components such as lipid-rich/necrotic core (LR/NC), calcification, loose matrix, and dense (fibrous) tissue were recorded as percentages of the total wall area. Intraclass correlation coefficients (ICCs) were computed to determine intrareader and inter-reader reproducibility. MRI measurements of plaque composition were statistically equivalent to those of histology for the LR/NC (23.7 versus 20.3%; P=0.1), loose matrix (5.1 versus 6.3%; P=0.1), and dense (fibrous) tissue (66.3% versus 64%; P=0.4). Calcification differed significantly when measured as a percentage of wall area (9.4 versus 5%; P<0.001). Intrareader and inter-reader reproducibility was good to excellent for all tissue components, with ICCs ranging from 0.73 to 0.95. CONCLUSIONS: MRI-based tissue quantification is accurate and reproducible. This application can be used in therapeutic clinical trials and in prospective longitudinal studies to examine carotid atherosclerotic plaque progression and regression.

Aged↗
PubMed2001

In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques.

BACKGROUND: High-resolution MRI has been shown to be capable of identifying plaque constituents, such as the necrotic core and intraplaque hemorrhage, in human carotid atherosclerosis. The purpose of this study was to evaluate differential contrast-weighted images, specifically a multispectral MR technique, to improve the accuracy of identifying the lipid-rich necrotic core and acute intraplaque hemorrhage in vivo. METHODS AND RESULTS: Eighteen patients scheduled for carotid endarterectomy underwent a preoperative carotid MRI examination in a 1.5-T GE Signa scanner using a protocol that generated 4 contrast weightings (T1, T2, proton density, and 3D time of flight). MR images of the vessel wall were examined for the presence of a lipid-rich necrotic core and/or intraplaque hemorrhage. Ninety cross sections were compared with matched histological sections of the excised specimen in a double-blinded fashion. Overall accuracy (95% CI) of multispectral MRI was 87% (80% to 94%), sensitivity was 85% (78% to 92%), and specificity was 92% (86% to 98%). There was good agreement between MRI and histological findings, with a value of kappa=0.69 (0.53 to 0.85). CONCLUSIONS: Multispectral MRI can identify the lipid-rich necrotic core in human carotid atherosclerosis in vivo with high sensitivity and specificity. This MRI technique provides a noninvasive tool to study the pathogenesis and natural history of carotid atherosclerosis. Furthermore, it will permit a direct assessment of the effect of pharmacological therapy, such as aggressive lipid lowering, on plaque lipid composition.

Carotid Arteries↗
PubMed2001

A multi-scale method for automatic correction of intensity non-uniformity in MR images.

In this paper, a novel multi-scale method for coil sensitivity profile correction is presented based on wavelet transform. A magnetic resonance (MR) image can be decomposed into two spaces by the wavelet transform: approximate space and residual space. The approximate templates in approximate space can be thought of as multi-scale sensitivity profiles of the surface coil for coil correction. When we choose a suitable filter for decomposition, one of the sensitivity profiles should be optimal among the multi-scale sensitivity profiles. The optimal sensitivity profile can be chosen automatically by an analysis of the contents of the two spaces. The multi-scale method does not rely on any data other than the image generated by the MR scanner. The experiment showed promising results based on one-dimensional simulation and images of phantom and human images.

Artifacts↗
PubMed2001

Comparison of carotid vessel wall area measurements using three different contrast-weighted black blood MR imaging techniques.

Measuring carotid artery plaque burden from MRI is a reliable method for monitoring regression and progression of atherosclerosis. However, to measure all available images would be very time consuming, and in practice the image quality (IQ) of these images may be inconsistent, which can directly impact the quality of measurement. It is hypothesized that if IQ is comparable among different contrast weighted images, then carotid artery area measurements obtained from different contrast images of the same location will produce identical results. To test this, T1, proton density and T2 weighted images were acquired from ten patients (51 +/- 7 years old). Carotid lumen and vessel wall area was measured using a custom designed software program. The results showed strong agreement evidenced with only small differences on both lumen (mean: 40.5 mm(2)) and wall (mean: 52.6 mm(2)) area measurement among different weighted images. The maximum absolute mean differences are less than 2.7 mm(2) and 4.4 mm(2), and 90(th) percentile of the absolute differences are 5.6 mm(2) and 8.2 mm(2) respectively. In conclusion, different contrast weighted images with high and comparable IQ will yield similar results in lumen and vessel wall area measurement. At each matched location, it is recommended that the image with the highest IQ be used for area measurement.

Carotid Arteries↗
PubMed2001

Assessment of a policy to reduce placement of prosthetic hemodialysis access.

BACKGROUND: The aim of this study was to evaluate the determinants of access patency and revision, including the effects of reducing the placement of prosthetic hemodialysis access. METHODS: A retrospective cohort study of all hemodialysis accesses placed at the Veteran's Administration Puget Sound Health Care System between 1992 and 1999 was conducted. A policy was instituted in 1996 that maximized the use of autogenous hemodialysis access. The impacts of the policy change, demographics, and comorbid factors on access type and patency, were examined. Primary and secondary patency rates were examined using the Kaplan--Meier method, and factors associated with failure and revision were examined using Cox proportional hazard models and Poisson regression. RESULTS: During the study, 104 accesses (61 prosthetic grafts and 43 autogenous fistulas) were placed prior to 1996, and 118 (31 prosthetic grafts and 87 autogenous fistulas) were placed after 1996. There was a significant increase in autogenous fistulas placed after 1996 (87 out of 118) compared with before 1996 (43 out of 104, P < 0.001). At one year, autogenous fistulas demonstrated superior primary patency (56 vs. 36%, P = 0.001) and secondary patency (72 vs. 58%, P = 0.003) compared with prosthetic grafts. After adjustment for age, race, side of access placement, and history of prior access placement, patients with a prosthetic graft were estimated to experience a 78% increase in the risk of primary access failure when compared with similar patients having an autogenous access [adjusted relative risk (aRR) = 1.78, 95% CI 1.21--2.62, P = 0.003)]. Similarly, the adjusted relative risk of secondary access failure for comparing prosthetic grafts with autogenous fistulas was estimated to be 2.21 (95% CI 1.38--3.54, P = 0.001). The adjusted risk of access revision was 2.89-fold higher for prosthetic grafts than for autogenous fistulas (95% CI 1.88--4.44, P < 0.001). CONCLUSIONS: Autogenous conduits demonstrated superior performance when compared with prosthetic grafts in terms of primary and secondary patency and number of revisions. A policy emphasizing the preferential placement of autogenous fistulas over prosthetic grafts may result in improved patency and a reduction in the number of procedures required to maintain dialysis access patency.

Adult↗
PubMed2001

Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study.

High-resolution magnetic resonance imaging (MRI) with flow suppression not only provides useful information on luminal and wall areas of the carotid artery but also can identify the principal tissue components of the carotid atherosclerotic plaque. The effects of intensive lipid-lowering therapy on these MRI tissue characteristics were examined in patients with coronary disease (CAD). Eight CAD patients who have been receiving intensive lipid-lowering treatment (niacin 2.5 g/d, lovastatin 40 mg/d, and colestipol 20 g/d) for 10 years in the Familial Atherosclerosis Treatment Study (FATS) follow-up were randomly selected from among 60 such treated patients. Eight CAD patients who were matched to the treated patients for age (+/-3 years), baseline low density lipoprotein (+/-5 mg/dL), and triglycerides (+/-50 mg/dL) but who had never been treated with lipid-lowering drugs were selected as controls. For each of these 32 carotid arteries, luminal and plaque areas were measured by planimetry, in a blinded protocol, from the magnetic resonance image that showed most plaque. Fibrous tissue, calcium, and lipid deposits were identified on the basis of established criteria. Plaque composition was estimated as a fraction of total planimetered area. Patients treated with 10-year intensive lipid-lowering therapy, compared with control subjects, had significantly lower low density lipoprotein cholesterol levels (84 versus 158 mg/dL, respectively; P<0.001) and higher high density lipoprotein cholesterol levels (51 versus 37 mg/dL, respectively; P<0.001). As a group, treated patients, compared with untreated control subjects, had a smaller core lipid area (0.7 versus 10.2 mm(2), respectively; P=0.01) and lipid composition (1% versus 17%, respectively). Group differences in luminal area (55 [treated] versus 44 [control] mm(2), P=NS) and plaque area (58 [treated] versus 64 [control] mm(2), P=NS) tended to favor treatment. MRI appears useful for estimating carotid plaque size and composition. Hyperlipidemic CAD patients frequently (97%) have at least moderate (>/=40% area stenosis) carotid plaque. In this case-control study, prolonged intensive lipid-lowering therapy is associated with a markedly decreased lipid content, a characteristic of clinically stable plaques.

Calcinosis↗
PubMed2001

High-Resolution magnetic resonance imaging of normal and atherosclerotic human coronary arteries ex vivo: discrimination of plaque tissue components.

BACKGROUND: Noninvasive detection of plaque lipid and calcium in human atherosclerosis may have clinical utility, because the presence of each may be associated with increased risk of plaque disruption. Magnetic resonance imaging (MRI) has the potential to detect both plaque lipid and calcium. However, no previous studies have: 1) used an MR coil with sufficient resolution to image the components of human coronary arteries, 2) evaluated the utility of a combination of different MR contrast weightings in discriminating plaque components in human coronary arteries, or 3) used sensitive and specific histological stains for lipid and calcium to determine their MR image characteristics in human atherosclerosis. METHODS: Using a custom-made surface coil on a whole-body, 1.5T MRI scanner, high resolution MR images were obtained from 22 nonatherosclerotic and atherosclerotic human coronary artery segments and then compared with histological sections stained for neutral lipid, calcium, and ribrous and cellular components. RESULTS: With a multicontrast protocol using T1-, proton density-, and T2-weighted images, statistically significant differences were found among MR image contrast values for regions identified by histological stains as containing lipid only, calcium only, mixed lipid and calcium, or fibrous tissue. All four of these histologically defined region types could be differentiated from one another by a multicontrast MRI protocol. Of the 22 segments, 10 (45%) contained areas with combined plaque lipid and calcium; calcium would not have been recognized histologically in these regions without the use of a specific calcium stain. CONCLUSIONS: These results demonstrate that multicontrast MRI can produce remarkably high-resolution images and can discriminate between clinically relevant components of the atherosclerotic vessel wall.

Calcium↗
PubMed2000

Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging.

BACKGROUND: The results of studies of advanced lesions of atherosclerosis suggest that the thickness of the fibrous cap that overlies the necrotic core distinguishes the stable lesion from one that is at high risk for rupture and thromboembolic events. We have developed a high-resolution MRI technique that can identify the fine structure of the lesion, including the fibrous cap, in vivo. The aim of the present study was to determine the agreement between in vivo MRI and lesion architecture as seen on histology and gross tissue examination to identify fibrous cap thickness and rupture. METHODS AND RESULTS: Twenty-two subjects who were scheduled for carotid endarterectomy underwent MRI with a 3-dimensional multiple overlapping thin slab angiography protocol. The appearance of the fibrous cap was categorized as (1) an intact, thick, (2) an intact, thin, or (3) a ruptured fibrous cap on MRI, gross, and histological sections. Thirty-six sites were available for comparison between MRI and histology. There was a high level of agreement between MRI and histological findings: 89% agreement, kappa (95% CI)=0.83 (0.67 to 1. 0), weighted kappa=0.87. Spearman's correlation coefficient was 0.88 (significant to the 0.01 level). CONCLUSIONS: These findings indicate that high-resolution MRI with a 3-dimensional multiple overlapping thin slab angiography protocol is capable of distinguishing intact, thick fibrous caps from intact thin and disrupted caps in atherosclerotic human carotid arteries in vivo. This noninvasive technique has the potential to permit studies that examine the relationship between fibrous cap changes and clinical outcome and to permit trials that evaluate therapy intended to "stabilize" the fibrous cap.

Carotid Arteries↗
PubMed2000

Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype.

The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P=0.005; DZOase, P=0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P<0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a "level crossing" approach that includes intervening phenotypes in the study of complexly inherited disease.

Aged↗
PubMed2000

Human carotid artery smooth muscle cells rarely express alpha(v)beta3 integrin at sites of recent plaque rupture.

Fibrin(ogen) is the major matrix ligand for beta3 integrins. If alpha(v)beta3 is the major receptor for fibrin(ogen) on intimal smooth muscle cells, we might expect to see this integrin associated with fibrin(ogen). Eighty-four specimens obtained from endarterectomies of 14 patients were studied. Fibrin was frequently observed in carotid intima even at the non-atherosclerotic areas. As for beta1 and beta3 integrins, beta1 was predominant in intima. The alpha(v)beta3 integrin expression was less frequent than alpha5beta1, another receptor for fibrin(ogen), in diffuse intimal thickening, fibrous cap and advanced plaques. Furthermore, alpha(v)beta3 was generally negative on smooth muscle cells in recent plaque ruptures. In conclusion, we suggest more attention should be paid on abundant fibrin matrix in intima. Histologically, the alpha5beta1 integrin rather than the alpha(v)beta3 is the major receptor for fibrin in intimal smooth muscle cells.

Adolescent↗
PubMed1998

Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging.

BACKGROUND: Current imaging modalities, such as contrast angiography, accurately determine the degree of luminal narrowing but provide no direct information on plaque size. Magnetic resonance imaging (MRI), however, has potential for noninvasively determining arterial wall area (WA). This study was conducted to determine the accuracy of in vivo MRI for measuring the cross-sectional maximum wall area (MaxWA) of atherosclerotic carotid arteries in a group of patients undergoing carotid endarterectomy. METHODS AND RESULTS: Fourteen patients scheduled for carotid endarterectomy underwent preoperative carotid MRI using a custom-made phased-array coil. The plaques were excised en bloc and scanned using similar imaging parameters. MaxWA measurements from the ex vivo MRI were used as the reference standard and compared with MaxWA measurements from the corresponding in vivo MR study. Agreement between the in vivo and ex vivo measurement was analyzed using the Bland-Altman method. The paired in vivo and ex vivo MaxWA measurements strongly agreed: the mean difference (in vivo minus ex vivo) in MaxWA was 13.1+/-6.5 mm2 for T1-weighted (T1W) imaging (mean MaxWA in vivo=94.7 mm2, ex vivo=81.6 mm2) and 14.1+/-11.7 mm2 for proton density-weighted (PDW) imaging (mean MaxWA in vivo=93.4 mm2, ex vivo=79.3 mm2). Intraobserver and interobserver variability was small, with intraclass correlation coefficients ranging from 0.90 to 0.98. CONCLUSIONS: MRI is highly accurate for in vivo measurement of artery WA in atherosclerotic carotid lesions. This imaging technique has potential application monitoring lesion size in studies examining plaque progression and/or regression.

Arteriosclerosis↗
PubMed1997

In vitro and in situ magnetic resonance imaging signal features of atherosclerotic plaque-associated lipids.

The goal of this study was to evaluate magnetic resonance imaging (MRI) signal features of the different types of lipids found in human atherosclerotic plaques. A 1.5-T SIGNA scanner was used to acquire T1-, T2-, and proton density-weighted data at four different temperatures for individual lipids and lipid mixtures designed to replicate the proportions of lipids found in plaques. Individual lipids and lipid mixtures were scanned both in a test tube and after implantation in the media of normal porcine aortas. Each of the three broad classes of lipids (triglycerides, unesterified and esterified cholesterol, and phospholipids) had different and distinct MR signal patterns, which allowed discrimination of these classes of lipids in vitro. Further, lipid implantation studies demonstrated that these distinct MR signal patterns could be used to readily distinguish each lipid type from surrounding porcine aortic media. MR signals from lipid mixtures demonstrated marked regional heterogeneity, similar to the heterogeneous lipid distribution characteristic of human atherosclerotic plaques. In summary, MR signals from lipid mixtures that mimic plaque lipid proportions can be detected at body temperature, especially in those mixtures with an increased percentage of cholesteryl esters. These studies raise the possibility that with further advances in technology, MRI may become a useful tool for determining the lipid content and composition of human atherosclerotic plaques in vivo.

Anhydrides↗
PubMed1997

Carotid plaque morphology and clinical events.

BACKGROUND AND PURPOSE: Studies have suggested that B-mode ultrasonography can be used to determine carotid plaque composition and that specific plaque characteristics are associated with a worse clinical outcome. However, histological studies examining the relationship between carotid plaque morphology and clinical outcome have reported conflicting findings. Furthermore, few investigators have described plaque morphology in quantifiable terms. This study examines the association between the volume of carotid plaque constituents and preoperative ischemic neurological symptoms. Constituents examined were chosen based on their potential for identification by current diagnostic imaging modalities such as ultrasound or MRI. METHODS: Atherosclerotic plaques from 43 patients undergoing carotid endarterectomy were examined histologically, with sections obtained every 0.5 to 1 mm. The lesions were examined for the presence and quantity of fibrous intimal tissue, intraplaque hemorrhage, lipid core, necrotic plaque core, and calcification. The quantity of each constituent was compared in plaques removed from symptomatic patients with those excised from asymptomatic individuals. Differences were analyzed with a Kolmogorov-Smirnov statistic. RESULTS: There was no difference between plaques removed from asymptomatic and symptomatic patients with regard to the presence and volume of fibrous intimal tissue, intraplaque hemorrhage, the lipid core, the necrotic core, or calcification. CONCLUSIONS: In patients with highly stenotic carotid lesions who are undergoing carotid endarterectomy, gross plaque composition is similar regardless of preoperative symptom status. Given this similarity, it is unlikely that differences in the volume of intraplaque hemorrhage, lipid core, necrotic core, or calcification in atherosclerotic carotid plaques explain their embolic history.

Aged↗
PubMed1996

A clinical marker for arterial wall healing: the double line.

PURPOSE: B-mode imaging of a normal arterial wall shows two echo-dense lines separated by an echolucent zone. Immediately after carotid endarterectomy, this double-line pattern is no longer detectable, but it subsequently reappears in some patients. The objective of this study was to test the hypothesis that the postoperative double line is associated with a lower incidence of carotid restenosis. METHODS: Carotid arteries were serially studied with B-mode ultrasound imaging at 2 weeks and 1, 2, 3, 6, 9, 12, 18, and 24 months after carotid endarterectomy. The wall of the common carotid artery 1 to 2 cm distal to the proximal endarterectomized shelf was analyzed for the presence, quality, and thickness of double lines. All hemodynamically significant stenoses (> or = 50% diameter reducing) were documented with standard duplex scanning criteria. RESULTS: Twenty-four carotid arteries in 23 patients were studied for a mean of 14.7 months (range, 3 to 24 months). A double line developed in 21 common carotid arteries (87.5%) at a mean time of 3.2 months (range, 0.5 to 9.0 months) after surgery with a mean thickness of 0.65 mm (SD = 0.17 mm) at the time of initial detection. A single hemodynamically significant stenosis developed in this group. All three of the remaining arteries that did not form the double-line pattern developed hemodynamically significant stenoses. Carotid restenosis was more likely to occur in arteries that did not form double lines (p < 0.05, Fisher's exact test). CONCLUSIONS: The majority of carotid arteries re-form a double line after endarterectomy. These arteries are less likely to develop restenotic lesions caused by myointimal hyperplasia.

Aged↗