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Biomedical subjects

Uri Goldbourt

Publications and source records attributed to Uri Goldbourt.

At least 19 recordsLinked to original sources
PubMed2006

Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease.

BACKGROUND: Mild renal insufficiency is increasingly recognized as an independent risk factor for cardiovascular disease. However, few data exist regarding its relation to risk of ischemic stroke. METHODS: Patients with chronic coronary heart disease and measured serum creatinine levels (n = 6,685) were followed up for incident ischemic stroke or TIA over 4.8 to 8.1 years. Glomerular filtration rate was estimated by the Cockroft-Gault equation and by the four-component Modification of Diet in Renal Disease (MDRD) equation and a rate < or =60 mL/minute/1.73 m2 defined chronic kidney disease (CKD). RESULTS: Among 6,685 patients, a quarter of patients had CKD. Adjusting for conventional risk factors and related medications, patients with CKD exhibited 1.54-fold hazard ratios (95% CI 1.13 to 2.09) of incident ischemic stroke or TIA by the Cockroft-Gault equation (1.53; 95% CI 1.16 to 2.01 by the MDRD equation). The corresponding adjusted hazard ratio associated with an increment of 1 SD in GFR was 0.71 (95% CI 0.57 to 0.88) when estimated by the Cockroft-Gault equation (0.84; 95% CI 0.75 to 0.95 estimated by the MDRD equation). CONCLUSIONS: Mild degrees of renal dysfunction are associated with increased risk of incident ischemic stroke or TIA in patients with pre-existing atherothrombotic disease. These findings expand the recommendation that patients with renal dysfunction should be considered as a high-risk group for cardiovascular disease and for ischemic stroke.

Age Distribution↗
PubMed2006

Serum homocysteine and long-term risk of myocardial infarction and sudden death in patients with coronary heart disease.

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 mumol/l increment was associated with a 25% higher risk.

Bezafibrate↗
PubMed2006

C-reactive protein as a predictor of incident ischemic stroke among patients with preexisting cardiovascular disease.

BACKGROUND AND PURPOSE: C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk. METHODS: We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years. RESULTS: Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels. CONCLUSIONS: These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Aged↗
PubMed2006

Perceptual, social, and behavioral factors associated with delays in seeking medical care in patients with symptoms of acute stroke.

BACKGROUND AND PURPOSE: Despite availability of reperfusion therapy for acute ischemic stroke, most patients remain ineligible mainly because of late hospital arrival. We hypothesized that perceptual, social, and behavioral factors affect delays in seeking help after symptom onset. METHODS: Patients presenting with stroke symptoms were interviewed about symptom experiences, interpretations, and reactions. Odds ratios (95% CI) for risk of delay >3 hours were estimated, and variables associated with increased risk and representing demographic, clinical, perceptual, social, and behavioral factors were included in an assessment of the effect of combined risk factors on delay. RESULTS: Among 209 patients (mean age 61.8+/-12 years, 69% men) the median time interval from symptom awareness to seeking help was 2 (0.5 to 9) hours and to hospital arrival, 4.2 (1.3 to 14.5) hours. On multivariate adjustment, perceiving symptoms as severe (odds ratio [OR]: 0.42; 0.17 to 0.95), advice from others to seek help (OR: 0.18; 0.05 to 0.63), and contacting an ambulance (OR: 0.26; 0.10 to 0.63) were associated with decreased risks of delay, whereas perceived control of symptoms (OR: 2.45; 1.08 to 5.71) increased risk of delay in seeking help. Risk of delay in hospital arrival was 3 times greater in women than in men. Increasing proportions of patients who delayed seeking help were observed with increasing numbers of combined risk factors, ranging from 17% to 94% for 0 to 1 and 6 to 7 factors, respectively. CONCLUSIONS: Perceptual, social, and behavioral factors contribute to delay in seeking medical care in acute ischemic stroke beyond demographic and clinical variables, and, when combined, further increase risk of delay. These findings may be important for designing programs to reduce delay.

Behavior↗
PubMed2006

CD40 ligand and risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.

BACKGROUND: CD40 ligand (CD40L) is a trimeric, transmembrane protein of the tumor necrosis factor family and together with its receptor CD40 is an important contributor to the inflammatory processes that lead to atherosclerosis, plaque destabilization, and thrombosis. METHODS: In order to assess the association between serum concentrations of CD40 ligand (CD40L) and risk of future ischemic stroke and coronary events among patients with chronic CHD, we obtained baseline serum samples from patients (n = 3090) with chronic CHD enrolled in a secondary prevention trial. With a prospective nested case-control design, we measured baseline CD40L concentration in sera of patients who subsequently developed myocardial infarction, sudden cardiac death or ischemic stroke during follow-up (cases, n = 233) and in 233 age- and gender-matched pairs without any subsequent cardiovascular events. RESULTS: Relative odds for recurrent cardiovascular events per one natural log unit difference of CD40L were 0.97 (95%CI, 0.82-1.16). No increase in relative odds for recurrent cardiovascular events was observed per increasing quartiles of CD40L concentrations. In analysis for individual end-points, different trends of risks were observed beyond the 95 percentile for ischemic stroke (OR 2.22; 95%CI, 0.46-12.5) and for recurrent coronary events (OR 0.35; 95%CI, 0.07-1.37), but falling short of statistical significance. CONCLUSION: High serum concentrations of CD40L were not associated with increased risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.

Biomarkers↗
PubMed2006

Dietary fat intake and risk of coronary heart disease: the Strong Heart Study.

BACKGROUND: The results of previous studies on the association between dietary fat intake and coronary heart disease (CHD) incidence are inconsistent. OBJECTIVE: The aim of this study was to examine the association between dietary fat intake and CHD incidence in American Indians in the Strong Heart Study. DESIGN: A total of 2938 participants aged 47-79 y and free of CHD at the second examination (1993-1995) were examined and followed for CHD, nonfatal CHD, and fatal CHD events to 31 December 2002. Dietary intake was assessed by using a 24-h diet recall and was calculated as percentages of energy. RESULTS: Participants were followed for a mean (+/-SD) of 7.2 +/- 2.3 y. During follow-up, 436 incident CHD cases (298 nonfatal CHD and 138 fatal CHD events) were ascertained. Participants aged 47-59 y in the highest quartile of intake of total fat, saturated fatty acids, or monounsaturated fatty acids had higher CHD mortality than did those in the lowest quartile [hazard ratio (95% CI): 3.57 (1.21, 10.49), 5.17 (1.64, 16.36), and 3.43 (1.17, 10.04), respectively] after confounders were controlled for. These associations were not observed for those aged 60-79 y. CONCLUSIONS: Total fat, saturated fatty acid, and monounsaturated fatty acid intake were strong predictors of CHD mortality in American Indians aged 47-59 y, independent of other established CHD risk factors. It may be prudent for American Indians to reduce their fat intake early in life to reduce the risk of dying from CHD.

Aged↗
PubMed2006

Serum uric acid and long-term mortality from stroke, coronary heart disease and all causes.

BACKGROUND: Increased serum uric acid (SUA) levels are linked to obesity, dyslipidemia, diabetes and hypertension. Whether SUA carries a risk for coronary heart disease (CHD) and stroke remains uncertain. DESIGN: A prospective cohort study. METHODS: Of an original cohort of middle-aged workers who were examined in 1963 and followed-up for 23 years, 9125 men, free of CHD at entry, are included in this study. Subjects were divided into quintiles according to baseline SUA levels. Hazard ratios (HR) for all-cause, CHD, and stroke mortality were estimated in SUA quintiles, with the third serving as a referent. RESULTS: During follow-up, 2893 deaths were recorded, including 830 ascribed to CHD and 292 to stroke. The HR for all death [1.22, 95% confidence interval (CI) 1.09-1.37] and CHD (1.29, 95% CI 1.05-1.58) were increased in the upper SUA quintile. Fatal stroke showed a U-shaped relationship as both the upper (HR 1.48, 95% CI 1.02-2.17) and bottom (HR 1.43, 95% CI 0.99-2.08) quintiles were associated with a higher risk. Adjustment for confounders reduced the HR of the upper quintile for all outcomes, but did not attenuate the association of the bottom quintile with stroke (HR 1.52, 95% CI 1.04-2.23). When analysed separately by stroke type, the latter association seemed to be stronger for hemorrhagic (HR 3.27, 95% CI 1.14-9.33) than for ischemic stroke (HR 1.34, 95% CI 0.87-2.05). CONCLUSION: In addition to findings supporting increased mortality among hyperuricemic subjects, we identified an association between low SUA levels and fatal stroke, which deserves further investigation.

Biomarkers↗
PubMed2006

Decrease in triglyceride level by bezafibrate is related to reduction of recurrent coronary events: a Bezafibrate Infarction Prevention substudy.

BACKGROUND: Fibrates were reported to be effective in reducing recurrent coronary events in coronary heart disease patients with elevated triglycerides. It is not known whether this effect is related to the extent of triglyceride reduction. METHODS: Participants comprised 3090 coronary heart disease patients enrolled in the Bezafibrate Infarction Prevention study, which showed a nonsignificant reduction (9.4%; P=0.26) in fatal or nonfatal myocardial infarction and sudden death during a mean follow-up time of 6.2 years. RESULTS: Significant reduction in triglyceride serum level was evident only among patients allocated to bezafibrate, ranging between 0.06 mmol/l (5 mg/dl) in the lowest decile of baseline triglycerides level and 0.68 mmol/l (60 mg/dl) in the highest baseline decile. The extent of triglyceride reduction with bezafibrate was significantly associated with the reduction of risk; relative risk reduction of 55% (hazards ratio: 0.45; 95% confidence interval: 0.24-0.84) was observed among patients with baseline triglycerides>or=2.26 mmol/l who reduced triglyceride level to >0.50 mmol/l (>44.3 mg/dl). In contrast, the risk of recurrent events among patients treated with bezafibrate and achieving less triglyceride reduction or failing to reduce triglyceride level was not significantly different from that of patients treated with placebo. CONCLUSION: Bezafibrate treatment was associated with significant risk reduction among coronary heart disease patients with elevated triglyceride levels that substantially reduced their triglyceride level with treatment.

Aged↗
PubMed2006

A national survey of acute cerebrovascular disease in Israel: burden, management, outcome and adherence to guidelines.

BACKGROUND: There are no national data on the burden and management of acute cerebrovascular disease in Israel. OBJECTIVES: To delineate the burden, characteristics, management and outcomes of hospitalized patients with acute cerebrovascular disease in Israel, and to examine adherence to current guidelines. METHODS: We prospectively performed a national survey in all 28 hospitals in Israel admitting patients with acute cerebrovascular events (stroke or transient ischemic attacks) during February and March 2004. RESULTS: During the survey period 2174 patients were admitted with acute cerebrovascular disease (mean age 71 +/- 13 years, 47% women; 89% ischemic stroke or TIA, 7% intracerebral hemorrhage and 4% undetermined stroke). Sixty-two percent of patients were admitted to departments of medicine and a third to neurology, of which only 7% were admitted to departments with a designated stroke unit. Head computed tomography was performed during hospitalization in 93% of patients. The overall rate of urgent thrombolytic therapy for acute ischemic stroke was 0.5%. Among patients with ischemic stroke or TIA, 94% were prescribed an antithrombotic medication at hospital discharge, and among those with atrial fibrillation about half were prescribed warfarin. Carotid duplex was performed in 30% and any vascular imaging study in 36% of patients with ischemic events. The mean (+/-SD) length of hospital stay was 12 +/- 27 days for ICH and 8 +/- 11 days for ischemic stroke. Among patients with ICH, 28% died during hospitalization and 66% died or remained with severe disability while for ischemic stroke the corresponding rates were 7% and 41% respectively. Mortality rates within 3 months were 34% for ICH and 14% for ischemic stroke. CONCLUSIONS: This national survey demonstrates the high burden of acute stroke in Israel and reveals discordance between existing guidelines and current practice. The findings highlight important areas for which reorganization is imperative for patients afflicted with acute stroke.

Acute Disease↗
PubMed2006

Physicians underdiagnose and undertreat obesity in ishemic heart disease patients: data from the HOLEM Study Group.

BACKGROUND: Obesity is an independent risk factor for ischemic heart disease and affects the status of other risk factors for cardiovascular disease. OBJECTIVE: To study the attitude of physicians to obesity by examining discharge letters of overweight patients with ischemic heart disease. METHODS: We used the HOLEM database for this analysis. The HOLEM project was designed to study the NCEP (National Cholesterol Education Program) guideline implementation among patients with IHD at hospital discharge. We documented the recording of risk factors and treatment recommendations for IHD by reviewing the discharge letters of 2994 IHD patients admitted to four central hospitals in Israel between 1998 and 2000. A follow-up visit was held 6-8 weeks after discharge, at which time the diagnosis of IHD was verified, risk factor status was checked, height and weight were measured and drug treatment was reviewed. RESULTS: Mean body mass index was 28.3 kg/m2 and 32% were obese (BMI > or = 30 kg/m2). Only 39.6% of the obese patients and 65.8% of the morbidly obese patients (BMI > or = 40 kg/m2) had "obesity" noted in their discharge letters, and weight loss recommendation was written in only 15% of the obese patients' discharge letters. Acute episodes like acute myocardial infarction and unstable angina did not influence the notation of obesity, and only BMI and the number of additional risk factors were positively correlated with the notation of this risk factor. CONCLUSIONS: Despite the importance of obesity, weight status was not noted and weight loss was not recommended in most of the discharge letters of obese IHD patients.

Aged↗
PubMed2005

Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial).

This study evaluated the association between changes in serum levels of high-density lipoprotein (HDL) cholesterol that occur under bezafibrate therapy and cardiac mortality in patients with coronary heart disease (CHD) who were enrolled in the Bezafibrate Infarction Prevention trial. We compared serum levels of HDL cholesterol in 1,509 patients in tertiles of on-treatment increments with those of 1,517 patients in the placebo group. Long-term follow-up showed that cardiac mortality decreased significantly with increasing tertiles of on-treatment change in HDL cholesterol (9.5%, 6.6%, and 6.3% of patients tertiles 1, 2, and 3, respectively, died of cardiac causes, p for trend = 0.02). In multivariate analysis, the magnitude of on-treatment increment of HDL cholesterol was independently associated with a decreased risk of cardiac death (hazard ratio 1.05, 95% confidence interval 0.74 to 1.47, for tertile 1; hazard ratio 0.73, 95% confidence interval 0.50 to 1.07, for tertile 2; hazard ratio 0.65, 95% confidence interval 0.43 to 0.97, for tertile 3, compared with placebo-allocated patients, p for trend = 0.02). Analyzing the association with change in HDL cholesterol as a continuous variable showed that the risk of cardiac mortality was decreased by 27% for every 5-mg/dl increase in on-treatment change in HDL cholesterol (p <0.001). In conclusion, although a definite secondary prevention effect of bezafibrate could not be found when examining the intervention group as a whole, our findings are consistent with a possible independent association between an increase in HDL cholesterol with bezafibrate therapy and a decrease in cardiac mortality. In appropriately selected patients, monitoring short-term response to bezafibrate therapy through change in HDL cholesterol may indicate the potential long-term benefit of the drug.

Aged↗
PubMed2005

The significance of various blood pressure indices for long-term stroke, coronary heart disease, and all-cause mortality in men: the Israeli Ischemic Heart Disease study.

BACKGROUND AND PURPOSE: Studies of blood pressure (BP) indices as disease predictors have offered conflicting conclusions. We compare pulse pressure (PP), systolic BP (SBP) and diastolic BP (DBP), and mean arterial pressure (MAP) as risk markers for long-term mortality with emphasis on stroke. METHODS: Male civil servants (40 to 65 years of age; n=9611) were examined in 1963 and followed up until 1986. Multivariate analysis was used to assess the association between BP indices and subsequent mortality. Stroke mortality was analyzed separately for initially normotensive (SBP< or =140 and DBP< or =90 mm Hg), hypertensive (SBP>140 and DBP>90 mm Hg), and men with isolated systolic hypertension (ISH; SBP>140 and DBP< or =90 mm Hg). RESULTS: During follow-up, 3167 men died, including 932 of coronary heart disease and 339 of stroke. All 4 BP indices were predictive of fatal stroke among hypertensive and normotensive men (hazard ratios [HRs] fluctuated between 1.59 and 2.51). In models with 2 BP indices among normotensive men, SBP but not DBP remained a predictor of stroke mortality. MAP and PP were independent predictors of stroke mortality. Among hypertensive men, SBP and DBP were independent predictors of stroke mortality (HRs, 1.68 and 1.51, respectively). MAP but not PP remained a predictor of stroke mortality. In men with ISH, the 4 BP indices predicted fatal stroke, with HRs fluctuating between 1.24 and 2.04. CONCLUSIONS: All 4 BP indices were predictors of stroke mortality among hypertensive and normotensive men, with DBP possibly the weaker predictor among the latter. Models with 2 BP indices yielded complex associations.

Adult↗
PubMed2005

Body fat distribution and long-term risk of stroke mortality.

BACKGROUND AND PURPOSE: Excess weight is an important determinant of cardiovascular disease, but the relationship between excess weight, its distribution, and stroke is yet unclear. We examined in a large prospective cohort study the association between body fat distribution and stroke mortality among middle-aged men. METHODS: A cohort of male civil servants and municipal employees free of cardiovascular disease in Israel (n=9151) were followed up for mortality over 23 years. The subscapular skinfold (SSF) was used as a measure of trunk and overall obesity and the ratio of subscapular to triceps skinfold thickness (SFR) as an indicator of trunk versus peripheral distribution of body fat. RESULTS: During the follow-up period, 316 died of stroke, and 865 died of coronary heart disease. The estimated age-adjusted hazard ratios (HRs) for stroke mortality, associated with 1 SD increment of SSF, was 1.12 (95% CI, 1.01 to 1.25) and for body mass index, 1.17 (1.06 to 1.30), but these associations were markedly weakened when adjusting for blood pressure. SFR was associated with an age-adjusted HR for stroke mortality of 1.14 (1.03 to 1.26). Further adjusting for systolic blood pressure, diabetes mellitus, cigarette smoking, and socioeconomic status (HR, 1.11; 1.01 to 1.23) as well as body mass index (HR, 1.11; 1.00 to 1.23) only mildly attenuated this association. Subjects with SFR in the upper quartile exhibited a approximately 1.5-fold higher adjusted HR (1.53; 1.10 to 2.12) compared with the lowest quartile. CONCLUSIONS: Indices of body fat and body fat distribution predict long-term stroke and coronary heart disease mortality among middle-aged men. SFR, an indicator of trunk versus peripheral distribution of body fat, is associated with stroke mortality, independent of main mediators of the effect of obesity on health and of body mass index.

Adipose Tissue↗
PubMed2005

Association of intentional changes in body weight with coronary heart disease event rates in overweight subjects who have an additional coronary risk factor.

Despite evidence that weight loss improves the severity of coronary heart disease (CHD) risk factors, a direct association between weight loss and CHD incidence has not been demonstrated. In 1994-2001, the authors conducted an observational study of intentional weight loss as related to CHD incidence among patients recruited from a network of clinics in Israel who received nutritional counseling from a dietitian to support the medical recommendation to lose weight. Subjects were outpatients aged 50-75 years with a body mass index of > or =27 kg/m(2), without CHD or cancer but with at least one risk factor for CHD in addition to overweight. Outcomes were documented over 4 years by repeated weight measurements and by medical record verification. Among 1,669 patients, 224 (13.4%) incidents of CHD were recorded. For subjects who underwent at least 6 months of dietetic counseling, the risk-factor-adjusted odds ratio for CHD incidence associated with a weight loss of 4.5 kg (the median level of weight loss) was 0.57 (95% confidence interval: 0.39, 0.84). In this, the largest known study of its type reported to date, intentional weight loss from a 6-month diet predicted lower incidence of CHD over 4 years.

Aged↗
PubMed2005

Monocyte chemoattractant protein-1 and recurrent cardiovascular events in patients with stable coronary heart disease.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) participates in the recruitment of mononuclear cells to the vessel wall. HYPOTHESIS: The aim of the study was to evaluate the potential association between serum concentration of MCP-1 and risk of future cardiovascular events in patients with chronic coronary heart disease. METHODS: A nested case control design was used. Baseline serum samples were taken from patients with coronary heart disease who were enrolled in a secondary prevention study. The MCP-1 levels were measured in those patients who had recurrent cardiovascular events during follow-up (n = 233) and compared with levels in age- and gender-matched controls. RESULTS: There were no differences in serum MCP-1 levels between cases and controls. The relative odds of a recurrent cardiovascular event for each 1 standard deviation difference in MCP-1 serum concentration (160 pg/ml) was 1.19 (95% confidence interval, 0.95-1.45). No increase in the relative odds for recurrent cardiovascular events was observed per increasing tertiles of MCP-1 concentrations. CONCLUSION: Elevated MCP-1 levels are not associated with long-term risk of cardiovascular events in patients with stable coronary disease.

Aged↗
PubMed2005

White blood cell count and the incidence of ischemic stroke in coronary heart disease patients.

PURPOSE: White blood cell (WBC) count is a marker of inflammation and has been associated with the development of cardiovascular disease. We investigated the relationship between WBC counts and the incidence of ischemic cerebrovascular disease in a large cohort of patients with pre-existing atherothrombotic disease and defined blood lipid boundaries. SUBJECTS AND METHODS: We followed up patients with documented coronary heart disease for 4.8 to 8.1 years. An extensive medical evaluation, conducted at baseline, included assessment of vascular risk factors and measures of blood lipids. Among 5435 patients with WBC counts, free of stroke, 295 developed an ischemic cerebrovascular disease (fatal and nonfatal). After review of available medical records, 186 of these cases had ischemic stroke or TIA. RESULTS: Higher WBC counts were associated with increased risk for ischemic cerebrovascular disease. Age-adjusted hazard ratio (HR) was 1.55 with 95% confidence interval (CI) 1.16-2.07, upper WBC tertile compared with the lowest. Adjusting for clinical covariates, WBC count remained an independent predictor for ischemic cerebrovascular disease (HR = 1.39; 95% CI 1.03-1.87, upper WBC tertile compared with the lowest). A similar trend appeared for the endpoint of ischemic stroke/transient ischemic attack (TIA). Further adjustment for plasma fibrinogen did not change the association materially (HR = 1.32; 95% CI 1.01-1.80; upper tertile of WBC compared with lowest). CONCLUSIONS: These findings support the role of WBC count as a simple inexpensive and readily available marker for risk stratification of ischemic cerebrovascular disease among patients with pre-existing atherothrombotic disease and defined blood lipid boundaries.

Aged↗