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C Porcellati

Publications and source records attributed to C Porcellati.

At least 37 records · Page 2Linked to original sources
PubMed1999

Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension.

BACKGROUND: It is unclear whether insulin and insulin-like growth factor-1 (IGF-1) are independent determinants of left ventricular (LV) mass in essential hypertension. METHODS AND RESULTS: We studied 101 never-treated nondiabetic subjects with essential hypertension. All had 24-hour noninvasive ambulatory blood pressure (ABP) monitoring and a 75-g oral glucose tolerance test. We determined fasting glucose, insulin, and IGF-1 and postload glucose and insulin 2 hours after glucose. Insulin resistance was estimated by the homeostasis model assessment (HOMA(IR)) formula. LV mass showed an association with body mass index (BMI) (r=0.47; P<0.01), postload insulin (r=0.54; P<0.01), HOMA(IR) (r=0.39; P<0.01), and IGF-1 (r=0. 43; P<0.01) and a weaker association with average 24-hour systolic and diastolic ABPs (r=0.29 and r=0.26; P<0.05) and basal insulin (r=0.31; P<0.05). Relative wall thickness was positively related to IGF-1 (r=0.39; P<0.01) but not to fasting or 2-hour postload insulin, HOMA(IR), and glucose. In a multiple regression analysis, the final LV mass model (R(2)=0.64) included IGF-1, postload insulin, average 24-hour systolic ABP, sex, and BMI. IGF-1 and postload insulin accounted for >40% of variability of LV mass. The final model (R(2)=0.36) for relative wall thickness included IGF-1 (16% total explained variability), average 24-hour systolic ABP, sex, BMI, and age but not insulin and HOMA(IR). CONCLUSIONS: These data indicate that insulin and IGF-1 are powerful independent determinants of LV mass and geometry in untreated subjects with essential hypertension and normal glucose tolerance.

Adult↗
PubMed1999

Calcium antagonists and cardiovascular risk in patients with hypertension and Type 2 diabetes mellitus: evidence from the PIUMA Study. Progetto Ipertensione Umbria Monitoraggio Ambulatoriale.

We conducted a retrospective analysis of all subjects with essential hypertension and Type 2 diabetes mellitus enrolled in the PIUMA (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) registry, in order to evaluate whether the use of calcium antagonists is associated with an increase in cardiovascular risk in these subjects. One hundred and sixty-four consecutive subjects with no previous cardiovascular morbid events and coexistence of essential hypertension and Type 2 diabetes mellitus were studied before therapy and followed for up to 12 years (mean 5). There were periodical contacts with family doctors and patients in order to ascertain the occurrence of major cardiovascular events. The use of calcium antagonists that preceded the event was considered for classification. None of the patients was lost to follow-up. At entry, the patients who were subsequently given calcium antagonists (n=50) had a higher clinical (174/98 vs 161/92 mmHg, both p<0.01) and 24-hr ambulatory blood pressure (150/90 vs 141/84 mmHg, both p<0.01) than those who were not. During follow-up there were 53 major cardiovascular morbid events (6.46 per 100 person-years). The rate of total cardiovascular events [5.6 vs 6.8 events per 100 person-years, relative risk 0.88 (95% CI: 0.47-1.61)] and that of cardiac events [4.0 vs 3.3 events per 100 person-years, relative risk 1.33 (95% CI: 0.62-2.89)] did not differ between users of calcium antagonists and non-users. The use of angiotensin converting enzyme inhibitors (n=66) was unrelated to the risk of cardiovascular events (relative risk 1.24, 95% CI: 0.71-2.16). In a Cox multivariate analysis, only age (p=0.002) and 24-hr pulse pressure (p=0.04) were independent predictors of cardiovascular events. In conclusion, this cohort study does not support the hypothesis that use of calcium antagonists is associated with an excess risk of adverse cardiovascular events in uncomplicated subjects with essential hypertension and Type 2 diabetes mellitus.

Aged↗
PubMed1999

Influence of cigarette smoking on the electrocardiographic diagnosis of left ventricular hypertrophy in arterial hypertension.

Electrocardiography (ECG) has a lower sensitivity for the diagnosis of left ventricular (LV) hypertrophy in smokers than in non-smokers, but the explanation for this finding is not known. In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, all subjects smoking > or = 15 cigarettes/day (n = 121, 89 men, age 48 +/- 11 years) were selected from 1443 untreated hypertensive subjects undergoing ECG and M-mode echocardiography, and matched with 484 hypertensive non-smokers by gender (same sex), age (+/- 5 years), and systolic and diastolic blood pressure (both +/- 5 mmHg) in a case-to-control design with a 1:4 matching ratio. Smokers and non-smokers did not differ by age, gender, body mass index, and blood pressure. The voltage of SV1 + RV5 or V6 and RI (p < 0.05), but not of SV3 + RaVL, was lower in smokers. Sensitivity of ECG was lower in smokers when using peripheral or left precordial voltage criteria (e.g. 11 vs 26% for Sokolow-Lyon voltage). When using definitions based on different criteria (voltage of S wave in V3, LV axis, LV strain), sensitivity was not dissimilar in smokers and non-smokers (e.g. 19 vs 18% for Romhilt-Estes score, 40 vs 34% for Perugia criterion). Thus, in hypertensive smokers, sensitivity of ECG is lower than in non-smokers when using peripheral or left precordial voltage criteria, probably due to increased chest size in smokers resulting from increased lung compliance. For LV hypertrophy detection, Sokolow-Lyon voltage should be avoided in hypertensive smokers and replaced by other criteria (Cornell voltage, Romhilt-Estes score, Perugia criterion), which are not influenced by cigarette smoking.

Adult↗
PubMed1998

Prognostic value of a new electrocardiographic method for diagnosis of left ventricular hypertrophy in essential hypertension.

OBJECTIVES: We tested the prognostic value of a new electrocardiographic (ECG) method (Perugia score) for diagnosis of left ventricular hypertrophy (LVH) in essential hypertension and compared it with five standard methods (Cornell voltage, Framingham criterion, Romhilt-Estes point score, left ventricular strain, Sokolow-Lyon voltage). BACKGROUND: Several standard ECG methods for assessment of LVH are used in the clinical setting, but a comparative prognostic assessment is lacking. METHODS: A total of 1,717 white hypertensive subjects (mean age 52 years; 51% men) were prospectively followed up for up to 10 years (mean 3.3). RESULTS: At entry, the prevalence of LVH was 17.8% (Perugia score), 9.1% (Cornell), 3.9% (Framingham), 5.2% (Romhilt-Estes), 6.4% (strain) and 13.1% (Sokolow-Lyon). During follow-up there were 159 major cardiovascular morbid events (33 fatal). The event rate was higher in the subjects with than in those without LVH (all p < 0.001) according to all methods except the Sokolow-Lyon method. By multivariate analysis, an independent association between LVH and cardiovascular disease risk was maintained by the Perugia score (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.5 to 2.8) and the Framingham (HR 1.91, 95% CI 1.1 to 3.2), Romhilt-Estes (HR 2.63, 95% CI 1.7 to 4.1) and strain methods (HR 2.11, 95% CI 1.4 to 3.2). The Perugia score showed the highest population-attributable risk for cardiovascular events, accounting for 15.6% of all cases, whereas the Framingham, Romhilt-Estes and strain methods accounted for 3.0%, 7.4% and 6.8% of all events, respectively. LVH diagnosed by the Perugia score was also associated with an increased risk of cardiovascular mortality (HR 4.21, 95% CI 2.1 to 8.7), with a population-attributable risk of 37.0%. CONCLUSIONS: The Perugia score carried the highest population-attributable risk for cardiovascular morbidity and mortality compared with classic methods for detection of LVH. Traditional interpretation of standard electrocardiography maintains an important role for cardiovascular risk stratification in essential hypertension.

Age Factors↗
PubMed1998

Lack of association between blood pressure variability and left ventricular mass in essential hypertension.

Blood pressure (BP) variability could induce detrimental effects on left ventricular (LV) structure in hypertension. We investigated the association between short-term BP variability, assessed with 24-h noninvasive ambulatory BP monitoring, and LV mass at echocardiography in 1822 untreated subjects (953 men, 869 women) with essential hypertension (EH). The standard deviation (SD) of daytime and night-time systolic BP (SBP, r = 0.13/0.10; both P < .001), but not of diastolic BP, showed a weak correlation with LV mass. Because the SD of daytime SBP showed a direct association with average 24-h SBP (r = 0.27), subjects were ranked into quartiles of the distribution of 24-h SBP. For each quartile, the subjects with SD of daytime (and night-time) SBP below or above the median were classified at low or high BP variability. In both genders, subjects with high daytime SBP variability were older than those at low variability (both P < .01). Within each quartile, LV mass did not differ between the groups at low v those at high SBP variability. Overall, age-adjusted LV mass index was 115 and 115 g/m2 in men at low and high daytime SBP variability (P = .84), and 116 and 114 g/m2 in men at low and high nighttime SBP variability (P = .31). The corresponding values in women were 98 and 99 g/m2 (P = .53) and 98 and 99 g/m2 (P = .64). In conclusion, when the effects of age, gender, and average 24-h BP are taken into account, short-term BP variability assessed with noninvasive monitoring is unrelated to LV mass in subjects with EH.

Aging↗
PubMed1998

Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension.

BACKGROUND: Previous studies revealed a direct association between resting heart rate and risk of mortality in essential hypertension. However, resting heart rate is a highly variable measure since it is affected by the alerting reaction to the visit. OBJECTIVE: To investigate whether the heart rate values recorded during the 24 h of ambulatory blood pressure monitoring are independent predictors of survival of uncomplicated subjects with essential hypertension. METHODS: We followed up 1942 initially untreated and uncomplicated subjects with essential hypertension (mean age 51.7 years, 52% men) for an average of 3.6 years (range 0-10 years). All subjects underwent baseline procedures including 24 h non-invasive blood pressure monitoring with simultaneous assessment of heart rate, one reading every 15 min for 24 h. MAIN OUTCOME MEASURES: All-cause mortality and cardiovascular morbidity. RESULTS: During follow-up there were 74 deaths from all causes (1.06 per 100 person-years) and 182 total (fatal plus non-fatal) cardiovascular morbid events (2.66 per 100 person-years). Clinic, average 24 h, daytime and night-time heart rates exhibited no association with total mortality. However, the subjects who subsequently died had had a blunted reduction of heart rate on going from day to night during the baseline examination. After adjustment for age (P < 0.001), diabetes (P < 0.001) and average 24 h systolic blood pressure (SBP, P= 0.002) in a Cox model, for each 10% less reduction in the heart rate from day to night the relative risk of mortality was 1.30 (95% confidence interval 1.02-1.65, P = 0.04). Rates of death were 0.38, 0.71, 0.94 and 2.0 per 100 person-years among subjects in the four quartiles of the distribution of the percentage reduction in heart rate from day to night The baseline day-night changes in the heart rate exhibited an inverse correlation to age and to clinic and ambulatory SBP and a direct association with the day-night changes in blood pressure. The degree of reduction of heart rate from day to night also had an independent inverse association with total cardiovascular morbidity after adjustment for age, diabetes and left ventricular hypertrophy, but this association did not remain significant when average 24 h SBP and the degree of day-night reduction in SBP were entered into the equation. CONCLUSIONS: A flattened diurnal rhythm of heart rate in uncomplicated subjects with essential hypertension is a marker of risk for subsequent all-cause mortality and this association persists after adjustment for several risk factors. For assessing these subjects, a limited and uniformly distributed period of ambulatory heart rate recording during the 24 h is clinically valuable.

Adult↗
PubMed1998

Early cardiac changes after menopause.

The mechanisms underlying the increased cardiovascular risk after menopause are incompletely known. To investigate whether menopause may induce left ventricular structural and functional adaptations in normotensive and hypertensive women, we compared in a case-control setting (1) 76 untreated hypertensive premenopausal women with 76 postmenopausal women and (2) 30 normotensive premenopausal women with 30 postmenopausal women. Subjects were individually matched by age (+/-5 years; range, 45 to 55), clinic systolic blood pressure (+/-5 mm Hg), and body mass index (+/-2 kgxm-2). All subjects underwent 24-hour blood pressure monitoring and M-mode echocardiography. Age, clinic and daytime blood pressure, body mass index, and smoking habits did not differ between the paired groups. After menopause, blood pressure fall from day to night was lower in both normotensives (10/15% versus 16/21%) and hypertensives (12/17% versus 16/21%) (all P<0.01). Menopause was also associated with a greater left ventricular relative wall thickness (38.8% versus 35.1% in normotensives, 40.2% versus 37.5% in hypertensives) and a reduced midwall fractional shortening (17.3% versus 18.6% in normotensives, 16.6% versus 17.9% in hypertensives) (all P<0.05). We conclude that menopause is associated with blunted day-night blood pressure reduction, impaired left ventricular systolic performance, and concentric left ventricular geometric pattern. These finding are independent of presence or absence of high blood pressure.

Blood Pressure↗
PubMed1998

Ambulatory pulse pressure: a potent predictor of total cardiovascular risk in hypertension.

A wide pulse pressure (PP) is a marker of increased artery stiffness and high cardiovascular (CV) risk. To investigate the prognostic value of ambulatory PP, which is currently unknown, we studied 2010 initially untreated subjects with uncomplicated essential hypertension (mean age, 51.7 years; 52% men). All subjects underwent baseline procedures including 24-hour noninvasive ambulatory blood pressure (BP) monitoring. The mean duration of follow-up was 3.8 years (range, 0 to 11 years), and CV morbidity and mortality were the outcome measures. There were 200 major CV events (2.61 per 100 person-years), 36 of which were fatal (0.47 per 100 person-years). In the 3 tertiles of the distribution of office PP, the rate of total CV events (per 100 persons per year) was 1.38, 2. 12, and 4.34, respectively, and that of fatal events was 0.12, 0.30, and 1.07 (log-rank test, both P<0.01). In the 3 tertiles of the distribution of average 24-hour PP, the rate of total CV events was 1.19, 1.81, and 4.92, and that of fatal events was 0.11, 0.17, and 1. 23 (log-rank test, both P<0.01). After controlling for several independent risk markers including white coat hypertension and nondipper status, we found that ambulatory PP was associated with the biggest reduction in the -2 log likelihood statistics for CV morbidity (P<0.05 versus office PP). In each of the 3 tertiles of office PP, CV morbidity and mortality increased from the first to the third tertile of average 24-hour ambulatory PP (log-rank test, all P<0.01). Age, left ventricular hypertrophy, and nondipper status were independent predictors of CV mortality, and the further predictive effect of ambulatory PP (P<0.001) was marginally but not significantly superior to that of office PP and average 24-hour systolic BP. We conclude that ambulatory PP is a potent risk marker in essential hypertension. CV morbidity is more closely predicted by ambulatory than by office PP even after control for multiple risk factors.

Blood Pressure Monitoring, Ambulatory↗
PubMed1998

White-coat hypertension: not guilty when correctly defined.

The coexistence of persistently high office blood pressure with normal blood pressujre outside the medical setting is often referred to as 'white-coat', 'office' or 'isolated clinic' hypertension. The definition of normal blood pressure outside the medical setting is controversial. In our experience, not only the prevalence of white-coat hypertension, but also left ventricular mass measured echocardiographically and the prevalence of left ventricular hypertrophy in this condition markedly vary on going from more restrictive (lower) to more liberal (higher) limits of ambulatory blood pressure normalcy over quite a narrow range. In a prospective study, cardiovascular morbidities of healthy normotensive controls and subjects with white-coat hypertension did not differ. A more recent analysis of our database supports the use of qujite a restrictive definition of white-coat hypertension (average daytime blood pressure < 130/80 mmHg) in order to identify the minority of subjects who have a low risk of cardiovascular morbid events during the subsequent years. A recent document published by the American Society of Hypertension suggests that slightly higher upper limits of ambulatory blood pressure normalcy (i.e. average daytime blood pressure < 135 mmHg systolic and 85 mmHg diastolic) should be used. In a follow-up study by our group, 37% of subjects with white-coat hypertension spontaneously evolved into cases of ambulatory hypertension, with accompanying increases in left ventricular mass. In that study, the probability of a subject developing ambulatory hypertension increased with the baseline values of ambulatory blood pressure and it was quite low (20%) for those with daytime blood pressures below 130/80 mmHg. In two recent controlled studies, the rate of development of ambulatory hypertension over time for untreated subjects did not differ between the normotensive control group and the group with white-coat hypertension. A final answer regarding the clinical significance of white-coat hypertension will come from very large surveys of the natural history of this condition in the long term. For now, we suggest a verdict of innocence for white-coat hypertension when low values of daytime ambulatory blood pressure (i.e. < 130/80 mmHg) and absence of organ lesions and other risk factors coexist.

Journal Article↗
PubMed1997

Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. SAMPLE Study Group. Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation.

BACKGROUND: In cross-sectional studies, ambulatory blood pressure (ABP) correlates more closely than clinic BP with the organ damage of hypertension. Whether ABP predicts development or regression of organ damage over time better than clinic BP, however, is unknown. METHODS AND RESULTS: In 206 essential hypertensive subjects with left ventricular hypertrophy (LVH), we measured clinic supine BP, 24-hour ABP, and left ventricular mass index (LVMI, echocardiography) before and after 12 months of treatment with lisinopril (20 mg UID) without or with hydrochlorothiazide (12.5 or 25 mg UID). Measurements included random-zero, clinic orthostatic, and home BP. In all, 184 subjects completed the 12-month treatment period. Before treatment, clinic supine BP was 165 +/- 15/105 +/- 5 mm Hg (systolic/diastolic), 24-hour average BP was 149 +/- 16/95 +/- 11 mm Hg, and LVMI was 158 +/- 32 g/m2. At the end of treatment, they were 139 +/- 12/87 +/- 7 mm Hg, 131 +/- 12/83 +/- 10 mm Hg, and 133 +/- 26 g/m2, respectively (P < .01 for all). Before treatment, LVMI did not correlate with clinic BP, but it showed a correlation with systolic and diastolic 24-hour average BP (r = .34/.27, P < .01). The LVMI reduction was not related to the reduction in clinic BP, but it was related to the reduction in 24-hour average BP (r = .42/.38, P < .01). Treatment-induced changes in average daytime and nighttime BPs correlated with LVMI changes as strongly as 24-hour BP changes. No substantial advantage over clinic supine BP was shown by clinic orthostatic, random-zero, and home BP. CONCLUSIONS: In hypertensive subjects with LVH, regression of LVH was predicted much more closely by treatment-induced changes in ABP than in the clinic BP. This provides the first longitudinally controlled evidence that ABP may be clinically superior to traditional BP measurements.

Adult↗
PubMed1997

Combined therapy with benazepril and amlodipine in the treatment of hypertension inadequately controlled by an ACE inhibitor alone.

In a multicenter, randomized, double-blind, placebo-controlled study, we evaluated the efficacy and tolerability of the combination of benazepril, 10 mg, and amlodipine, 2.5 or 5 mg once daily, compared with benazepril, 10 mg, monotherapy in patients with hypertension inadequately controlled with angiotensin-converting enzyme (ACE)-inhibitor monotherapy. After a 2-week placebo and 4-week single-blind benazepril, 10 mg once daily, run-in period, 448 patients, 213 men and 235 women, aged 24-73 years (mean, 55 years), with mean diastolic blood pressure (DBP) > or =95 and < or =120 mm Hg at the end of the benazepril run-in period, were randomized to receive one of the following treatments once daily for 8 weeks: (a) benazepril, 10 mg, plus placebo (BZ10); (b) benazepril, 10 mg, plus amlodipine, 2.5 mg (BZ10/AML2.5); or (c) benazepril, 10 mg, plus amlodipine, 5 mg (BZ10/AML5). Before the patients were admitted to the trial, at the end of the placebo run-in and the benazepril run-in period and at the end of weeks 4 and 8 of the treatment period, sitting and standing blood pressure (BP), heart rate (HR), and body weight were measured 22-26 h after the intake of the trial medication. Both BZ10/AML2.5 and BZ10/AML5 combinations showed better antihypertensive activity than did BZ10 monotherapy at the terminal visit as demonstrated by (a) the 24-h postdosing sitting and standing systolic BP (SBP) and DBP values, which were statistically lower with combination therapy than with BZ10; (b) the success rate, which was statistically higher with both the combinations (69.2% in the BZ10/AML2.5 and 65.8% in the BZ10/AML5 group) compared with the BZ10 group (40.5%). The tolerability was good in the three treatment groups. No significant abnormal laboratory data were detected. There was no difference in efficacy and safety/tolerability between the BZ10/AML2.5 and BZ10/AML5 groups.

Adolescent↗
PubMed1997

Prognostic significance of the white coat effect.

The difference between clinic and ambulatory blood pressure (BP) has been used to quantify the pressure reactivity to the doctor's visit (white coat effect). We investigated the prognostic significance of the clinic-ambulatory BP difference in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study. A total of 1522 subjects contributed 6371 person-years of observation. All subjects had an initial off-therapy diagnostic workup including 24-hour noninvasive ambulatory BP monitoring. The predicted values of ambulatory BP progressively diverged from the identity line (white coat effect of 0 mm Hg) with increasing clinic BP, but the predicted values of clinic BP tended toward the identity line with increasing ambulatory BP. Hence, the clinic-ambulatory BP difference showed a direct association with clinic BP and an inverse association with ambulatory BP. Consequently, a high clinic-ambulatory BP difference predicted both a high clinic and a low ambulatory BP, whereas a low clinic-ambulatory BP difference predicted both a low clinic and a high ambulatory BP. The clinic-ambulatory BP difference showed also a direct association with age. During up to 9 years of follow-up (mean, 4.2 years), there were 157 major cardiovascular morbid events (125 nonfatal and 32 fatal). The rate of total cardiovascular morbid events did not differ (log-rank test) among the four quartiles of the distribution of the clinic-ambulatory BP difference (2.13, 2.92, 2.10, and 2.83 events per 100 patient-years for systolic BP and 2.94, 2.14, 2.58, and 2.16 events per 100 patient-years for diastolic BP). Also, the rate of fatal cardiovascular events did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference. The clinic-ambulatory BP difference, taken as a measure of the white coat effect, does not predict cardiovascular morbidity and mortality in subjects with essential hypertension.

Ambulatory Care↗
PubMed1997

Altered circadian blood pressure profile and prognosis.

BACKGROUND: In a previous analysis of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale we found a higher rate of cardiovascular morbid events among hypertensive nondippers than we did among dippers (5.86 versus 1.18 events per 100 person-years, P = 0.0002) for women, whereas the difference between the two groups was smaller and not statistically significant for men (4.15 versus 2.48 events per 100 person-years). These differences held in a multivariate analysis after adjustment for several confounders including average 24 h ambulatory blood pressure. In another analysis, the rate of occurrence of cardiovascular end-points was higher among nondippers than it was among dippers regardless of the definition of day and night (0600-2200 h and 2200-0600 h, awake and asleep, and 1000-2000 h and 2400-0600 h) and of the dividing line between dippers and nondippers (10 versus 0% day-night difference in blood pressure). OBJECTIVE: To test in a subsequent analysis based on a larger sample and a longer follow-up period, for both sexes, the prognostic value of a blunted diurnal rhythm of blood pressure. METHOD: We used the night: day ratio of ambulatory blood pressure, a continuous and normally distributed variable. RESULTS: A night: day systolic blood pressure ratio > 0.899 for men and > 0.909 for women (upper tertiles of distributions) identified a subset of subjects with greater than normal cardiovascular risk for any level of concomitant risk factors, wherease the hight:day diastolic blood pressure ratio was not statistically significant as an independent predictor. The excess risk for subjects in the upper tertile of the night: day systolic blood pressure ratio held after adjustment for several risk markers, including average 24 h ambulatory blood pressure. CONCLUSION: These data suggest that a blunted reduction in blood pressure from day to night predicts an increased cardiovascular morbidity at any level of concomitant risk factors including average 24 h ambulatory blood pressure. Nondippers can be defined in terms of a night: day ambulatory systolic blood pressure ratio > 0.899 for men and > 0.909 for women, regardless of the diastolic blood pressure profile.

Journal Article↗