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Tim Nawrot

Publications and source records attributed to Tim Nawrot.

18 recordsLinked to original sources
PubMed2006

Association between arterial properties and renal sodium handling in a general population.

Mean arterial pressure drives pressure-natriuresis and determines arterial structure and function. In a population sample, we investigated the relation between arterial characteristics and renal sodium handling as assessed by the clearance of endogenous lithium. We ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries in 1069 untreated subjects (mean age: 41.6 years; 50.1% women; 18.8% hypertensive subjects). While accounting for covariates and standardizing for the sodium excretion rate in both sexes, CC and DC of the femoral artery increased with higher fractional distal sodium reabsorption. Differences associated with a 1-SD change in fractional distal reabsorption of sodium were 51.7 mm(2)/kPax10(-3) (95% CI: 23.9 to 79.5; P=0.0002) and 0.56x10(-3)/kPa (95% CI: 0.17 to 0.94; P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption was associated with decreases in femoral and brachial diameter, amounting to 111.6 mum (95% CI: 38.2 to 185.1; P=0.003) and 52.5 mum (95% CI: 10.0 to 94.9; P=0.016), respectively. There was no consistent association between the properties of the elastic carotid artery and renal sodium handling. In conclusion, higher fractional sodium reabsorption in the distal nephron is associated with higher femoral CC and DC, and higher proximal sodium reabsorption is associated with decreased brachial and femoral diameters. These findings demonstrate that there might be an influence of renal sodium handling on arterial properties or vice versa or that common mechanisms might influence both arterial and renal function.

Absorption↗
PubMed2006

House dust as possible route of environmental exposure to cadmium and lead in the adult general population.

Contaminated soil particles and food are established routes of exposure. We investigated the relations between biomarkers of exposure to cadmium and lead, and the metal loading rates in house dust in the adult residents of an area with a soil cadmium concentration of > or = 3 mg/kg (n=268) and a reference area (n=205). We determined the metal concentrations in house dust allowed to settle for 3 months in Petri dishes placed in the participants' bedrooms. The continuously distributed vegetable index was the first principal component derived from the metal concentrations in six different vegetables. The biomarkers of exposure (blood cadmium 9.2 vs. 6.2 nmol/L; 24-h urinary cadmium 10.5 vs. 7.0 nmol; blood lead 0.31 vs. 0.24 micromol/L), the loading rates of cadmium and lead in house dust (0.29 vs. 0.12 and 7.52 vs. 3.62 ng/cm(2)/92 days), and the vegetable indexes (0.31 vs. -0.44 and 0.13 vs. -0.29 standardized units) were significantly higher in the contaminated area. A two-fold increase in the metal loading rate in house dust was associated with increases (P<0.001) in blood cadmium (+2.3%), 24-h urinary cadmium (+3.0%), and blood lead (+2.0%), independent of the vegetable index and other covariates. The estimated effect sizes on the biomarkers of internal exposure were three times greater for house dust than vegetables. In conclusion, in the adult population, house dust is potentially an important route of exposure to heavy metals in areas with contaminated soils, and should be incorporated in the assessment of health risks.

Adult↗
PubMed2006

Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Hypertension promotes carotid intima-media thickening. We reviewed the randomized controlled trials that evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intima-media thickness. METHODS: We searched the PubMed and the Web of Science databases for randomized clinical trials, published in English before 2005, and included 22 trials. RESULTS: In 8 trials including 3329 patients with diabetes or coronary heart disease, antihypertensive treatment initiated with an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, or a calcium-channel blocker (CCB), compared with placebo or no-treatment, reduced the rate of intima-media thickening by 7 microm/year (P=0.01). In 9 trials including 4564 hypertensive patients, CCBs, ACE inhibitors, an angiotensin II receptor blocker or an alpha-blocker, compared with diuretics or beta-blockers, in the presence of similar blood pressure reductions, decreased intima-media thickening by 3 microm/year (P=0.03). The overall beneficial effect of the newer over older drugs was largely attributable to the decrease of intima-media thickening by 5 microm/year (P=0.007) in 4 trials of CCBs involving 3619 patients. In 5 trials including 287 patients with hypertension or diabetes, CCBs compared with ACE inhibitors did not differentially affect blood pressure, but attenuated intima-media thickening by 23 microm/year (P=0.02). The treatment induced changes in carotid intima-media thickness correlated with the changes in lumen diameter (P=0.02), but not with the differences in achieved blood pressure (P>0.53). CONCLUSIONS: CCBs reduce carotid intima-media thickening. This mechanism might contribute to their superior protection against stroke.

Adrenergic beta-Antagonists↗
PubMed2006

Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring.

We hypothesized that 1 minus the slope of diastolic on systolic pressure during 24-hour ambulatory monitoring (ambulatory arterial stiffness index [AASI]) might reflect arterial stiffness. We compared AASI with established measures of arterial stiffness and studied its distribution in Chinese and European populations. We used 90207 SpaceLabs monitors and the SphygmoCor device to measure AASI, central and peripheral pulse pressures, the central (CAIx) and peripheral (PAIx) systolic augmentation indexes, and aortic pulse wave velocity. In 166 volunteers, the correlation coefficient between AASI and pulse wave velocity was 0.51 (P<0.0001). In 348 randomly recruited Chinese subjects, AASI correlated (P<0.0001) with CAIx (r=0.48), PAIx (r=0.50), and central pulse pressure (r=0.50). AASI increased with age and mean arterial pressure but decreased with body height. Both before and after adjustment for arterial wave reflections by considering height and heart rate as covariates, AASI correlated more (P<0.0001) closely with CAIx and PAIx than 24-hour pulse pressure. Among normotensive subjects, the 95th percentile of AASI was 0.55 in Chinese and 0.57 in 1617 Europeans enrolled in the International Database on Ambulatory Blood Pressure Monitoring. The upper boundary of the 95% prediction interval of AASI in relation to age ranged from 0.53 at 20 years to 0.72 at 80 years. In conclusion, AASI is a new index of arterial stiffness that can be easily measured under ambulatory conditions. Pending additional validation in outcome studies, normal values of AASI are probably <0.50 and 0.70 in young and older subjects, respectively.

Adolescent↗
PubMed2006

Environmental exposure to cadmium and risk of cancer: a prospective population-based study.

BACKGROUND: Cadmium is a ubiquitous environmental pollutant, which accumulates in the human body such that 24-h urinary excretion is a biomarker of lifetime exposure. We aimed to assess the association between environmental exposure to cadmium and cancer. METHODS: We recruited a random population sample (n=994) from an area close to three zinc smelters and a reference population from an area with low exposure to cadmium. At baseline (1985-89), we measured cadmium in urine samples obtained over 24 h and in the soil of participants' gardens, and followed the incidence of cancer until June 30, 2004. We used Cox regression to calculate hazard ratios for cancer in relation to internal (ie, urinary) and external (ie, soil) exposure to cadmium, while adjusting for covariables. FINDINGS: Cadmium concentration in soil ranged from 0.8 mg/kg to 17.0 mg/kg. At baseline, geometric mean urinary cadmium excretion was 12.3 nmol/day for people in the high-exposure area, compared with 7.7 nmol/day for those in the reference (ie, low-exposure) area (p<0.0001). During follow-up (median 17.2 years [range 0.6-18.8]), 50 fatal cancers and 20 non-fatal cancers occurred, of which 18 and one, respectively, were lung cancers. Overall cancer risk was significantly associated with a doubling of 24-h cadmium excretion (hazard ratio 1.31 [95% CI 1.03-1.65], p=0.026. Population-attributable risk of lung cancer was 67% (95% CI 33-101) in the high-exposure area, compared with that of 73% (38-108) for smoking. For lung cancer, adjusted hazard ratio was 1.70 (1.13-2.57, p=0.011) for a doubling of 24-h urinary cadmium excretion, 4.17 (1.21-14.4, p=0.024) for residence in the high-exposure area versus the low-exposure area, and 1.57 (1.11-2.24, p=0.012) for a doubling of cadmium concentration in soil. INTERPRETATION: Historical pollution from non-ferrous smelters continues to present a serious health hazard, necessitating targeted preventive measures.

Adult↗
PubMed2006

Reference values in white Europeans for the arterial pulse wave recorded by means of the SphygmoCor device.

Measurement of blood pressure together with applanation tonometry at the radial artery allows the reproducible assessment of various indexes of arterial stiffness, including the peripheral (PPp) and central pulse pressures (PPc) and the peripheral (Alp) and central augmentation indexes (Alc). We defined preliminary diagnostic thresholds, using the distributional characteristics of these hemodynamic measurements in a reference population. We randomly recruited 870 subjects from 3 European populations. PPp was the average difference between systolic and diastolic blood pressure measured five times at one home visit. For measurement of PPc, Alp and Alc, we used the SphygmoCor device. We selected subjects without hypertension, diabetes, dyslipidemia in need of medical treatment or previous or concomitant cardiovascular disease. The study population included 228 men and 306 women (mean age 34.9 years). All hemodynamic measurements were curvilinearly related to age, and Alp and Alc were lower in men than in women. In men at age 40, the upper 95% prediction bands of the relations of the hemodynamic measurements with age approximated 60 mmHg for PPp, 40 mmHg for PPc, 90% for Alp, and 30% for Alc. For PPc, Alp and Alc, these thresholds must be adjusted for age, leading to lower and higher thresholds at younger and older age, respectively. In addition, in women of any age, the Alp and Alc thresholds must be increased by 10% and 7%, respectively. Pending validation in prospective outcome studies, distributional characteristics of arterial stiffness indexes in a reference population can be used to generate operational thresholds for use in clinical practice.

Adolescent↗
PubMed2005

Prevalence, persistence, and clinical significance of masked hypertension in youth.

Masked hypertension, an elevated daytime ambulatory blood pressure in the presence of a normal office blood pressure, confers an increased cardiovascular risk to adults. We investigated the prevalence, persistence, and clinical significance of masked hypertension in children and adolescents. We enrolled 592 youths (6 to 18 years old). Youths with masked hypertension (n=34) and a random sample of the normotensive participants (n=200) were followed-up. In a nested case-control study, we compared echocardiographic left ventricular mass among cases with persistent masked hypertension and normotensive controls. At baseline, mean age was 10.2 years; 535 youths were normotensive on office and daytime ambulatory blood pressure measurement (90.4%), and 45 had masked hypertension (7.6%). Compared with normotensive controls, participants with masked hypertension had a higher ambulatory pulse rate, were more obese, and were 2.5-times more likely to have a parental history of hypertension. Among 34 patients with masked hypertension (median follow-up 37 months), 18 became normotensive, 13 had persistent masked hypertension, and 3 had sustained hypertension. Patients with persistent masked hypertension (n=17) or who progressed from masked to sustained hypertension (n=3) had a higher left ventricular mass index (34.9 versus 29.6 g/m2.7; P=0.023) and a higher percentage with left ventricular mass index above the 95th percentile (30% versus 0%; P=0.014) than normotensive controls. In children and adolescents, masked hypertension is a precursor of sustained hypertension and left ventricular hypertrophy. This condition warrants follow-up and, once it becomes persistent, is an indication for blood pressure-lowering treatment.

Adolescent↗
PubMed2005

Are published characteristics of the ambulatory blood pressure generalizable to rural Chinese? The JingNing population study.

OBJECTIVE: We investigated the ambulatory blood pressure (BP) in rural Chinese and compared its characteristics with those reported in other population-based studies. METHODS: We enrolled inhabitants from six villages of the JingNing County, China. We recorded the ambulatory BP using 90207 SpaceLabs monitors. Trained physicians measured the conventional BP at the participants' homes. Hypertension was defined as a conventional BP of > or = 140/ > or = 90 mmHg or a condition requiring the intake of antihypertensive drugs. Using MEDLINE, we searched for population-based studies on ambulatory BP monitoring. RESULTS: The 356 participants (12-86 years) included 192 (53.9%) women and 117 (32.9%) hypertensive patients. In all participants, systolic/diastolic BP averaged 129/80 mmHg at home. The ambulatory BP means were 121/77 mmHg over 24 h, 126/81 mmHg during daytime (0800 to 1800 h) and 112/70 mmHg during night-time (2200 to 0400 h). The awake and asleep BPs averaged 126/82 and 112/70 mmHg, respectively. Using previously published definitions of daytime (1000 to 2000 h) and night-time (midnight to 0600 h) instead of those given above, inflated the BP differences with the awake and asleep BPs from 0.4/0.2 to 1.2/1.0 mmHg and from 0.3/0 to 1.4/1.6 mmHg, respectively. Compared with daytime values, conventional BP was 2.7/3.1 mmHg lower in normotensive individuals, but 14.9/1.3 mmHg higher in hypertensive patients. In our normotensive individuals, the whole-day and night-time diastolic BPs were from 1 to 4 mmHg and from 3 to 7 mmHg higher than in five other population studies in Caucasians or Japanese, whereas night-time BP in our participants was 9/5 mmHg lower than in Chinese living in Taiwan. CONCLUSIONS: We demonstrated significant differences in the characteristics of the ambulatory blood pressure across Asian and Caucasian populations. To what extent different activity patterns and genetic and environmental factors explain this context-dependency remains to be clarified.

Adolescent↗
PubMed2005

Epistatic interaction between alpha- and gamma-adducin influences peripheral and central pulse pressures in white Europeans.

BACKGROUND: Adducin is a membrane skeleton protein consisting of alpha- and beta- or alpha- and gamma-subunits. Mutations in alpha- and beta-adducin are associated with hypertension. In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding alpha-adducin (Gly460Trp), beta-adducin (C1797T) and gamma-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness. METHODS: We measured peripheral and central PP by conventional sphygmomanometry and applanation tonometry, respectively. We randomly recruited 642 subjects (162 nuclear families and 70 unrelated individuals) from three European populations. In multivariate analyses, we used generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: Peripheral and central PP averaged 46.1 and 32.6 mmHg, respectively. Among carriers of the alpha-adducin Trp allele, peripheral and central PP were 5.8 and 4.7 mmHg higher in gamma-adducin GG homozygotes than in their AA counterparts, due to an increase in systolic pressure. gamma-Adducin GG homozygosity was associated with lower urinary Na/K ratio among alpha-adducin Trp allele carriers and with higher urinary aldosterone excretion among alpha-adducin GlyGly homozygotes. Sensitivity analyses in founders and offspring separately, and tests based on the transmission of the gamma-adducin G allele across families, confirmed the interaction between the alpha- and gamma-adducin genes. CONCLUSIONS: In alpha-adducin Trp allele carriers, peripheral and central PP increased with the gamma-adducin G allele. This epistatic interaction is physiologically consistent with the heterodimeric structure of the protein and its influence on transmembranous sodium transport.

Adult↗
PubMed2005

Obesity is associated with increased arterial stiffness from adolescence until old age.

OBJECTIVE: To our knowledge, only two previous studies have investigated the age dependence of the relationship between the characteristics of large arteries and excessive body weight. We therefore investigated whether the relationship between arterial stiffness and body mass index (BMI) was consistent across an age range from 10 to 86 years. METHODS: Using a cross-sectional population-based design, we randomly recruited 1306 individuals (median age 43.9 years; 50.5% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries and carotid-femoral pulse wave velocity. We analysed men and women separately while adjusting for significant covariates, including age, mean arterial pressure, heart rate, current smoking, alcohol intake and use of antihypertensive drugs. RESULTS: Before and after adjustment, arterial diameter increased with BMI in all territories, with an opposite trend for arterial distensibility. In men and women, the relationships of brachial and femoral properties with BMI were consistent across the whole age range. In men and women, carotid distensibility decreased more with BMI at young than old age. In middle-aged and older women, but not in men of any age, pulse wave velocity increased with higher BMI. CONCLUSIONS: Across a wide age range, the diameter and stiffness of muscular arteries increased with higher BMI. In elastic arteries, the relationship between arterial stiffness and BMI was more complex and varied with sex and age. The mechanisms underlying the influence of adiposity on the properties of muscular and elastic arteries and the reversibility of these associations by weight reduction at young age need further clarification.

Adolescent↗
PubMed2004

Association of peripheral and central arterial wave reflections with the CYP11B2 -344C allele and sodium excretion.

OBJECTIVE: Angiotensin II and aldosterone, generated by the angiotensin-converting enzyme (ACE) and aldosterone synthase (CYP11B2), respectively, not only regulate sodium and water homeostasis, but also influence vascular remodeling in response to high blood pressure. In the European Project on Genes in Hypertension (EPOGH), we therefore investigated whether the ACE I/D and CYP11B2 C-344T polymorphisms influence early arterial wave reflections, a measure of vascular stiffness. METHODS: We measured the peripheral and central augmentation index of systolic blood pressure by applanation tonometry at the level of the radial artery in 622 subjects (160 families and 64 unrelated individuals) randomly recruited from three European populations, whose average urinary sodium excretion ranged from 196 to 245 mmol/day. In multivariate analyses, with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations by means of generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: The peripheral and central augmentation indexes were significantly higher in CYP11B2 -344C allele carriers than in -344T homozygotes. In offspring, early wave reflections increased with the transmission of the -344C allele. This effect of the CYP11B2 polymorphism occurred in subjects with a higher than median urinary sodium excretion (210 mmol/day). The ACE I/D polymorphism did not influence augmentation of systolic blood pressure. CONCLUSIONS: The CYP11B2 C-344T polymorphism affects arterial stiffness. However, sodium intake seems to modulate this genetic effect.

Adult↗
PubMed2004

Prevalence, pathophysiology and treatment of isolated systolic hypertension in the elderly.

Isolated systolic hypertension is the predominant type of hypertension in the elderly and is associated with cardiovascular complications such as stroke, coronary heart disease and heart failure. In this review, the role of arterial stiffness, endothelial function, atherosclerosis and oxidative stress in the pathogenesis of isolated systolic hypertension is extensively discussed. Placebo-controlled intervention trials such as the Systolic Hypertension in Europe Trial and the Systolic Hypertension in the Elderly Program have clearly shown that pharmacological treatment of isolated systolic hypertension improves outcome in the elderly. Nevertheless, isolated systolic hypertension remains the major subtype of untreated and uncontrolled hypertension.

Aged↗
PubMed2003

Isolated systolic hypertension and the risk of vascular disease.

Hypertension is present in 60% to 70% of the population over 60 years of age and may result in cardiovascular complications such as stroke, coronary heart disease, and heart failure. In this review, the role of arterial stiffness, endothelial function, atherosclerosis, and oxidative stress in the pathogenesis of hypertension is discussed extensively. Antihypertensive drug treatment may control high blood pressure and prevent complications. This review summarizes the results of several placebo-controlled and comparative clinical trials that have studied the efficacy of different classes of antihypertensive drugs.

Aged↗
PubMed2003

Salt, endogenous ouabain and blood pressure interactions in the general population.

OBJECTIVE: Experimental data show that ouabain is a modulator of the sodium-potassium pump, which plays an important role in sodium homeostasis and blood pressure regulation. We investigated the distribution of plasma ouabain in the general population in relation to blood pressure and other determinants of sodium homeostasis. METHODS: In 379 subjects enrolled in a Belgian population study, we measured plasma ouabain, clinical characteristics including blood pressure, serum and urinary electrolytes, urinary aldosterone excretion, various lifestyle factors, and the Gly460Trp polymorphism of the alpha-adducin gene. Our statistical methods included analysis of covariance and multiple linear regression. RESULTS: Plasma ouabain (median, 140 pmol/l) correlated independently and positively with male gender (n = 182, P = 0.002), smoking (n = 116, P = 0.05), urinary potassium excretion (mean 69 mmol/day, P < 0.0001), and mutation of the alpha-adducin gene (n = 161, P < 0.0001). Both before and after adjustment for covariables, continuous as well as categorical analyses revealed a significant interaction (P < or = 0.02) between plasma ouabain and urinary sodium excretion (mean 194 mmol/day) in relation to blood pressure (mean systolic blood pressure/diastolic blood pressure, 123/76 mmHg). In individuals with plasma ouabain values below the median, blood pressure increased by 2.2 mmHg systolic and 1.4 mmHg diastolic for each 50 mmol/day increment in urinary sodium excretion (P < or = 0.01). No association between blood pressure and urinary sodium excretion was found when plasma ouabain exceeded the median. CONCLUSIONS: Plasma ouabain behaves as a blood pressure modulating factor, possibly released in response to potassium, either inhibiting the pressor effect of an excessive salt intake or counteracting the depressor action of sodium depletion.

Adult↗
PubMed2003

Are low dehydroepiandrosterone sulphate levels predictive for cardiovascular diseases? A review of prospective and retrospective studies.

STUDY OBJECTIVE: It has been suggested that low levels of dehydroepiandrosterone sulphate (DHEAS) are predictive for cardiovascular diseases in men. We aimed to review the available evidence from prospective cohort studies and retrospective case-control studies. METHODS: We extracted summary statistics from 4 case-control studies and 8 cohort studies, and calculated the pooled relative risk associated with a 2 micromol/l increase in DHEAS. MAIN RESULTS: The number of subjects included in each of the individual studies ranged from 94 to 2134, mean age from 48 to 83 years and mean DHEAS levels from 1.2 to 7.3 pmol/l. In men, coronary mortality was available as outcome in 3 cohort studies and 1 case-control study. Combining data from these 4 studies showed a 15% (95% CI: 4%-28%, p = 0.008) increase in fatal coronary heart disease associated with a 2 micromol/l decrease in DHEAS. However, statistical significance was lost when the retrospective study causing significant heterogeneity (p = 0.02) was excluded. Fatal and non-fatal coronary events were reported in 1 cohort study and 3 case-control studies. The average increase in fatal plus non-fatal coronary heart disease associated with a 2 micromol/l decrease in DHEAS amounted to 13% (2%-26%, p = 0.02). The available data did not allow drawing any conclusions on the prognostic value of DHEAS in women, nor on the relationship between DHEAS and total or cardiovascular mortality or stroke in men. CONCLUSIONS: The present findings suggest that, in men, low serum levels of DHEAS may be associated with coronary heart disease. However, whether DHEA supplementation has any cardiovascular benefit is not clear. Data from prospective randomised trials are needed.

Aged↗
PubMed2002

Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek's hypothesis revisited.

Polychlorinated aromatic hydrocarbons (PCAHs) have been described as endocrine disruptors in animals and in accidentally or occupationally exposed humans. In the present study we examined the effect of moderate exposure to PCAHs on sexual maturation. Two hundred adolescents (mean age, 17.4 years) who resided in two polluted suburbs and a rural control area in Flanders (Belgium) participated. We measured the serum concentration of polychlorinated biphenyl (PCB) congeners 138, 153, and 180 and dioxin-like compounds [chemically activated luciferase expression (CALUX) assay] as biomarkers of exposure. School physicians assessed the pubertal development of boys and girls and measured testicular volume. In one suburb near two waste incinerators, compared with the other suburb and the control area, fewer boys (p < 0.001) had reached the adult stages of genital development (62% vs. 92% and 100%, respectively) and pubic hair growth (48% vs. 77% and 100%). Also, in the same suburb, fewer girls (p = 0.04) had reached the adult stage of breast development (67% vs. 90% and 79%). In individual boys, a doubling of the serum concentration of PCB congener 138 increased the odds of not having matured into the adult stage of genital development by 3.5 (p = 0.04); similarly for PCB congener 153 in relation to male pubic hair growth, the odds ratio was 3.5 (p = 0.04). In girls, a doubling of the serum dioxin concentration increased the odds of not having reached the adult stage of breast development by 2.3 (p = 0.02). Left plus right testicular volume was lower in both polluted areas than in the control area (42.4 mL vs. 47.3 mL, p = 0.005) but was not related to the current exposure of the adolescents to PCAHs. Through endocrine disruption, environmental exposure to PCAHs may interfere with sexual maturation and in the long-run adversely affect human reproduction.

Adolescent↗