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A Charloux

Publications and source records attributed to A Charloux.

At least 37 records · Page 2Linked to original sources

Dynamic heart rate variability: a tool for exploring sympathovagal balance continuously during sleep in men.

We have recently demonstrated that the overnight profiles of cardiac interbeat autocorrelation coefficient of R-R intervals (rRR) calculated at 1-min intervals are related to the changes in sleep electroencephalographic (EEG) mean frequency, which reflect depth of sleep. Other quantitative measures of the Poincaré plots, i.e., the standard deviation of normal R-R intervals (SDNN) and the root mean square difference among successive R-R normal intervals (RMSSD), are commonly used to evaluate heart rate variability. The present study was designed to compare the nocturnal profiles of rRR, SDNN, and RMSSD with the R-R spectral power components: high-frequency (HF) power, reflecting parasympathetic activity; low-frequency (LF) power, reflecting a predominance of sympathetic activity with a parasympathetic component; and the LF-to-HF ratio (LF/HF), regarded as an index of sympathovagal balance. rRR, SDNN, RMSSD, and the spectral power components were calculated every 5 min during sleep in 15 healthy subjects. The overnight profiles of rRR and LF/HF showed coordinate variations with highly significant correlation coefficients (P < 0.001 in all subjects). SDNN correlated with LF power (P < 0.001), and RMSSD correlated with HF power (P < 0.001). The overnight profiles of rRR and EEG mean frequency were found to be closely related with highly cross-correlated coefficients (P < 0. 001). SDNN and EEG mean frequency were also highly cross correlated (P < 0.001 in all subjects but 1). No systematic relationship was found between RMSSD and EEG mean frequency. In conclusion, rRR appears to be a new tool for evaluating the dynamic beat-to-beat interval behavior and the sympathovagal balance continuously during sleep. This nonlinear method may provide new insight into autonomic disorders.

Adult↗

Enhanced brain natriuretic peptide response to peak exercise in heart transplant recipients.

We investigated the atrial (ANP) and brain natriuretic peptides (BNP), catecholamines, heart rate, and blood pressure responses to graded upright maximal cycling exercise of eight matched healthy subjects and cardiac-denervated heart transplant recipients (HTR). Baseline heart rate and diastolic blood pressure, together with ANP (15.2 +/- 3.7 vs. 4.4 +/- 0.8 pmol/l; P < 0.01) and BNP (14.3 +/- 2. 6 vs. 7.4 +/- 0.6 pmol/l; P < 0.01), were elevated in HTR, but catecholamine levels were similar in both groups. Peak exercise O2 uptake and heart rate were lower in HTR. Exercise-induced maximal ANP increase was similar in both groups (167 +/- 34 vs. 216 +/- 47%). Enhanced BNP increase was significant only in HTR (37 +/- 8 vs. 16 +/- 8%; P < 0.05). Similar norepinephrine but lower peak epinephrine levels were observed in HTR. ANP and heart rate changes from rest to 75% peak exercise were negatively correlated (r = -0.76, P < 0.05), and BNP increase was correlated with left ventricular mass index (r = 0.83, P < 0.01) after heart transplantation. Although ANP increase was not exaggerated, these data support the idea that the chronotropic limitation secondary to sinus node denervation might stimulate ANP release during early exercise in HTR. Furthermore, the BNP response to maximal exercise, which is related to the left ventricular mass index of HTR, is enhanced after heart transplantation.

Adult↗

Ultradian rhythms in hydromineral hormones.

The maintenance of hydromineral homeostasis depends on the coordinated action of arginine vasopressin (AVP), atrial natriuretic peptide (ANP), the renin-angiotensin-aldosterone system and other recently identified endocrine or paracrine hormones. Several reports have pointed out the changes in urinary excretion and osmolality during the sleep-wake cycle and the rapid eye movement (REM)-non(N)REM sleep cycles. No such changes occur for ANP levels which have a flat profile over 24 h. The pulsatile fluctuations of AVP are described as random. The ultradian rhythm of plasma renin activity (PRA) depends on the regularity of the REM-NREM sleep cycles and the nocturnal curves reflect all disturbances in the internal sleep structure. A study with a shift in the normal sleep time clearly demonstrated that both PRA and aldosterone oscillations are sleep-stage dependent. These hormones could account for the ultradian variations in renal function. The nocturnal oscillations in sympathovagal balance may play an additional role. It is suggested that a central generator synchronizes endocrine, renal, autonomic and sleep processes.

Activity Cycles↗

Oscillations in sympatho-vagal balance oppose variations in delta-wave activity and the associated renin release.

To determine the potential role of the sympathetic nervous system in the generation of the oscillations in PRA over the 24-h period, we used the autocorrelation coefficient of RR interval (rRR), a new tool to evaluate the sympatho-vagal balance continuously. We determined the influence of the sympathetic nervous system both on the nocturnal PRA oscillations associated to increases in delta-wave activity and on the daytime oscillations that occur randomly in awake subjects. PRA and rRR were determined every 10 min during 24 h in nine healthy subjects under continuous bed rest. Electroencephalographic spectral analysis was used to establish the variations in delta-wave activity during sleep, from 2300-0700 h. The overnight profiles in PRA, rRR and delta-wave activity were analyzed using a modified version of the pulse detection program ULTRA. The temporal link among the profiles of rRR, PRA, and delta-wave activity was quantified using cross-correlation analysis. During sleep, large oscillations in PRA were strongly linked to variations in delta-wave activity. They were preceded by opposite oscillations in rRR, decreases in rRR reflecting predominant vagal activity, and increases in rRR reflecting sympathetic dominance. During the waking periods, the levels of rRR were higher, with smaller variations. The daytime PRA oscillations were not associated with any significant changes in rRR, and conversely, significant oscillations in rRR were not followed by any significant changes in PRA. In conclusion, the sympathetic nervous system is not directly involved in the generation of renin oscillations observed under basal conditions. During sleep, the oscillations in sympatho-vagal balance are inversely related to the variations in delta-wave activity and the associated renin release. The processes that give the intermittent signal for concomitant increases in slow wave activity and renin release from the kidney remain to be identified.

Adult↗

Normal short-term renal response to acute volume expansion in heart transplant recipients: a role for atrial natriuretic peptide?

BACKGROUND: The breakdown of blood pressure and body fluid homeostasis observed in heart transplant (Htx) recipients may partly be due, as in heart failure, to a blunted renal response to elevated atrial natriuretic peptide (ANP). METHOD: This possibility was addressed through determination of the relationship between ANP, the urinary cyclic guanosine monophosphate (cGMP), a biologic marker of ANP renal activity, and the early renal responses to 10 mL/kg isotonic saline infusion over 30 minutes in 8 control subjects and 8 matched Htx recipients. RESULTS: Urine flow, natriuresis, and urinary cGMP excretion increased similarly in both groups, resulting in elimination of, respectively, 1/2 and 2/3 of the sodium and the water load during the experiment that lasted 4 hours and 30 minutes. Plasma renin and aldosterone decreases were similar in both groups. Elevated ANP further increased in Htx after saline infusion (from 19.5 +/- 3.7 to 33.8 +/- 5.6 pmol/L, P < .001). Plasma cGMP paralleled ANP in both groups (r = 0.81; P < .001). Significant correlations were observed between plasma ANP and urinary cGMP excretion (r = 0.48, P < .025 and r = 0.43, P < .05 in Htx recipients and control subjects) and between plasma ANP and urinary sodium excretion (r = 0.64, P < .001 in Htx recipients). CONCLUSION: In spite of a relative renal hyporesponsiveness to the cardiac hormone, with higher plasma ANP being not associated with increased renal excretions in Htx recipients, ANP is likely to participate in the appropriate short-term renal response to acute volume expansion in Htx recipients.

Aldosterone↗

A phase II trial of radiochemotherapy with daily carboplatin, after induction chemotherapy (carboplatin and etoposide), in locally advanced nonsmall-cell lung cancer: final analysis.

PURPOSE: To evaluate feasibility and efficacy of concomitant radiochemotherapy (CRCT) in Stage IIIB nonsmall-cell lung cancer (NSCLC), two induction chemotherapy cycles combining etoposide and carboplatin were first delivered, followed by CRCT with daily radiation fraction in association with carboplatin. METHODS AND MATERIALS: Forty patients with biopsy-proven, locally advanced unresectable nonmetastatic NSCLC were enrolled. Induction chemotherapy consisted of two cycles (day 1 and day 28) of etoposide (VP16:100 mg/m2, days 1 to 3) and carboplatin (CBDCA:350 mg/m2, day 1). Irradiation starting at day 56, delivered 66 Gy in 2 Gy daily fraction, 5 days a week, along with a daily dose of CBDCA (15 mg/m2) given intravenously 2 to 4 h before radiation. In nonprogressive patients under induction chemotherapy, two additional cycles of VP16-CBDCA were administered 4 weeks after the completion of CRCT. RESULTS: Out of the 40 patients enrolled (38 males, 2 females), 37 (93%) received induction chemotherapy as scheduled, with 38% Grade 3-4 hematological toxicity. Response rate to induction chemotherapy was 11% (4/37). No tumor became resectable. CRCT was delivered to 32 of these 37 patients, with full doses given to 91% of them. Clinical and hematological Grade 3-4 toxicity rates were 21 and 13%, respectively. Additional chemotherapy was delivered in 12 of 26 nonprogressive patients. At final evaluation, performed 3 months after the end of CRCT, 38% of 26 evaluable patients were responders (4 complete and 6 partial), leading to a 25% (10 of 40) overall objective response rate. Of these 10 responders, 8 became responders after CRCT only. Overall, the 1-year local control rate was 28% (11 of 40). The median survival time was 9 months and the 1-year and 2-year overall survival rates were 38 and 15%, respectively. Thirty-six patients died from local progression (25 patients), distant metastasis (9 patients), or pulmonary fibrosis (2 patients). CONCLUSION: Concomitant CRCT with CBDCA is feasible with acceptable induction chemotherapy-related toxicity and a 1-year local control rate of 28%. Response rate to induction chemotherapy was low and better chemotherapy combination should be used to reduce distant failure probability and to improve local response rate before CRCT.

Adult↗

Moderate endurance training has no effect on the parathyroid function of heart transplant patients.

The benefit of retraining for heart transplant recipients (HTR) is now well established. The rehabilitation of these patients can be compromised by osteopenia and bone fractures. The resting levels of parathyroid hormone (PTH) and exercise-induced increases are higher in HTR than in healthy controls. To evaluate the effect of a moderate endurance training programme on parathyroid activity, six HTR, an average of 18 months after transplant, and seven healthy sedentary controls have been studied. None of the subjects had a history of bone disease. Two exercise tests (square wave endurance exercise tests, SWEET) with identical work rates were performed before and after training. Intact PTH, ionized calcium (Ca2+), phosphorus (Pi) and pH were measured at rest, during exercise and in the recovery periods. Training consisted of a 45-min SWEET three times a week for 6 weeks. Levels of Ca2+, Pi and PTH showed a significant increase during the exercise session in both groups. Ca2+ and Pi levels decreased rapidly after the cessation of exercise whereas PTH reached a peak at the 10th min of the recovery in both groups. This increase in PTH was significantly higher in HTR than in controls. However, despite a significant improvement of total endurance work (+ 28% in HTR, +29% in controls) this endurance training had no effect on resting levels of PTH, plasma Ca2+ or Pi, nor on their exercise-induced variations. The exercise-induced decrease in pH was less pronounced after training which is evidence of training. We conclude that a short endurance training programme does not alter the moderate hyperparathyroidism of HTR. The effect of such a training programme on bone mass and bone mineral density needs now to be evaluated.

Acid-Base Equilibrium↗

International differences in epidemiology of lung adenocarcinoma.

In Europe, the squamous cell carcinoma is the most frequent non-small cell lung cancer (NSCLC) subtype and until now, no increase in incidence of lung adenocarcinoma (ADC) has been described (except in the Netherlands), in contrast to North America where ADC predominates. Our aim was to compare the percentage of ADC in Montreal (MTL), Canada, with that in Strasbourg (STBG), France. We prospectively identified patients with NSCLC in MTL and in STBG over an 8-month period and described the distribution of NSCLC by sex, age, subtype and smoking history. A total of 172 patients in MTL and 166 in STBG were identified. The male/female ratio was significantly different in STBG (12:1) and in MTL (2:1). The percentage of ADC was significantly higher in MTL (40%) than in STBG (30%). This difference is partly due to the higher number of women with NSCLC in Montreal combined with the predominance of ADC in women. The proportion of ADC decreased with age in STBG, but was similar in each age category in MTL. In STBG, most women with NSCLC had never smoked (69%), in contrast to MTL where only 16% of women had never smoked. In conclusion, ADC is more frequent in MTL than in STBG. This is partly due to the higher number of women with NSCLC in MTL combined with the predominance of ADC in women. The greatest proportion of ADC subtype in the youngest cohorts of men in STBG suggests that ADC may be on the rise in this city.

Adenocarcinoma↗

Prognostic value of histology in patients with non-small cell lung cancer.

To evaluate the impact of non-small cell lung cancer (NSCLC) histological subtypes on survival, we performed a retrospective multivariate analysis of survival in 361 patients with a NSCLC diagnosed in 1987 and 1988 at the University Hospital in Strasbourg, France. There were 262 (73%) squamous cell carcinomas (SQ), 59 (16%) adenocarcinomas other than bronchioloalveolar carcinoma (ADOBAC), 24 (7%) bronchioloalveolar carcinoma (BAC) and 16 (4%) large cell carcinomas (LC). The proportion of metastatic disease was significantly higher in the ADOBAC group than in the SQ group (30% vs. 15%, P < 0.001). In operated patients, only extent of disease and age were independent prognostic factors. In patients with unresectable NSCLC, extent of disease had also the heaviest impact on survival. However, in these unresected patients, ADOBAC had a pejorative impact on survival, in contrast to BAC which was of better prognosis. If these results are confirmed by prospective studies, this will support stratification according to histological subtypes in clinical trials involving inoperable NSCLC patients.

Adult↗

The increasing incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung adenocarcinoma.

Lung adenocarcinoma is the most common cell type in females (smokers or non-smokers) and in non-smoking males. Its incidence has been increasing in younger cohorts of males and females until very recent years. Changes in classification and in pathological techniques account for some of this increase. In females and non-smoker males, the increase could be partly due to a detection bias in former studies. Nevertheless, successive cohorts over time seem more likely to develop adenocarcinoma and less likely to develop squamous cell carcinoma. These differences between birth cohorts suggest that the increasing incidence of adenocarcinoma is not only due to changes in pathological diagnosis. Geographical differences are also observed: in Europe, the squamous cell type still predominates and an increase in incidence of adenocarcinoma has only been reported in the Netherlands. In Asia, in the 1960s and 1970s, the proportion of adenocarcinoma was higher than in North America or Europe and seems to be increasing. To what extent these differences are due to differences. In establishing diagnosis remains unknown. Despite these biases in temporal and geographical trends detailed in this review, there has probably been a true increase in incidence of adenocarcinoma. An explanation for this should be sought in studies on detailed smoking history and passive smoking exposure, occupational exposure, diet and cooking, pollution and other environmental factors.

Adenocarcinoma↗

The concept of Raynaud's phenomenon of the lung revisited.

PURPOSE: Having observed that a cold pressor test (CPT) induces a decrease in carbon monoxide single breath diffusing capacity (DLco) in normal subjects contrary to the findings of Fahey et al (Am J Med. 1984; 76:263-269), we compared the response to CPT for the two types of Raynaud's phenomenon. PATIENTS: Two groups of 8 patients suffering from primary or secondary Raynaud's phenomenon were examined. METHODS: Single breath diffusing capacity, mean pulmonary artery pressure (PAP), cardiac output (CO), pulmonary capillary wedge pressure (PwP), and pulmonary vascular resistance (PVR) were measured before and 30 minutes after CPT, which consisted of immersing both hands in a water bath at 12 degrees C for 2 minutes. RESULTS: Cold pressor testing induced no change in DLco or cardiovascular parameters in patients with secondary Raynaud's phenomenon. Conversely, in patients with the primary form, it induced a significant decrease in DLco (16%), PAP (20%), and PVR (27%), whereas CO and PwP remained unaltered. CONCLUSIONS: The concept of pulmonary Raynaud's phenomenon had to be reconsidered, as it is also observed in normal subjects, and is due to a vasodilatation and not to a vasoconstriction of the pulmonary artery (Frans et al, J Appl Physiol. 1994; 76:750-755). In patients with primary Raynaud's phenomenon, the decrease in DLco is not only a physiological response, but a pathological response to a CPT, as it is significantly more marked in patients than in control subjects (16% versus 10% for controls, same reference). The contribution by Fahey et al remains important, however, in that it allows assessing whether a patient with Raynaud's phenomenon suffers from the primary or secondary form of the disease.

Adult↗

Structure of skeletal muscle in heart transplant recipients.

OBJECTIVES: This study sought to define the ultrastructural characteristics of skeletal muscle in heart transplant recipients (HTRs) in relation to exercise capacity compared with that in age-matched control subjects. BACKGROUND: Muscle structural features seem to play an important role in the limitation of exercise capacity of HTRs long after transplantation. METHODS: The structure of the vastus lateralis muscle was analyzed by ultrastructural morphometry in 16 HTRs and 20 healthy control subjects. Maximal oxygen consumption (peak Vo2) was determined by an incremental exercise test. RESULTS: Peak Vo2 was significantly lower (by 35%) in HTRs. Fiber size, volume density of mitochondria and intramyocellular lipid deposits were not significantly different between HTRs and control subjects. In contrast, the capillary density and the capillary/fiber ratio were both significantly reduced in HTRs (by 24% and 27%, respectively). CONCLUSIONS: A normal volume density of mitochondria and a reduced capillary network are the main characteristics of muscle ultrastructure in HTRs by 10 months after transplantation. The muscle structural abnormalities and reduced exercise capacity might be related to immunosuppressive therapy with cyclosporine and corticosteroids as well as deconditioning.

Adult↗

[Passive smoking and bronchial cancer: a difficult relation to establish].

There is a certain controversy over whether there is a relationship between passive smoking and bronchogenic cancer. The first epidemiology studies has found a small increase in the relative risk. Experimental work in animals have demonstrated that the smoke produced by a burning cigarette contains more cancerogenic agents than the smoke inhaled by a smoker. In man where only epidemiology studies are possible, the problem lies in quantifying exposure to passive smoking. Questionnaires or assay of markers such as CO and HbCO, thiocyanates, nicotine and its metabolite cotinine and certain adduits have been used. There are many possibilities for bias in such studies including classification of smokers among non-smokers, confounding factors (age, profession, eating habits), subjects' memory, and data collection errors. Meta-analyses have attempted to overcome the lack of power in many studies. Some of these meta-analyses have used correction factors to take into account publication bias. Meta-analyses have led to the conclusion that the risk for women exposed to their husband's tobacco smoke is somewhat increased compared with a non-smoking non-exposed population. The relative risk is about 2-fold higher and has been observed in Greece. The existence of a dose-intensity relationship has not been confirmed. Likewise, it is impossible to conclude concerning the role of passive smoking in children due to the small amount of data available.

Bronchial Neoplasms↗

Early alternating chemotherapy and radiotherapy schedule in limited disease stage small cell lung cancer.

44 patients with limited small cell lung cancer were treated with six cycles of chemotherapy (cisplatinum 60 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, etoposide 100 mg/m2 days 1-3) alternating with three courses of mediastinal irradiation, the first one starting 7 days after the first day of chemotherapy. A total dose of 55 Gy was delivered. Prophylactic cranial irradiation (30 Gy after the third cycle of chemotherapy) was left to the physician's discretion. 4 patients had radical surgery before combined modality treatment. 29 patients finished the scheduled program. The complete response rate (bronchoscopically confirmed) was 25.6% after two cycles of chemotherapy and 41% at the end of treatment. Median survival time was 17.2 months, with an estimated survival of 32% at 2 years. Main toxicity was haematological with one early toxic death and six premature interruptions of treatment. We conclude that this treatment modality is feasible and efficacious. Prospective studies comparing chemotherapy with alternating or concurrent early radiotherapy schedules in limited disease small cell lung cancer are needed to determine the best treatment modality.

Adult↗

[Contribution of an induction treatment in the surgical treatment of locally advanced non-small-cell cancers].

From October 1988 to July 1990, 18 patients with marginally resectable non-small cell cancer (10 stage IIIa and 8 stage IIIb) were entered in a phase-II trial combining induction therapy with a subsequent thoracotomy. Induction therapy included 2 courses of chemotherapy (5-FU and cisplatinum) and radiotherapy (30 Gray in split course). Partial response was observed in 10 patients, and minimal response in 3. Thoracotomy disclosed unresectability in 3 patients. Fifteen complete resections consisted in 1 lobectomy and 14 pneumonectomies. There were no operative deaths (30 days). Postoperative recovery was uneventful in 3 patients with exploratory thoracotomy and in 1 patient with lobectomy. Following pneumonectomy, we observed 2 bronchopleural fistulae and 1 empyema. On pathology, 10 patients were stage IIIa, and 3 were stage I, whereas no residual tumor was found in 2 patients. During follow-up, local recurrence occurred in 2, and metastases in 8. On December 31st, 1993, 3 patients were alive at 44, 52, and 62 months respectively. Nine patients had died from cancer, and 3 from unrelated causes. Estimated survival was 66.7% at 1 year, 33.3% at 3 years, and 20% at 5 years. We conclude that induction therapy allowed satisfactory resection for marginally resectable tumors. Operative morbidity was increased in this group. However, the 5-year survival was similar to resectable stage IIIa cancer.

Adult↗

[Monoclonal antibodies and bronchial cancer].

Techniques of production of monoclonal antibodies (MoAb) have provided powerful tools to study biological lung cancer behavior. Immunochemistry is more sensitive than conventional light microscopy examination to detect tumour cells in sputum or pleural effusion, or small cell lung cancer metastases in bone marrow. Immunochemistry is also helpful for the differential diagnosis of carcinoma versus lymphoma or sarcoma, using antibodies directed against antigens such as cytokeratins, vimentin, EMA, LCA, SP100, CEA. In lung cancer, immunochemistry may detect neuroendocrine differentiation, or help to distinguish metastatic carcinoma from primary lung cancer. A positive immunostaining with CEA, Leu-M1, SP1, B72-3 supports the diagnosis of pleural metastatic adenocarcinoma versus mesothelioma. Immunoscintigraphy is a non invasive imaging technique which allows local and distant disease evaluation and could replace in the future the present staging work up. To evaluate the potential therapeutic efficacy of MoAbs in Lung cancer, phase I studies have been performed. Therapeutic effect is based on: 1) indirect cytotoxicity (cells are killed by ADCC or K cells) or direct cytotoxicity (MoAb are carriers of toxins, radioisotopes or drugs). 2) Immune response modulation by anti-idiotypic Ab. 3) Interferences with growth factors. Results of most of phase I trials are disappointing. Improvement of MoAb selectivity, improvement of conjugates stability, reduction of humoral response to MoAb, enhanced tumour localisation, and reduction of nonspecific captation should lead to a better efficacy.

Animals↗

Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer.

Vinorelbine (Navelbine, NVB) is a new semi-synthetic vinca alkaloid that is currently used in the treatment of advanced breast cancer and advanced non-small-cell lung cancer (NSCLC). In this study we investigated the tumoral and healthy pulmonary tissue concentrations of NVB in previously untreated NSCLC patients undergoing surgery. A total of 13 patients (mean age, 60 years; range, 42-70 years) were included and received NVB (20 mg/m2) at 1 h (mean, 1.1 h; SD, 0.2 h; n = 6 patients) and 3 h (mean, 3.0 h; SD, 0.6 h; n = 7 patients) before tumor resection. A tumoral and adjacent healthy lung-tissue specimen as well as simultaneously sampled serum were analyzed for NVB by high-performance liquid chromatography (HPLC). NVB levels were much higher in tissue than in serum (up to 300-fold). The tissue/serum ratio increased between the 1-h sampling time (range, 0.1-100) and the 3-h time point (range, 10-300). In all patients but two, NVB concentrations were lower in tumors than in healthy lung tissue. The tumor/healthy tissue ratio ranged from 0.06 to 1.3 (median, 0.09) at 1 h and from 0.18 to 1.1 (median, 0.55) at 3 h. This ratio increased between the 1-h sampling time and the 3-h time point as a consequence of increasing tumor levels (median, 50.4 ng/g at 1 h and 278 ng/g at 3 h). In four patients, concentrations could be measured in necrotic and peripheral tumor zones, showing lower values in necrotic areas. Thus, these data indicate that NVB is highly distributed in lung tissue, with the disposition rate being slower in tumor tissue than in healthy parenchyma during the first 3 h.

Adult↗