Anatomy and physiology of the autonomic nervous system: Implication on the choice of diagnostic/monitoring tools in 2023.

The autonomic nervous system (ANS) harmoniously regulates all internal organic functions (heart rate, blood pressure, vasomotion, digestive tract motility, endocrinal secretions) and adapts them to the needs. It's the control of so-called vegetative functions, which allows homeostasis but also allostasis of our body. ANS is divided into two systems often understood as antagonistic and complementary: the sympathetic and the parasympathetic systems. However, we currently know of many situations of co-activation of the two systems. Long seen as acting through "reflex" control loops passing through the integration of peripheral information and the efferent response to the peripheral organ, more recent electrophysiological and brain functional imaging knowledge has been able to identify the essential role of the central autonomic network. This element complicates the understanding of the responses of the reflex loops classically used to identify and quantify dysautonomia. Finding the "ANS" tools best suited for the clinician in their daily practice is a challenge that we will attempt to address in this work.

Care through cohort studies: sociological survey of the PROOF cohort study on vascular and cognitive aging.

BACKGROUND: The success of health research depends on the involvement of participants. Few studies have examined the participation of subjects in cohorts. Drawing on a sociological survey on a French cohort around aging, this study proposes to question the nature of interactions between researchers and subjects that would help to understand the motivations of subjects to participate and remain in health research studies. METHODS: Qualitative study combining participant observation within the research laboratory that conducted the cohort and semi-structured interviews with subjects included in the cohort and with members of the research team. RESULTS: This study highlights the existence of two-way care: from the laboratory to the subjects and from the cohort to researchers. Health research seems to correspond to a complex association between subjects concerned with aging and the expected benefits of exceptional monitoring. Research is incorporated into subjects' daily lives, allowing a shift in the purpose of research from overmedicalization to medical safety that subjects experienced as a form of care. CONCLUSIONS: In cohort studies, care is understood as a form of attention to the person through high-quality medical follow-up. Aging is turned into a matter of concern that subjects, in collaboration with researchers, strive to control.

Structural skin changes in elderly people investigated by reflectance confocal microscopy.

BACKGROUND: Reflectance confocal microscopy (RCM) is particularly suitable for the study of skin ageing because it provides nearly histological information in vivo and non-invasively. However, there are no studies that evaluated RCM skin features of a large population older than 70 years. OBJECTIVES: The aim of our investigation was to study age-related skin changes in an elderly population by RCM and to evaluate their topographical and gender differences. METHODS: We obtained RCM images of photoprotected (volar arm) and chronic (face) and intermittently photoexposed (dorsal forearm) body sites of 209 volunteers (105 women and 104 men, mean age: 77.5, range 74-81 years). 15 previously reported and new RCM parameters related to skin ageing were assessed. RESULTS: Photoexposed sites had thicker suprapapillary epidermis, more linear, distant and thin furrows, higher presence of mottled pigmentation, polycyclic papillae and coarse and huddled collagen and lower presence of dermal papillae than the photoprotected site. Irregular honeycomb pattern was not higher in photoexposed sites, indicating that it is probably more dependent on intrinsic ageing. Two ageing scores defined for facial skin ageing (epidermal disarray score and epidermal hyperplasia score) were found useful for the identification of photoageing. Gender differences only concerned some RCM parameters (i.e. thickness of different layers of the epidermis, furrows and collagen score) and some body sites, in line with the fact that women and men of our cohort had no major differences in clinically visible skin ageing. CONCLUSIONS: Our study confirmed that RCM is a powerful non-invasive technique to microscopically quantify ageing signs and our observations contribute to highlight the differences between intrinsic and extrinsic ageing.

Long-lasting active lifestyle and successful cognitive aging in a healthy elderly population: The PROOF cohort.

OBJECTIVES: The aim of this study was to determine whether cognitive reserve in the elderly affects the evolution of cognitive performance and what its relationship is with active lifestyles in later life. METHODS: Cognitive performance was evaluated at baseline and 8 years later in 543 participants of the PROOF cohort, initially aged 67 years. Subjects were categorized as Cognitively Elite (CE), Cognitively Normal (CN) or Cognitively Impaired (CI) at each evaluation. At follow-up, demographic data and lifestyle, including social, intellectual and physical behaviors, were collected by questionnaires. RESULTS: As much as 69% (n=375) remained unchanged, while 25.5% (n=138) decreased and 5.5% (n=30) improved. When present, the reduction in cognitive status was most often limited to one level, but was dependent on the initial level, affecting up to 73% of the initially CN, but only 58% of the initially CE. Cognitive stability was significantly associated with the degree of social engagement at follow-up (CE: P=0.009; CN: P=0.025). CONCLUSION: In the healthy elderly, high cognitive ability predicts both cognitive ability and social involvement in later life. Cognitive decline by only one level may also extend the time to reach impairment, underlining the importance of the so-called cognitive reserve.

Sympathetic overactivity due to sleep fragmentation is associated with elevated diurnal systolic blood pressure in healthy elderly subjects: the PROOF-SYNAPSE study.

AIMS: Sleep fragmentation is a landmark of sleep disorders, because microarousals are systematically associated with sympathetic surges (i.e., sympathetic arousals). However, the impact of sympathetic sleep fragmentation on blood pressure (BP) remains understudied. We assessed the relationships between 24 h ambulatory BP monitoring, the autonomic arousal index (AAI) derived from pulse transit time, and heart rate variability indices. We hypothesized that repeated sympathetic arousals during sleep are associated with elevated BP in a large population of elderly volunteers. METHODS AND RESULTS: Volunteer subjects (n = 780, 57.4% women) with a mean age of 68.7 years and free of known sleep-disordered breathing, coronary heart diseases, and neurological disorders underwent polygraphy, 24 h ECG Holter monitoring, and 24 h ambulatory BP monitoring. Multivariate regressions showed that sleep fragmentation, expressed by AAI, was associated with elevated diurnal (P = 0.008) and 24 h (P = 0.005) systolic BP and higher risk for 24 h [odds ratio (OR): 1.70 (1.04-2.80), P = 0.036] systolic hypertension, independently of confounders such as sleep-disordered breathing, body mass index, sex, diabetes, hypercholesterolaemia, and self-reported sleep duration and quality. Increased AAI was associated with higher nocturnal and diurnal low-frequency power (P < 0.001) and low-to-high-frequency ratio (P < 0.001), suggesting nocturnal and diurnal sympathetic overactivity. CONCLUSION: In healthy elderly subjects, repetitive sympathetic arousals during sleep are associated with elevated systolic BP and higher risk of hypertension, after controlling for confounders. Sympathetic overactivity is the proposed underlying mechanism. CLINICAL TRIAL REGISTRATION: NCT00766584 and NCT00759304.

Sex differences in obstructive sleep apnoea in an elderly French population.

Obstructive sleep apnoea (OSA) affects females and males differently, and increases in prevalence with age. The aim of the present study was to characterise clinical, anthropometric and polygraphic sex differences in a large elderly OSA population. A total of 641 subjects aged 68 yrs were examined. Measurements of fat mass, using dual-energy X-ray absorptiometry (DEXA) and polygraphy, were obtained in all subjects. An apnoea/hypopnoea index (AHI) of >15 events·h⁻¹ identified the presence of OSA. OSA was diagnosed in 57% of the sample, 34% having a mild form and 23% having an AHI of >30 events·h⁻¹. Females with OSA exhibited a lower AHI, less severe hypoxaemia and greater peripheral fat mass, and frequently reported anxiety and depression. Comparison of females with and without OSA did not reveal significant differences in clinical, anthropometric and DEXA data. After adjustment for body mass index, hypertension, diabetes, smoking, anxiety and depression, logistic regression analysis revealed that the presence of hypertension was significantly associated with OSA risk in females (OR 1.52, p = 0.04). In a general community healthy population, the prevalence of undiagnosed OSA in females increases with age, with a risk similar to that in males. In females, the clinical spectrum, anthropometric data and fat distribution appear to be more sex-related than OSA-dependent. The occurrence of OSA contributes to hypertensive risk in elderly females.

Is tidal expiratory flow limitation predictive of sleep-related disorders in the elderly?

Sleep-related disorders represent an important health burden and their prevalence increases with age. In patients with snoring or sleepiness, the presence of expiratory flow limitation (EFL), determined via the negative expiratory pressure (NEP) method, is related to the apnoea/hypopnoea index (AHI). In this study, we examined whether EFL can be used to predict obstructive sleep apnoea syndrome (OSAS) in healthy asymptomatic older subjects. A group of 72-yr-old subjects (n = 448, 44% males) with a mean body mass index of 25.5±3.8 kg·m(-2) were examined. All subjects underwent spirometry, NEP (-5 cmH(2)O, sitting position) and ventilatory polygraphy (VP). Spirometry was within normal values in 88% of the group and EFL was present in 143 (32%) subjects with a higher prevalence in females (89 out of 249 versus 54 out of 199 in females and males, respectively). VP showed an AHI<15 h(-1) in 238 subjects (53%) and OSAS with an AHI ≥15 h(-1) in 47%. EFL was found in 15% of subjects with OSAS. Consequently, EFL had low sensitivity and specificity in the prediction of OSAS (31.4% and 67.7%, respectively). We conclude that the prevalence of EFL is elevated in healthy older subjects and cannot be used to predict the presence of sleep-related disorders in an older population.

Decrease in gait variability while counting backward: a marker of "magnet effect"?

Counting backward (CB) and walking are both rhythmic tasks. An improvement of CB performance has been reported while walking, and has been interpreted as a "magnet effect" which is the tendency of biological oscillators to attract each other. The objective of this study was to compare the coefficient of variation (CoV) of stride time (ST) and the number of enumerated figures while single- and dual-tasking between older adults who increased and decreased their CoV of ST while CB. The number of enumerated figures and the CoV of ST under single-task (i.e., CB while sitting or walking alone) and dual-task (i.e., CB while walking) were measured among 100 community-dwelling older subjects (mean, 69.8 ± 0.07 years). Subjects were separated into two groups according to the dual-task-related changes in CoV of ST (i.e., either above or below the mean value of CoV of ST under single-task). Seventeen participants decreased their CoV of ST while CB compared to usual walking (2.6 ± 1.6% vs. 2.0 ± 1.3%, P < 0.001), while 83 increased their CoV of ST (1.7 ± 0.6% vs 3.4 ± 2.3%, P < 0.001). The subjects who decreased their CoV of ST had a tendency to enumerate more figures while walking compared to sitting (20.9 ± 6.3 vs 19.4 ± 4.7, P = 0.046) unlike those who increased their CoV of ST (20.3 ± 5.0 vs 21.8 ± 6.0 while sitting, P = 0.001). We found that most of subjects had worse gait and CB performance while dual-tasking. Conversely, a limited number of subjects improved significantly their gait performance and simultaneously had a tendency to improve their CB performance while walking compared to sitting. This behavior was observed only among subjects with the highest gait variability and could be interpreted as an implicit strategy based on the "magnet effect".

Association between C-reactive protein and unrecognised sleep-disordered breathing in the elderly.

Elevated levels of C-reactive protein (CRP) have been reported in patients with sleep-disordered breathing (SDB) and may represent an inflammatory marker of cardiovascular risk. However, the association of CRP with SBD in presumed healthy elderly subjects is unknown. In total, 851 (58.5% females) 68-yr-old subjects, who were free of any known cardiac or sleep disorders, were prospectively examined. Subjects underwent unattended polygraphy, and the apnoea/hypopnoea index (AHI) and oxyhaemoglobin desaturation index (ODI) were assessed. Elevated levels of CRP were found on the morning after the sleep study in patients with more severe SDB. A significant correlation was found between CRP levels, time spent at night with arterial oxygen saturation <90% and ODI. No association was found between CRP levels and AHI. After adjustments for body mass index, smoking status, hypertension, diabetes and dyslipidaemia, a significant association remained between CRP levels and ODI >10 events.h(-1). CRP levels were frequently increased in a large sample of elderly subjects free of major cardiovascular disease. CRP levels were not correlated with the AHI and the indices of sleep fragmentation; the ODI >10 events.h(-1) was the strongest predictor of raised CRP level. The present results suggest that, in the elderly, intermittent hypoxaemia may underlie inflammatory processes leading to cardiovascular morbidity.

Cognitive complaints, neuropsychological performance and affective disorders in elderly community residents.

BACKGROUND: Previous studies have assessed the relationship between subjective cognitive complaints and objective impairment. While some of them found that cognitive complaints were explained by affective disorders, other researches found a relationship between cognitive complaints and neuropsychological performance. Most of them focused on memory functioning. However, elderly normal adults also display a decline in executive functions. This study aimed to assess the relationship between cognitive complaints, objective memory and executive performance and affective disorders. METHODS: This study was carried out with 937 community-dwelling elderly individuals recruited from the electoral list of the city of Saint-Etienne, France. Cognitive complaints were assessed using the MacNair scale. Cognitive performances were measured via a large battery of memory and executive-performance tests chosen for their capacity to detect subtle cognitive impairment. Anxiety and depressive symptoms were assessed using scales devised by Pichot and Goldberg. RESULTS: Cognitive complaints were associated with lower scores on verbal-memory tests and several executive-performance tests. Moreover, affective disorders were related to some of the executive-performance test scores, but they were not related to scores on the Free and Cued Selective Reminding Test, Digit Symbol Substitution Test and Trail Making B scores. CONCLUSIONS: Cognitive complaints of the elderly can reflect objective memory and executive-performance impairments, independent of affective disorders. Cognitive complaints should be assessed using both memory and executive-performance tests.

Energetic status and mitochondrial oxidative capacity of rat skeletal muscle in response to creatine analogue ingestion.

A creatine analogue, beta-guanidinopropionic acid (beta-GPA), was administered in the food (1% w/w) of 8 male rats for 6 weeks, while 8 control rats received a standard diet. Mitochondrial oxidative capacity and cytosolic modulators of mitochondrial oxidative phosphorylation (free ADP, ATP-to-free ADP ratio) were evaluated in the soleus and extensor digitorum longus (EDL) muscles. Mitochondrial adaptation to the diet was significantly different between muscles. Citrate synthase activity and mitochondrial ATP synthesis rate were 35 and 45% higher in EDL muscle, respectively, whereas they were virtually unchanged in the soleus muscle. In both muscles, 3-hydroxyacyl-CoA dehydrogenase activity remained unaffected. Regardless of muscle type, creatine, phosphocreatine and ATP concentrations, as well as the total adenine nucleotide content (ATP + ADP + AMP), were significantly lower in beta-GPA fed rats. Whereas free ADP concentration remained unchanged, a significantly greater decrease in ATP-to-free ADP ratio was observed in EDL than in the soleus muscle. It is suggested that regulation of mitochondrial oxidative phosphorylation, through changes in metabolite concentrations, could be an important factor to consider for mitochondrial adaptation induced by beta-GPA feeding.

Screening of obstructive sleep apnea syndrome by heart rate variability analysis.

BACKGROUND: Enhanced nocturnal heart rate variability (HRV) has been evoked in sleep-related breathing disorders. However, its capacity to detect obstructive sleep apnea syndrome (OSAS) has not been systematically determined. Thus, we evaluated the discriminant power of HRV parameters in a first group of patients (G1) and validated their discriminant capacity in a second group (G2). METHODS AND RESULTS: In G1, 39 of 91 patients (42.8%) were identified as diseased by polysomnography, as were 24 of 52 patients (46%) in G2. Time-domain HRV variables (SD of NN intervals [SDNN], mean of the standard deviations of all NN intervals for all consecutive 5-minute segments of the recording [SDNN index], square root of the mean of the sum of the squares of differences between adjacent normal RR intervals [r-MSSD], and SD of the averages of NN intervals in all 5-minute segments of the recording [SDANN]) were calculated for daytime and nighttime periods, as well as the differences between daytime and nighttime values (Delta[D/N]). Correlations between HRV variables and OSAS status were analyzed in G1 by use of receiver-operating characteristic (ROC) curves and logistic regression analysis. By ROC curve analysis, 7 variables were significantly associated with OSAS. After adjustment for other variables through multiple logistic regression analysis, Delta[D/N]SDNN index and Delta[D/N] r-MSSD remained significant independent predictors of OSAS, with ORs of 8.22 (95% CI, 3.16 to 21.4) and 2.86 (95% CI, 1.21 to 6.75), respectively. The classification and regression tree methodology demonstrated a sensitivity reaching 89.7% (95% CI, 73.7 to 97.7) with Delta[D/N] SDNN index and a specificity of 98.1% (95% CI, 86.4 to 100) with Delta[D/N] SDNN using appropriate thresholds. These thresholds, applied to G2, yielded a sensitivity of 83% using Delta[D/N] SDNN index and a specificity of 96.5% using Delta[D/N] SDNN. CONCLUSIONS: Time-domain HRV analysis may represent an accurate and inexpensive screening tool in clinically suspected OSAS patients and may help focus resources on those at the highest risk.

Subjective sleep and cognitive complaints in 65 year old subjects: a significant association. The PROOF cohort.

OBJECTIVE: The prevalence of subjective sleep and cognitive complaints increases with age. The purpose of this study was to investigate the link between subjective cognitive and sleep complaints in a population aged 65. DESIGN AND SETTING: analysis of a cohort of 1011 subjects aged 65 years old at time of inclusion. METHODS: Older people underwent a cognitive tests battery and a nocturnal polygraphy recording. Subjective cognitive difficulties were scored on the McNair and Kahn Scale. Subjective sleep complaints were evaluated according to the St. Mary's Hospital Sleep Questionnaire and the Epworth Sleepiness Scale score. RESULTS: In a 65 years old population, an association between subjective cognitive difficulties and poor sleep quality was observed. This remained significant after adjustment on gender, depression score, anxiety, educational level, medication intake, Apnea/Hypopnea index, Body Mass Index and Mini-Mental State Examination (OR = 2.1; p = 0.0002). Similar significant association was demonstrated between subjective cognitive difficulties and daytime sleepiness (OR = 2.6; p = 0.0007). CONCLUSION: There was a significant association between subjective cognitive and sleep complaints, and daytime sleepiness in our population of older people.

Accuracy of an automatic and patient-triggered long-term solid memory ambulatory cardiac event recorder.

This study evaluated the R-Test Evolution, a new type of cardiac event recorder bearing both patient-triggered and automatic capabilities. Its 7-day automatic arrhythmia analysis showed promising clinical advantages, especially when investigating patients with unexplained rare events such as syncope, feeling of weakness or faintness, palpitations, stroke, or in patients inconsistent in their use of patient-triggered recordings.

Raynaud's phenomenon of the lung. A reality both in primary and secondary Raynaud syndrome.

Vasospasm of RP is thought to occur in the lungs. To assess pulmonary vasospasm, we analyzed the early and late Dsb variations after a digital CPT. Sixteen normal volunteers and 20 patients (7 with primary, 13 with secondary RP) were included. A clinical RP was conducted on ten patients, nine with secondary and one with primary RP. The Dsb analysis showed: no significant variations in control subjects, a quick and short fall in primary RP significant after 15 min and a delayed fall in secondary RP significant after 45 min. A Dsb decrease was noticed even if no clinical RP occurred. The pallor phase of RP was associated with a concomitant decrease in the DCO and the hyperemic phase, with a Dsb increase. These results agree with those of previous studies with a few differences.

Initial combined cryotherapy and irradiation for unresectable non-small cell lung cancer. Preliminary results.

In unresectable non-small cell lung cancer (NSCLC) with a patent mainstem bronchus, some studies of obstructive tumors, showed (1) a poor role for irradiation in obtaining efficient debulking and (2) an interest in preliminary laser treatment in these patients. Cryotherapy is another method to obtain debulking. Moreover, several studies showed that cryotherapy would increase the radiosensitivity of a tumor. We performed a preliminary protocol combining successively initial cryotherapy followed by irradiation in inoperable NSCLC (either for local or functional contraindications). Thirty-eight patients were included and treated first by cryotherapy performed under general anesthesia and then with external irradiation in a curative intent. The efficiency of cryotherapy assessed on bronchoscopy was found to be volume-efficient (VE) in 26 of the 38 patients and non-volume-efficient (NVE) in the other 12 patients. After irradiation in the VE group, 17 of the 26 patients had no bronchial residual tumor (NRT). In contrast, all of the patients in the NVE group had a bronchial residual tumor (RT). Survival in the VE group (median, 397 days) was significantly higher than the survival of the NVE group (median, 144 days). Survival was found to be independent of the surgical contraindication (local or functional). The best survival was associated both with the efficiency of the initial debulking (VE) by cryotherapy and with the local control (NRT) induced by the irradiation (median, 560 days). Local control was obtained in 65 percent (17/26) of the cases in the VE group and was never observed in the NVE group. In our study the VE group's local control is better than the 35 percent usually reported after irradiation alone. These results argue for the efficient potentiation of irradiation by cryotherapy.

Comparison of muscle near-infrared spectroscopy and femoral blood gases during steady-state exercise in humans.

Near-infrared spectroscopy (NIRS) is a noninvasive way of measuring muscular oxygenation. We evaluated the relationship between NIRS signal [infrared muscle oxygen saturation (IR-SO2mus)] and the femoral venous oxygen saturation (SfvO2) during cycling exercise. Six healthy subjects performed a 30-min steady-state exercise at 80% maximal oxygen uptake in normoxia and hypoxia (inspired O2 fraction = 0.105). IR-So2mus was recorded continuously throughout the tests with the NIRS probe located on the vastus lateralis. During exercise, blood samples were withdrawn every 5 min from radial artery and femoral vein catheters. In normoxia, IR-So2mus initiated a transient nonsignificant decrease at 5 min, then returned to preexercise level, whereas SfvO2 showed a fast decrease, reaching 18% saturation at 10 min without further change. By contrast, in hypoxia, IR-SO2mus and SfvO2 demonstrated a parallel decrease then stabilized at 10 min. We conclude that IR-SO2mus appears to parallel SfvO2 when both the arterial and venous oxygen contents decrease during steady-state exercise in hypoxia, whereas IR-SO2mus does not follow SfvO2 change in normoxia.

Wavelet transform to quantify heart rate variability and to assess its instantaneous changes.

Heart rate variability is a recognized parameter for assessing autonomous nervous system activity. Fourier transform, the most commonly used method to analyze variability, does not offer an easy assessment of its dynamics because of limitations inherent in its stationary hypothesis. Conversely, wavelet transform allows analysis of nonstationary signals. We compared the respective yields of Fourier and wavelet transforms in analyzing heart rate variability during dynamic changes in autonomous nervous system balance induced by atropine and propranolol. Fourier and wavelet transforms were applied to sequences of heart rate intervals in six subjects receiving increasing doses of atropine and propranolol. At the lowest doses of atropine administered, heart rate variability increased, followed by a progressive decrease with higher doses. With the first dose of propranolol, there was a significant increase in heart rate variability, which progressively disappeared after the last dose. Wavelet transform gave significantly better quantitative analysis of heart rate variability than did Fourier transform during autonomous nervous system adaptations induced by both agents and provided novel temporally localized information.

Influence of training on NIRS muscle oxygen saturation during submaximal exercise.

PURPOSE: Endurance training improves the oxygen delivery and muscle metabolism. Muscle oxygen saturation measured by near infrared spectroscopy (IR-SO(2)), which is primarily influenced by the local delivery/demand balance, should thus be modified by training. We examined this effect by determining the influence of change in blood lactate and muscle capillary density with training on IR-SO(2) in seven healthy young subjects. METHODS: Two submaximal exercise tests at 50% (Ex1) and 80% pretraining VO(2max) (Ex2) were performed before and after a 4-wk endurance-training program. RESULTS: VO(2max) increased only slightly (+8%, NS) with training but the training effect was confirmed by the increased capillary density (+31%, P < 0.01) and citrate synthase activity (50%, P < 0.01), determined from muscle biopsy samples. Before training, blood lactate increased during the first 5 min of Ex1 and then remained constant (3.8 +/- 0.5 mmol x L(-1), P < 0.01), whereas it increased continuously during Ex2 (8.9 +/- 1.8 mmol x L(-1), P < 0.001). After training, lactate decreased significantly and remained constant during the two bouts of exercise (2.0 +/- 0.4 and 3.7 +/- 1.2 at the end of Ex1 and Ex2, respectively, both P < 0.001). During Ex1, IR-SO(2) dropped initially at the onset of exercise and recovered progressively without reaching the resting level. Training did not change this pattern of IR-SO(2). During Ex2, IR-SO(2) decreased progressively during the 15 min of exercise (P < 0.05); IR-SO2 kept constant after the initial drop after training. We found a significant relationship (r = 0.42, P = 0.03) between blood lactate and IR-SO(2) at the end of both bouts of exercise; this relationship was closer before training. By contrast, IR-SO(2) or IR-BV was not related to the capillary density. CONCLUSION: The training-induced adaptation in blood lactate influences IR-SO(2) during mild- to hard-intensity exercise. Thus, NIRS could be used as a noninvasive monitoring of training-induced adaptations.