Mouth breathing compromises adherence to nasal continuous positive airway pressure therapy

STUDY OBJECTIVES: Mouth leak compromises nasal continuous positive airway pressure (CPAP) therapy. We hypothesized that patients who breathe mainly through their mouths during sleep, compared to those who breathe mainly through their noses, would have more mouth leak during CPAP and therefore lower adherence to CPAP. DESIGN: A case-control study to compare adherence to CPAP at 1 year in mouth breathers (MBs) with nose breathers (NBs). SETTING: University teaching hospital with a sleep laboratory. PATIENTS: Fifty-one CPAP-naive patients (4 women), with a respiratory disturbance index (RDI) > 15/h. Of the 51 patients, 30 patients breathed through their mouths (mouth breathing > 70% of total sleep time [TST]), and 21 patients breathed through their noses (mouth breathing < 30% of TST). MBs between 30% and 70% of TST were excluded. INTERVENTIONS: Overnight polysomnography was performed at baseline, during CPAP titration, and at 3 months. Patients were followed up for 1 year after beginning CPAP. MEASUREMENTS AND RESULTS: To measure mouth breathing, nasal and oral thermistors during polysomnography were separated by a 3 x 6-cm silicon transverse diaphragm. RDI decreased from (mean +/- SD) 37.8 +/- 21.5 to 1.8 +/- 2.6/h at 3 months. Throughout the study, adherence to CPAP (mean daily CPAP use in hours) was better in NBs. Most NBs (71%) but only 30% of MBs used CPAP daily for > 4 h at 1-year follow-up. Mouth breathing decreased significantly from 84 +/- 8.9% at baseline to 22 +/- 14.4% at 3 months. CONCLUSION: Patients with moderate-to-severe sleep-disordered breathing and a high percentage of mouth breathing during sleep were less adherent to CPAP therapy than patients exhibiting a low percentage of mouth breathing.     

Continuous positive airway pressure therapy improves cardiovascular autonomic function for persons with sleep-disordered breathing

BACKGROUND: Sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular morbidity. Dysfunction of the cardiovascular autonomic nervous system may be a potential mechanism whereby SDB is linked to cardiovascular disease. Repetitive sympathetic activation during apneic episodes may impair cardiovascular reflex function, and increased sympathetic activity can stimulate renin release. Given that patients with SDB may have reduced cardiovascular autonomic function, the purpose of this study was to determine whether treatment with continuous positive airway pressure (CPAP) for 6 weeks would improve autonomic function. METHODS: Twenty-nine participants with a diagnosis of SDB, who completed 6 weeks of CPAP therapy, were evaluated for cardiovascular autonomic nerve fiber function at baseline and post therapy. Autonomic function tests included the following: R-R interval variation during deep breathing measured by vector analysis (ie, mean circular resultant [MCR]) and expiration/inspiration (E/I) ratio; and the Valsalva maneuver. Participants were also evaluated prior to CPAP therapy for plasma renin activity levels. RESULTS: Participants in this study showed improved cardiovascular autonomic function after 6 weeks of treatment (baseline vs follow-up) as assessed by the mean (+/- SD) MCR (33.2 +/- 22.5 vs 36.9 +/- 24.2, respectively; p < 0.05) and E/I ratio (1.20 +/- 0.12 vs 1.24 +/- 0.14, respectively; p < 0.01). Improved vagal tone was also noted for subjects with elevated renin levels. CONCLUSIONS: Treatment of SDB with CPAP for 6 weeks improved vagal tone and may be beneficial in reducing the risk of developing clinical manifestations of cardiovascular autonomic dysfunction (eg, increased risk of mortality).     

Sleep structure correlates of continuous positive airway pressure variations during application of an autotitrating continuous positive airway pressure machine in patients with obstructive sleep apnea syndrome

STUDY OBJECTIVES: To evaluate the relationship between sleep structure and continuous positive airway pressure (CPAP) delivered by an automatic CPAP (auto-CPAP) machine in patients with obstructive sleep apnea syndrome (OSAS). DESIGN: Nocturnal polysomnography was performed during CPAP administration by an auto-CPAP machine (Autoset Clinical 1; ResMed; Sydney, Australia). SETTING: Sleep-disorders center in a research institute. PATIENTS: Fifteen subjects with newly diagnosed OSAS deserving home CPAP treatment. Measurements and results: During the night, in most cases, the lowest CPAP level was recorded during a prolonged nonrapid eye movement (NREM) sleep period uninterrupted by arousals, whereas the highest level during wake-sleep transitions or NREM sleep fragmented by arousals. In four subjects, rapid eye movement sleep was always associated with increasing CPAP. Sleep efficiency was negatively correlated with CPAP variability, evaluated as the SD of the mean nocturnal CPAP level averaged epoch by epoch (r = 0.63, p < 0.02). Eighty-eight percent of rapid CPAP augmentations (increases by at least 2 cm H(2)O in less-than-or-equal 2 min) were observed during sleep-wake transitions or after arousals/awakenings (Ar/Aw); 63% of such Ar/Aw were not preceded by any detectable respiratory abnormality. CONCLUSIONS: CPAP levels and variations during auto-CPAP application may be mainly related to sleep continuity and efficiency. The recording of a highly variable pressure during auto-CPAP administration in an unattended environment must raise the question whether the patient's sleep quality was acceptable. A poor sleep quality during an autotitration night could lead to an undesirable overestimation of the CPAP level needed for use with fixed-level CPAP machines.     

Effect of continuous positive airway pressure ventilation on nocturnal ST-segment changes in patients with sleep-disordered breathing

Objective To determine whether sleep-disordered breathing (SDB) may lead to nocturnal myocardial ischemia and whether the severity of this ischemia may be relieved by nasal continuous positive airway pressure (CPAP). Methods Overnight polysomnogram examination and simultaneous 3-channel Holter monitoring were performed on 76 patients with moderate to severe SDB and no history of coronary heart disease. All the cases were treated with CPAP for one night. ST depression was defined as a ST segment decrease of more than 1 mm from baseline and lasting 1 min or more. The total duration (minutes) of ST depression was indexed to the total sleep time (minutes per hour of sleep). Results Twenty-eight patients (37%) showed ST segment depression during their sleep. Before CPAP treatment, the respiratory disturbance index (RDI) and arousal index were significantly higher during periods of ST depression than when ST segments were isoelectric, whereas no significant difference was found in blood oxygen saturation (SaO2). After the CPAP treatment of patients with ST depression, the duration of ST depression was significantly reduced from 36.8±18.9 to 11.4±13.2 min/h (P＜0.05). ST depression-related indexes, including RDI, arousal index and the percentage of sleep time spent at SaO2 below 90% (TS90/ TST), were all significantly decreased, with RDI from 63.4±23.8 to 8.1±6.6 /h, arousal index from 51.2±18.9 to 9.6±5.4 /h, and TS90/ TST from 50.6±21.4 to 12.9±14.7% (P＜0.05). Conclusion ST-segment depression is rather common in patients with moderate to severe SDB, and CPAP treatment can significantly reduce the duration of ST depression. ST depression in these patients may reflect the myocardial ischemia that really exists and the non-ischemic changes associated with recurrent SDB.     

Prevalence of sleep-disordered breathing and continuous positive airway pressure compliance: results in chinese patients with first-ever ischemic stroke

OBJECTIVE: To assess the prevalence of sleep-disordered breathing (SDB), continuous positive airway pressure (CPAP) acceptance, and CPAP compliance in patients who have experienced ischemic stroke. DESIGN: A case-controlled study. SETTING: A university hospital. MEASUREMENTS AND RESULTS: We recruited 23 women and 28 men, who were admitted to the hospital within 4 days of stroke onset, with a mean (+/- SD) age of 64.2 +/- 13.0 years and a body mass index (BMI) of 24.3 +/- 4.4 kg/m(2) for this study. Twenty-seven patients (53%) and 9 patients (17.6%), respectively, reported a history of snoring and severe daytime sleepiness prior to experiencing a stroke, while the mean Epworth sleepiness scale score was 6.8 +/- 3.6. Polysomnography revealed 34 patients (67%) with an apnea-hypopnea index (AHI) of > or = 10 events per hour, 31 patients (61%) with an AHI of > or = 15 events per hour, and 25 patients (49%) with an AHI of > or = 20 events per hour. Significant obstructive SDB, defined as an AHI of > or = 20/h, was more prevalent in ischemic stroke patients than in control subjects (49% vs 24%, respectively; p = 0.04) and was associated with a higher BMI (p = 0.046). Among the 34 patients with an AHI of > or = 10/h, CPAP titration was tolerated by 16 patients, but only 4 patients who had typical sleep apnea features proceeded to home CPAP treatment with objective compliance over a period of 3 months of 2.5 +/- 0.6 h per night. A subgroup of 20 patients not receiving CPAP showed partial spontaneous improvement of SDB at 1 month (baseline AHI, 32.3 +/- 17.6 events per hour; AHI at 1 month, 23.0 +/- 18.8 events per hour; p = 0.01) with a trend toward improvement for the obstructive but no significant change for the central events, whereas no improvement in AHI was noted for the four patients receiving CPAP. CONCLUSION: There is a high prevalence of obstructive SDB in patients who have experienced acute ischemic stroke, which, in many cases, is different from classic obstructive sleep apnea syndrome, and this is reflected by the lack of significant sleepiness, poor CPAP acceptance, and partial spontaneous improvement at 1 month.     

Hypotensive effects of positive airway pressure ventilation in heart failure patients with sleep-disordered breathing

Introduction

Obstructive sleep apnoea (OSA) as well as central sleep apnoea (CSA) are highly prevalent in heart failure (HF) patients. Positive airway pressure (PAP) therapy is usually intended to treat OSA and CSA. The aim of the present study was to investigate immediate hemodynamic effects of PAP therapy in these patients.

Materials and methods

In 61 consecutive HF patients (NYHA????II, EF????45%) with moderate to severe OSA or CSA (AHI????15/h) blood pressure (BP) and heart rate (HR) response to PAP therapy initiation was investigated during mask fitting with patients being awake and in supine position. While applying an endexspiratory pressure of 5.8?±?0.9?cm H₂O, there was a significant decrease in systolic (?8.9?±?12.1?mmHg, p?p?p?=?n.s.).

Results

At least a transient drop in mean arterial pressure ??70?mmHg was seen in 10% of these patients. Logistic regression analysis revealed a significant impact of baseline BP on potential BP drops: lower baseline BP was associated with BP drops.

Conclusion

PAP therapy may cause unexpected hypotension especially in patients with low baseline BP as seen in HF patients treated according to current guidelines. Whether these hypotensive effects sustain, cause any harm to the patients and/or is responsible for non-acceptance or non-adherence of PAP therapy needs to be determined.     

A heated humidifier reduces upper airway dryness during continuous positive airway pressure therapy.

Upper airway dryness is a frequent side-effect of nasal continuous positive airway pressure (nCPAP) therapy in obstructive sleep apnoea (OSA). In this situation, heated humidification is often used. Alternatively, oily nose drops are frequently applied to relieve dryness. The present study aimed to investigate the efficacy of a heated humidifier in comparison with oily nose drops. Twenty-four OSA patients complaining of serious nCPAP-related upper airway dryness were randomized to 6 weeks of treatment either with heated humidification (HC 100, Fischer & Paykel, Inc., Auckland, New Zealand) or oily nose drops (Colda-Stop, Desitin, Inc., Germany). The patients completed questionnaires on the degree and frequency of upper airway dryness, compliance with nCPAP, intention to terminate nCPAP and comfort during the nCPAP therapy. All 12 patients treated with heated humidification improved in terms of the degree and frequency of upper airway dryness, and reported greater comfort when using the nCPAP device. All patients in the heated humidification group intending to terminate nCPAP therapy because of upper airway dryness persisted with nCPAP on addition of humidification. In contrast, only five out of 12 patients (42%) in the oily nose drops group reported their degree of upper airway dryness to be improved (P = 0.003), only three patients (25%) reported an improvement in the frequency of upper airway dryness (P < 0.001), and only five patients (42%) reported greater comfort when using the nCPAP device with oily nose drops (P < 0.001). In the group using oily nose drops none of the three patients who intended to terminate nCPAP therapy persisted with nCPAP. Heated humidification is highly effective and superior to oily nose drops in reducing the symptoms of upper airway dryness during nCPAP.     

Snoring detection during auto-nasal continuous positive airway pressure.

A bench study using an artificial lung model was performed to evaluate the snoring detection sensitivity of six (commercially available) auto-nasal continuous positive airway pressure (NCPAP) devices. Snoring was simulated by a loudspeaker connected to the lung model and abruptly activated during 1 s of each inspiratory period to induce pressure oscillation. The oscillation frequencies chosen were 30, 60, 90, and 120 Hz. For each frequency, the amplitude of the pressure oscillation produced by the loudspeaker was adjusted to find the threshold at which the auto-nCPAP devices detected snoring. Differences in pressure-amplitude thresholds of up to three-fold were found across auto-nCPAP devices. A randomized clinical study to compare the effects of the least sensitive (Virtuoso LX; Respironics, Nantes, France) and one of the most sensitive, (Goodknight 418A; Malinckrodt, Nancy, France) devices, in two groups of six patients with obstructive sleep apnoea syndrome was then conducted. Goodknight 418A was more sensitive than Virtuoso LX for detecting snoring (mean +/- SD 92 +/- 11% versus 50 +/- 39% respectively, p = 0.03). To conclude, striking differences exist between auto-nasal continuous positive airway pressure devices in sensitivity for detecting snoring.     

Heated humidification or face mask to prevent upper airway dryness during continuous positive airway pressure therapy

STUDY OBJECTIVES: The objectives of this study were (1) to evaluate the way in which nasal continuous positive airway pressure (CPAP) therapy influences the relative humidity (rH) of inspired air; and (2) to assess the impact on rH of the addition of an integrated heated humidifier or a full face mask to the CPAP circuitry. DESIGN: The studies were performed in 25 patients with obstructive sleep apnea syndrome receiving long-term nasal CPAP therapy and complaining of nasal discomfort. During CPAP administration, temperature and rH were measured in the mask either during a night's sleep for 8 patients or during a daytime study in which the effects of mouth leaks were simulated in 17 patients fitted with either a nasal mask (with or without humidification) or a face mask alone. SETTING: University hospital sleep disorders center. MEASUREMENTS AND RESULTS: Compared with the values obtained with CPAP alone, integrated heated humidification significantly increased rH during the sleep recording, both when the mouth was closed (60 +/- 14% to 81 +/- 14%, p < 0.01) and during mouth leaks (43 +/- 12% to 64 +/- 8%, p < 0.01). During the daytime study, a significant decrease in rH was observed with CPAP alone. Compared with the values measured during spontaneous breathing without CPAP (80 +/- 2%), the mean rH was 63 +/- 9% (p < 0.01) with the mouth closed and 39 +/- 9% (p < 0. 01) with the mouth open. The addition of heated humidification to CPAP prevented rH changes when the mouth was closed (82 +/- 12%), but did not fully prevent the rH decrease during simulation of mouth leaks (63 +/- 9%) compared with the control period (80 +/- 2%, p < 0. 01). Finally, attachment of a face mask to the CPAP circuitry prevented rH changes both with the mouth closed (82 +/- 9%) and with the mouth open (84 +/- 8%). CONCLUSIONS: These data indicate that inhaled air dryness during CPAP therapy can be significantly attenuated by heated humidification, even during mouth leaks, and can be totally prevented by using a face mask.     

Dynamic behavior of respiratory system during nasal continuous positive airway pressure in spontaneously breathing premature newborn infants

The end-expiratory lung-volume level of premature newborn infants is maintained above passive resting volume during active breathing, through the combination of reduced time constant and high respiratory rate. To determine whether nasal continuous positive airway pressure (NCPAP) alters this characteristic dynamic breathing pattern, we studied the effects of various NCPAP levels on the dynamic elevation of end-expiratory lung volume level (DeltaEELV) in spontaneously breathing premature newborn infants, using respiratory inductive plethysmography (RIP). Eleven premature newborn infants with moderate respiratory failure were included. NCPAP levels were set in a random order to 0, 2, 4, and 6 cm H2O. Tidal volume (Vt), rib-cage contribution to Vt (%RC), phase angle between abdominal and thoracic motions (theta), respiratory rate (RR), and inspiratory and expiratory times (Ti and Te) were continuously recorded by RIP. The slope of the linear part of the expiratory flow-volume relation was extrapolated up to zero flow level to evaluate the dynamic elevation of the functional residual capacity (FRC) (DeltaEELV). The time-constant of the respiratory system (tauRS) was calculated as the slope of the linear part of the expiratory flow-volume loop. At NCPAP = 6 cm H2O, DeltaEELV reached 0.6 +/- 0.2 times the Vt at NCPAP = 0 cm H2O. An increase in NCPAP level resulted in a significant decrease in DeltaEELV (P < 0.01). A decrease in DeltaEELV during NCPAP was associated with a significant increase in Te from 0.62 +/- 0.13 sec at NCPAP = 0 cm H2O to 0.80 +/- 0.07 sec at NCPAP = 6 cm H2O (P < 0.05), and a decrease in tauRS from 0.4 +/- 0.1 sec at NCPAP = 0 cm H2O to 0.24 +/- 0.04 sec at NCPAP = 6 cm H2O (P < 0.01). These results indicate that the characteristic spontaneous breathing pattern causing a dynamic elevation of FRC is abolished by NCPAP. We speculate that the dynamic volume-preserving mechanisms resulting from expiratory flow braking are no longer required during NCPAP, as the constant pressure may passively elevate FRC.     

Predicting effective continuous positive airway pressure

PURPOSE: The purpose of this study was to compare the pressure required to abolish apneas as predicted from a previously derived algorithm (Ppred) with the true effective pressure (Peff) determined during a continuous positive airway pressure (CPAP) titration study. SETTING: Sleep clinic of a university hospital. METHODS: We prospectively studied 329 patients with sleep apnea undergoing CPAP titration. The following protocol was employed. Titration began at a pressure (Ppred) calculated from a previously derived equation based on body mass index, neck circumference, and apnea/hypopnea index (AHI). If AHI at Ppred was > 10, the pressure was increased in steps of 1 cm H(2)O until AHI became < 10. If, on the other hand, AHI at Ppred was < 10, the pressure was reduced in increments of 1 cm H(2)O until AHI became > 10. The lowest pressure that abolishes sleep apnea is defined as the Peff. Paired t tests, linear correlation, and distribution of (Ppred - Peff) were used to compare Peff and Ppred. RESULTS: Successful titration was accomplished in 276 patients (84%). Mean Ppred was similar to mean Peff (8.1 +/- 2.2 vs 8.1 +/- 2.6 cm H(2)O, respectively). There was a significant correlation between these two pressures (r = 0.73; p = 0.0001). Examination of the distribution of (Peff - Ppred) revealed that in 63% of patients, Ppred was within +/- 1 cm H(2)O of Peff; in 83% of patients, the two measures were within +/- 2 cm H(2)O; and in 95%, within +/- 3 cm H(2)O. CONCLUSION: We conclude that pressure predicted from an algorithm based on simple anthropometric and sleep variables constitutes a good starting point for CPAP titration, allowing the optimum pressure to be achieved with only a few incremental changes.     

Obesity hypoventilation syndrome: hypoxemia during continuous positive airway pressure

BACKGROUND: Polysomnography findings between matched groups with obstructive sleep apnea (OSA) and OSA plus obesity-hypoventilation syndrome (OHS) before and after continuous positive airway pressure (CPAP), particularly in the extremely severe obese (body mass index [BMI] >or= 50 kg/m2), are unclear. DESIGN: Prospective study of subjects (BMI >or= 50 kg/m2) undergoing diagnostic polysomnography. Subjects with an apnea-hypopnea index (AHI) >or= 15/h underwent a second polysomnography with CPAP. The effect of 1 night of CPAP on sleep architecture, AHI, arousal indexes, and nocturnal oxygenation was assessed. OHS was defined as those subjects with obesity, PaCo2 > 45 mm Hg, and PaO2 < 70 mm Hg in the absence of lung disease. RESULTS: Twenty-three subjects with moderate-to-severe OSA and 23 subjects with moderate-to-severe OSA plus OHS underwent a 1-night trial of CPAP. Both groups were matched for spirometry, BMI, and AHI, but oxygen desaturation was worse in the OSA-plus-OHS group. CPAP significantly improved rapid eye movement (REM) duration (p < 0.005), AHI (p < 0.005), arousal indexes (p < 0.005), and percentage of total sleep time (TST) with oxygen saturation (SpO2) < 90% (p < 0.005) in both groups. In subjects with OSA plus OHS, 43% continued to spend > 20% of TST with SpO2 < 90%, compared to 9% of the OSA group, despite the adequate relief of upper airway obstruction. CONCLUSIONS: Extremely severe obese subjects (BMI >or= 50 kg/m2) with moderate-to-severe OSA plus OHS exhibit severe oxygen desaturation but similar severities of AHI, arousal indexes, and sleep architecture abnormalities when compared to matched subjects without OHS. CPAP significantly improves AHI, REM duration, arousal indexes, and nocturnal oxygen desaturation. Some subjects with OHS continued to have nocturnal desaturation despite the control of upper airway obstruction; other mechanisms may contribute. Further long-term studies assessing the comparative role of CPAP and bilevel ventilatory support in such subjects with OHS is warranted.     

Mechanical work on the lungs and work of breathing with positive end-expiratory pressure and continuous positive airway pressure.

The mechanical work on the lung required during spontaneous breathing with positive end-expiratory pressure (PEEP) was compared with different methods of continuous positive airway pressure (CPAP) in nine young healthy athletes (surfers) at levels of 5, 10, 15, and 20 cm H2O. At the level of 20 cm H2O, PEEP increased the mean total work per minute by 116 percent and the total work per liter by 121 percent. The percent increase rose linearly with the level of PEEP. In contrast, with methods of CPAP that maintained the airway pressure (Paw) constant, the total work per minute decreased by 45 per cent at a PEEP of 10 cm H2O and remained at this level with PEEP of 15 and 20 cm H2O. Use of PEEP did not increase the functional residual capacity (FRC) in these spontaneously breathing subjects. In contrast, CPAP resulted in a rise in FRC proportional to the level of CPAP. This suggests that CPAP must be applied in a manner that maintains Paw constant to provide optimal assistance to ventilation.     

Effects of continuous positive airway pressure on Cheyne-Stokes breathing in congestive heart failure]

To investigate the effects of a continuous positive airway pressure (CPAP) of 5 cmH2O for three months on sleep disordered breathing and cardiac function in congestive heart failure (CHF), we performed physiological tests before and after the CPAP treatment in six male patients with stable CHF, whose echocardiographic left ventricular ejection fraction (LVEF) was below 30%. The control polysomnography revealed that all six had Cheyne-Stokes breathing (with central sleep apnea in four, and central sleep hypopnea in two). Prior to the CPAP, the number of episodes of apnea/hypopnea per hour of sleep, the contribution of slow wave sleep to total sleep time, LVEF and the cardio-thoracic ratio were 34.7 +/- 21.4, 4.1 +/- 1.5%, 24.4 +/- 2.3% and 58.4 +/- 3.7% (mean +/- SD), respectively. After the CPAP, these values changed to 6.0 +/- 7.0, 16.5 +/- 8.3%, 34.3 +/- 3.3% and 55.0 +/- 4.2%, respectively, all of which changes showed a statistical significance (p < 0.05). We conclude that CPAP is an effective treatment for CHF with Cheyne-Stokes breathing, improving sleep disordered breathing, sleep quality and cardiac function, and providing a new non-pharmacological approach for CHF.     

The effect of continuous positive airway pressure therapy on nasal patency

Background

Nasal congestion and obstruction are reported in the majority of continuous positive airway pressure (CPAP) users and are frequently cited as reasons for noncompliance. To our knowledge, no study has demonstrated a change in objective or subjective nasal patency in patients with obstructive sleep apnea (OSA) after a therapeutic trial of CPAP therapy.

Methods

This prospective nonrandomized trial tested the hypothesis that CPAP therapy would result in both objective and subjective improvements in nasal patency in patients with OSA. Prior to initiation of CPAP, acoustic rhinometry (AR) was used to determine nasal volume and minimum cross‐sectional area in the upright and reclined positions. Subjective nasal patency was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire. Both assessments were repeated at follow‐up visits.

Results

AR data demonstrated a statistically significant increase in total nasal volume (TV) in the reclined position (p = 0.002) and minimum cross‐sectional area (MCA) in both the sitting and reclined positions (p = 0.006, p = 0.021) in OSA patients after >30 days of CPAP therapy and with >70% compliance. NOSE scores decreased significantly (p = 0.038) representing an improvement in nasal patency.

Conclusion

Objective and subjective measurements of TV and MCA increased after initiation of CPAP therapy in this prospective study.