Computing sleep deficiency.

Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints.

A new German Charité Jet Lag Scale for jet lag symptoms and application.

Travelling across multiple time zones provokes adaptation of endogenous circadian rhythm to the new time zone. Within the context of previous studies, an English-language state-of-health questionnaire, the Columbia Jet Lag Scale, is the only sufficiently validated scale for jet lag and its symptoms. This study presents a new state-of-health questionnaire in German, one intended to achieve standardisation of surveys on jet lag. The questionnaire was applied to define the baseline for the prevalence of jet lag symptoms based on a reference group (n = 36). The jet lag score ascertained was subsequently applied to determine the frequency of jet lag in a group of 53 subjects. Systematic investigation of the frequency of jet lag symptoms had not been previously presented. Among the group of 53 travelling test subjects, 60% demonstrated moderate jet lag symptoms. Practitioner Summary: This introduction of the Charité Jet Lag Scale, the first German jet lag questionnaire, calls attention to this topic for the first time since a 2000 publication in Ergonomics. Our systematic investigation of jet lag frequency, with the new scale, determined moderate jet lag symptoms among 60% of subjects.

Jet lag modification.

Athletes often are required to travel for sports participation, both for practice and competition. A number of those crossing multiple time zones will develop jet lag disorder with possible negative consequences on their performance. This review will discuss the etiology of jet lag disorder and the techniques that are available to shorten or minimize its effects. This includes both pharmacological and nonpharmacological approaches.

[Biological rhythm, sleep and jet lag]. / Biologische Rhythmen, Schlaf und Jet Lag.

Sleep is an active recovery process, which is governed by biological rhythms. This rhythmic variation influences almost all bodily functions and dictates the optimal time for sleep. Sleep itself is an inconsistent state mainly characterized by the alteration between REM and NREM sleep. Vital regenerative processes occur during sleep. Sleep is a basic prerequisite for wellbeing, health and performance. If the synchronization between sleep and the biological rhythms is disturbed, malfunctions of the organism have to be expected. Such a state can be found by a sudden shift of local time by travelling across time zones (jet lag). Therapeutic strategies can reduce the symptoms associated with the state of jet lag.

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach.

We present ten insights that can be gained from computational models based on molecular mechanisms for the mammalian circadian clock. These insights range from the conditions in which circadian rhythms occur spontaneously to their entrainment by the light-dark (LD) cycle and to clock-related disorders of the sleep-wake cycle. Endogenous oscillations originate spontaneously from transcription-translation feedback loops involving clock proteins such as PER, CRY, CLOCK and BMAL1. Circadian oscillations occur in a parameter domain bounded by critical values. Outside this domain the circadian network ceases to oscillate and evolves to a stable steady state. This conclusion bears on the nature of arrhythmic behavior of the circadian clock, which may not necessarily be due to mutations in clock genes. Entrainment by the LD cycle occurs in a certain range of parameter values, with a phase that depends on the endogenous period of the circadian clock. A decrease in PER phosphorylation is accompanied by a decrease in endogenous period and a phase advance of the clock; this situation accounts for the familial, advanced sleep phase syndrome (FASPS). The mirror delayed sleep phase syndrome (DSPS) can be accounted for, similarly, by an increase in PER phosphorylation and a rise in autonomous period. Failure of entrainment by the LD cycle in the model corresponds to the non-24 h sleep-wake cycle syndrome, in which the phase of the circadian clock drifts in the course of time. Quasi-periodic oscillations that develop in these conditions sometimes correspond to long-period patterns in which the circadian clock is nearly entrained for long bouts of time before its phase rapidly drifts until a new regime of quasi-entrainment is re-established. In regard to jet lag, the computational approach accounts for the two modes of re-entrainment observed after an advance or delay which correspond, respectively, to an eastward or westward flight: the clock adjusts in a direction similar (orthodromic) or opposite (antidromic) to that of the shift in the LD cycle. Computational modeling predicts that in the vicinity of the switch between orthodromic and antidromic re-entrainment the circadian clock may take a very long time to resynchronize with the LD cycle. Repetitive perturbations of the circadian clock due, for example, to chronic jet lag -a situation somewhat reminiscent of shift work- may lead to quasi-periodic or chaotic oscillations. The latter irregular oscillations can sometimes be observed in normal LD cycles, raising the question of their possible relevance to fragmented sleep patterns observed in narcolepsy. The latter condition, however, appears to originate from disorders in the orexin neural circuit, which promotes wakefulness, rather than from an irregular operation of the circadian clock.

Prediction of probabilistic sleep distributions following travel across multiple time zones.

STUDY OBJECTIVES: To parameterize and validate a model to estimate average sleep times for long-haul aviation pilots during layovers following travel across multiple time zones. The model equations were based on a weighted distribution of domicile- and local-time sleepers, and included algorithms to account for sleep loss and circadian re-synchronization. DESIGN: Sleep times were collected from participants under normal commercial operating conditions using diaries and wrist activity monitors. PARTICIPANTS: Participants included a total of 306 long-haul pilots (113 captains, 120 first officers, and 73 second officers). MEASUREMENT AND RESULTS: The model was parameterized based on the average sleep/wake times observed during international flight patterns from Australia to London and Los Angeles (global R2 = 0.72). The parameterized model was validated against the average sleep/wake times observed during flight patterns from Australia to London (r2 = 0.85), Los Angeles (r2 = 0.79), New York (r2 = 0.80), and Johannesburg (r2 = 0.73). Goodness-of-fit was poorer when the parameterized model equations were used to predict the variance across the sleep/wake cycles of individual pilots (R2 = 0.42, 0.35, 0.31, and 0.28 for the validation flight patterns, respectively), in part because of substantial inter-individual variability in sleep timing and duration. CONCLUSIONS: It is possible to estimate average sleep times during layovers in international patterns with a reasonable degree of accuracy. Models of this type could form the basis of a stand-alone application to estimate the likelihood that a given duty schedule provides pilots, on average, with an adequate opportunity to sleep.

Chronobiological disorders: current and prevalent conditions.

In recent decades, the hectic lifestyle of industrialized societies has wrought its effects on the quality of sleep, and these effects are evidenced by a profusion of sleep-related disorders. Regular exposure to artificial light, coupled with social and economic pressures have shortened the time spent asleep. Otherwise, Circadian Rhythm Sleep Disorders are characterized by desynchronization between the intrinsic circadian clock and the extrinsic cycles of light/dark and social activities. This desynchronization produces excessive sleepiness and insomnia. The International Classification of Sleep Disorders describes nine sleep disorders under the category of Circadian Rhythm Sleep Disorders. Currently, this diagnosis is made based on the patient's history, a sleep log alone, or the sleep logs and actigraphy conducted for at least 7 days. This review contains an overview of current treatment options, including chronotherapy, timed bright light exposure, and administration of exogenous melatonin.

Accelerometry-assessed sleep duration and timing in late childhood and adolescence in Scottish schoolchildren: A feasibility study.

Children and adolescents commonly suffer from sleep and circadian rhythm disturbances, which may contribute to poorer mental health and wellbeing during this critical developmental phase. Many studies however rely on self-reported sleep measures. This study assessed whether accelerometry data collection was feasible within the school setting as a method for investigating the extent of sleep and circadian disruption, and associations with subjective wellbeing, in Scotland. Fourteen days of wrist-worn accelerometry data were collected from 69 pupils, aged 10-14 years. Objective measures of sleep timing, sleep duration and circadian rest-activity patterns were derived. Questionnaires assessed subjective sleep timing, depressive symptoms, and experiences of wearing the accelerometer. Pupils slept on average less than 8 hours per night, failing to meet standard age-specific recommendations. Sleep timing was later and duration longer on weekends compared to weekdays (B = 0.87, 95% confidence interval (CI) 0.70, 1.04; B = 0.49, 95% CI 0.29, 0.69), indicating social jetlag. Lower daytime activity was correlated with higher depressive symptoms (r = -0.84, p = 0.008). Compared to primary school pupils, secondary pupils had shorter sleep window duration and lower circadian relative amplitude. Over half of participants reported some discomfort/inconvenience wearing the accelerometer. These data highlight that inadequate sleep is prevalent in this sample of schoolchildren. Future, larger scale investigations will examine in more detail the associations between sleep, circadian function and physical activity with mental health and wellbeing.

A practical approach to circadian rhythm sleep disorders.

Circadian rhythm sleep disorders are common in clinical practice. The disorders covered in this review are delayed sleep phase disorder, advanced sleep phase disorder, free-running, irregular sleep-wake rhythm, jet lag disorder and shift work disorder. Bright light treatment and exogenous melatonin administration are considered to be the treatments of choice for these circadian rhythm sleep disorders. Circadian phase needs to be estimated in order to time the treatments appropriately. Inappropriately timed bright light and melatonin will likely worsen the condition. Measurements of core body temperature or endogenous melatonin rhythms will objectively assess circadian phase; however, such measurements are seldom or never used in a busy clinical practice. This review will focus on how to estimate circadian phase based on a careful patient history. Based on such estimations of circadian phase, we will recommend appropriate timing of bright light and/or melatonin in the different circadian rhythm sleep disorders. We hope this practical approach and simple recommendations will stimulate clinicians to treat patients with circadian rhythm sleep disorders.

Some chronobiological and physiological problems associated with long-distance journeys.

Long-distance travel is becoming increasingly common. Whatever the means of transport, any long journey will be associated with "travel fatigue". The symptoms associated with this phenomenon result from a changed routine (particularly sleep lost and meals) and the general disruption caused by travel. Planning any trip well in advance will minimise many of these problems, but some factors are less easy to guard against. These problems include sitting in cramped and uncomfortable conditions and, with flights, the hypoxic environment in the cabin. After arrival at the destination in another country, there can be problems coping with the local language, alterations in food and different customs. If the flight has crossed the equator, then there is likely to be a change in season and natural lighting and, if it has crossed several time zones, there will also be the problem of "jet lag", caused by a transient desynchrony between the "body clock" and the new local time. Moreover, the new environment might differ from the place of departure with regard to ambient temperature and humidity, altitude, natural lighting (including ultraviolet radiation) and pollution. The traveller needs to be aware of these changes before setting off, so that appropriate preparations (clothing, for example) can be made.

[CME: Jet Lag Jetlag]. / CME: Jetlag CME-Fragen.

CME: Jet Lag Jetlag Abstract. Crossing several time zones by air travel leads to a temporary desynchronization of the internal clock with the external light/dark cycle. In the following jet lag occurs typically including difficulties falling asleep or waking up early as well as day-time sleepiness and significant reduction of wellbeing and fitness. To provide optimal medical advice, it is necessary to understand the human circadian rhythm and sleep-wake regulation. In consideration with additional information on travel plans, an approach to alleviate jet lag symptoms can be developed. This article addresses different supportive measures and advice on how to adjust to a new time zone and reduce jet lag symptoms.

[Diagnosis and comorbidities of Circadian Rhythm Sleep Disorders]. / Diagnostic et comorbidités des troubles du rythme veille-sommeil.

Circadian rhythm sleep disorders (CRSD) result from a disturbed endogenous clock (intrinsic CRSD) or from a misalignment between the biological clock and an imposed environment (extrinsic CRSD). Among intrinsic CRSD, one distinguishes the delayed sleep-wake phase disorder, the advanced sleep-wake phase disorder, the irregular sleep-wake rhythm disorder and the non-24-hour sleep-wake rhythm disorder. Shift work disorder, jet lag disorder and circadian sleep-wake disorder not otherwise specified are extrinsic CRSD. Prevalences of the different CRSD remain largely unknown. Some CRSD are particularly frequent such as sleep delayed phase syndrome in adolescents. Overall, CRSD are probably under-diagnosed. CRSD generate insomnia and excessive daytime somnolence. A biological clock dysfunction has to be evoked in case of insomnia or sleepiness. Furthermore, as CRSD can overlap with other sleep disorders, their diagnosis and treatment are essential. CRSD cause significant mental, physical or socio-professional sufferings. They are frequently associated with comorbidities, mainly neurodevelopmental, psychiatric and neurodegenerative disorders. Regarding neurodevelopmental comorbidities, therapy using a chronobiological approach is complementary to the usual clinical care. It helps to limit the significant impact of CRSD on quality of live, daytime functioning, social interactions and neurocognitive difficulties in the children. In psychiatry, sleep disorders and circadian rhythms sleep-wake disorders are a factor of vulnerability, of suicidal risk, of relapse and pharmacoresistance. Thus, diagnosis of CRSD associated with a psychiatric disorder is of major importance. Treatment using a chronobiological approach reinforcing the entrainment of the sleep-wake cycle is complementary to usual treatments. Sleep disorders and circadian sleep-wake rhythm disorders can be a preclinical sign of Alzheimer's and Parkinson's disease. In the elderly, a beginning neurodegenerative disorder can be associated with a CRSD and complaints of sleepiness, nocturnal awakenings and/or irregular sleep-wake cycles. Patients affected by neurogenerative disorders are particularly vulnerable for having CRSD. Data from different studies suggest that CRSD participate in pathophysiology of Alzheimer's disease. Even though treatment of CRSD associated with neurodegenerative disorders is entirely part of the treatment strategy, it remains uncertain to which extend this treatment may impact disease progression.

Circadian Rhythm Sleep-Wake Disorders in Older Adults.

The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows wakefulness throughout the day and a long consolidated sleep episode at night. Mismatch between the desired timing of sleep and the ability to fall and remain asleep is a hallmark of the circadian rhythm sleep-wake disorders. This article discusses changes in circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep-wake disorders; and how neurologic diseases in older patients affect circadian rhythms and sleep.

Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review.

OBJECTIVE: This the first of two articles reviewing the scientific literature on the evaluation and treatment of circadian rhythm sleep disorders (CRSDs), employing the methodology of evidence-based medicine. In this first part of this paper, the general principles of circadian biology that underlie clinical evaluation and treatment are reviewed. We then report on the accumulated evidence regarding the evaluation and treatment of shift work disorder (SWD) and jet lag disorder (JLD). METHODS: A set of specific questions relevant to clinical practice were formulated, a systematic literature search was performed, and relevant articles were abstracted and graded. RESULTS: A substantial body of literature has accumulated that provides a rational basis the evaluation and treatment of SWD and JLD. Physiological assessment has involved determination of circadian phase using core body temperature and the timing of melatonin secretion. Behavioral assessment has involved sleep logs, actigraphy and the Morningness-Eveningness Questionnaire (MEQ). Treatment interventions fall into three broad categories: 1) prescribed sleep scheduling, 2) circadian phase shifting ("resetting the clock"), and 3) symptomatic treatment using hypnotic and stimulant medications. CONCLUSION: Circadian rhythm science has also pointed the way to rational interventions for the SWD and JLD, and these treatments have been introduced into the practice of sleep medicine with varying degrees of success. More translational research is needed using subjects who meet current diagnostic criteria.

Social jetlag: misalignment of biological and social time.

Humans show large differences in the preferred timing of their sleep and activity. This so-called "chronotype" is largely regulated by the circadian clock. Both genetic variations in clock genes and environmental influences contribute to the distribution of chronotypes in a given population, ranging from extreme early types to extreme late types with the majority falling between these extremes. Social (e.g., school and work) schedules interfere considerably with individual sleep preferences in the majority of the population. Late chronotypes show the largest differences in sleep timing between work and free days leading to a considerable sleep debt on work days, for which they compensate on free days. The discrepancy between work and free days, between social and biological time, can be described as 'social jetlag.' Here, we explore how sleep quality and psychological wellbeing are associated with individual chronotype and/or social jetlag. A total of 501 volunteers filled out the Munich ChronoType Questionnaire (MCTQ) as well as additional questionnaires on: (i) sleep quality (SF-A), (ii) current psychological wellbeing (Basler Befindlichkeitsbogen), (iii) retrospective psychological wellbeing over the past week (POMS), and (iv) consumption of stimulants (e.g., caffeine, nicotine, and alcohol). Associations of chronotype, wellbeing, and stimulant consumption are strongest in teenagers and young adults up to age 25 yrs. The most striking correlation exists between chronotype and smoking, which is significantly higher in late chronotypes of all ages (except for those in retirement). We show these correlations are most probably a consequence of social jetlag, i.e., the discrepancies between social and biological timing rather than a simple association to different chronotypes. Our results strongly suggest that work (and school) schedules should be adapted to chronotype whenever possible.

Effects of Long-Haul Transmeridian Travel on Subjective Jet-Lag and Self-Reported Sleep and Upper Respiratory Symptoms in Professional Rugby League Players.

PURPOSE: To examine the effects of 24-h travel west across 11 time zones on subjective jet-lag and wellness responses together with self-reported sleep and upper respiratory symptoms in 18 professional rugby league players. METHODS: Measures were obtained 1 or 2 d before (pretravel) and 2, 6, and 8 d after travel (post-2, post-6, and post-8) from Australia to the United Kingdom (UK) for the 2015 World Club Series. RESULTS: Compared with pretravel, subjective jet-lag remained significantly elevated on post-8 (3.1 ± 2.3, P < .05, d > 0.90), although it was greatest on post-2 (4.1 ± 1.4). Self-reported sleep-onset times were significantly earlier on post-2 than at all other time points (P < .05, d > 0.90), and large effect sizes suggested that wake times were earlier on post-2 than on post-6 and post-8 (d > 0.90). Although significantly more upper respiratory symptoms were reported on post-6 than at pretravel (P < .05, d ˃ 0.90), no incidence of injury and negligible changes in wellness and muscle strength and range of motion (P > .05, d < 0.90) were evident after travel. CONCLUSIONS: Results suggest that westward long-haul travel between Australia and the UK exacerbates subjective jet-lag and sleep responses, along with upper respiratory symptoms, in professional rugby league players. Of note, the increase in self-reported upper respiratory symptoms is a reminder that the demands of long-haul travel may be an additional concern in jet-lag for traveling athletes. However, due to the lack of sport-specific performance measures, it is still unclear whether international travel interferes with training to the extent that subsequent competition performance is impaired.

A 30-Minute, but Not a 10-Minute Nighttime Nap is Associated with Sleep Inertia.

STUDY OBJECTIVES: To assess sleep inertia following 10-min and 30-min naps during a simulated night shift. METHODS: Thirty-one healthy adults (aged 21-35 y; 18 females) participated in a 3-day laboratory study that included one baseline (BL) sleep (22:00-07:00) and one experimental night involving randomization to either: total sleep deprivation (NO-NAP), a 10-min nap (10-NAP) or a 30-min nap (30-NAP). Nap opportunities ended at 04:00. A 3-min psychomotor vigilance task (PVT-B), digit-symbol substitution task (DSST), fatigue scale, sleepiness scale, and self-rated performance scale were undertaken pre-nap (03:00) and at 2, 17, 32, and 47 min post-nap. RESULTS: The 30-NAP (14.7 ± 5.7 min) had more slow wave sleep than the 10-NAP (0.8 ± 1.5 min; P < 0.001) condition. In the NO-NAP condition, PVT-B performance was worse than pre-nap (4.6 ± 0.3 1/sec) at 47 min post-nap (4.1 ± 0.4 1/sec; P < 0.001). There was no change across time in the 10-NAP condition. In the 30-NAP condition, performance immediately deteriorated from pre-nap (4.3 ± 0.3 1/sec) and was still worse at 47 min post-nap (4.0 ± 0.5 1/sec; P < 0.015). DSST performance deteriorated in the NO-NAP (worse than pre-nap from 17 to 47 min; P < 0.008), did not change in the 10-NAP, and was impaired 2 min post-nap in the 30-NAP condition (P = 0.028). All conditions self-rated performance as better than pre-nap for all post-nap test points (P < 0.001). CONCLUSIONS: This study is the first to show that a 10-min (but not a 30-min) nighttime nap had minimal sleep inertia and helped to mitigate short-term performance impairment during a simulated night shift. Self-rated performance did not reflect objective performance following a nap.

Further assessments of the relationship between jet lag and some of its symptoms.

The disruption of circadian rhythms following time-zone transitions gives rise to the syndrome of jet lag. The power of some of the symptoms of jet lag to predict the amount of jet lag measured at the same and at different times of the day has been investigated. Eleven healthy subjects were studied in an Isolation Unit for two days after a simulated flight from the UK to Beijing (8 time zones to the east). At six time-points (08:30, 11:00, 14:00, 17:00, 20:00, and 23:00 h), the subjects recorded their jet lag, and the differences from "normal" (that is, from days in which there is no jet lag) of alertness, hunger, indigestion, concentration, motivation, and irritability. They recorded at 08:30 h the type of food they had eaten since rising at 08:00h and, at the other times, the type of food eaten in the last three hours. Assessments were made by visual analogue scales or, in the case of type of food, by a nominal scale. Following the time-zone transition, the adjustment of meals appeared to be complete almost immediately. Jet lag and its symptoms were present during both experimental days. Jet lag tended to rise during the course of the daytime, accompanied by falls in alertness, motivation, and concentration. Correlation matrices between jet lag and each of the other variables were produced, using lags between the variable (from up to 5 time-points before the assessment of jet lag to 5 time-points afterwards) and pooling the results from both days. These matrices indicated that significant correlations existed only between jet lag and alertness, concentration, and motivation, and then only when these other variables were assessed at the same time as jet lag or 1 or 2 time-points earlier. Jet lag was then treated as the dependent variable and the symptoms as covariates in analysis of covariances (ANCOVAs), with the days treated as a random effect. This analysis enabled the significance of potential predictors of jet lag, together with their beta-coefficients (the relationship between a unit change of each significant predictor and the change in jet lag), to be calculated. Falls in alertness and motivation were significant predictors of increased jet lag, provided that they were measured at the same time, when they accounted for about 50% of the jet lag; when measured at other time-points, they did not act as significant predictors. It is concluded that the amount of jet lag varies during the course of the day and that it can be predicted from contemporaneous assessments of alertness and motivation-but not from assessments made at other times of the day, nor from other variables that are symptoms of jet lag, even though these other variables are significantly increased. In considering the results of this and our previous study, we reiterate the view that the exact meaning of "jet lag" is complex and that the particular combination of factors that contribute to it might vary with the time of day that the assessment is made. Inferences about any decrements due to time-zone transitions cannot be made reliably at times of the day that differ from the time when jet lag is assessed.

Chronotype predicts positive affect rhythms measured by ecological momentary assessment.

Evening chronotype, a correlate of delayed circadian rhythms, is associated with depression. Altered positive affect (PA) rhythms may mediate the association between evening chronotype and depression severity. Consequently, a better understanding of the relationship between chronotype and PA may aid in understanding the etiology of depression. Recent studies have found that individuals with evening chronotype show delayed and blunted PA rhythms, although these studies are relatively limited in sample size, representativeness and number of daily affect measures. Further, published studies have not included how sleep timing changes on workday and non-workdays, or social jet lag (SJL) may contribute to the chronotype-PA rhythm link. Healthy non-depressed adults (n = 408) completed self-report affect and chronotype questionnaires. Subsequently, positive and negative affects were measured hourly while awake for at least two workdays and one non-workday by ecological momentary assessment (EMA). Sleep variables were collected via actigraphy and compared across chronotype groups. A cosinor variant of multilevel modeling was used to model individual and chronotype group rhythms and to calculate two variables: (1) amplitude of PA, or the absolute amount of daily variation from peak to trough during one period of the rhythm and (2) acrophase, or the time at which the peak amplitude of affect rhythms occurred. On workdays, individuals with evening chronotype had significantly lower PA amplitudes and later workday acrophase times than their morning type counterparts. In contrast to predictions, SJL was not found to be a mediator in the relationship between chronotype and PA rhythms. The association of chronotype and PA rhythms in healthy adults may suggest the importance of daily measurement of PA in depressed individuals and would be consistent with the hypothesis that evening chronotype may create vulnerability to depression via delayed and blunted PA rhythms.