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# Why, when and how to assess autonomic nervous system maturation in neonatal care units: A practical overview

Hugues Patural, Vincent Pichot, Frédéric Roche, Antoine Giraud

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Hugues Patural, Vincent Pichot, Frédéric Roche, Antoine Giraud. Why, when and how to assess autonomic nervous system maturation in neonatal care units: A practical overview. Neurophysiologie Clinique = Clinical Neurophysiology, 2023, 53 (2), pp.102855. 10.1016/j.neucli.2023.102855. hal-04858428

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# Why, when and how to assess autonomic nervous system maturation in neonatal care units: A practical overview

<figure><img src="image_3.png" /></figure>

Hugues Patural<sup>a,b,*</sup>, Vincent Pichot<sup>b</sup>, Frédéric Roche<sup>b</sup>, Antoine Giraud<sup>a,b</sup>

Received 3 March 2023; accepted 5 March 2023

Available online 23 March 2023

KEYWORDS

Autonomic nervous
system;
Dysautonomia;
Neonate;
Neurodevelopment;
Prematurity

**Abstract** The evaluation of the autonomic reactivity of newborns by heart rate variability (HRV) analysis is a simple and essential aid to identifying pathological situations of dysautonomia. Thanks to this relatively simple and reproducible analytic tool, the pediatrician can identify and target children at high risk of life-threatening events, i.e., those with insufficient intrinsic capacity for cardiorespiratory self-regulation, who should benefit from close cardiorespiratory monitoring. Different mathematical algorithms integrate delayed or real-time variations in the length of the RR interval to better understand the state of autonomic maturation of the newborn. HRV analysis, as a non-invasive tool for assessing autonomic balance, is essential to assess the functioning of the autonomic nervous system and, more specifically, parasympathetic/sympathetic balance. Despite many recognized diagnostic and therapeutic implications, its application to neonatal medicine is not yet well understood.

© 2023 Elsevier Masson SAS. All rights reserved.

Introduction

The autonomic nervous system (ANS), a key component for
the survival of any individual, regulates variations in heart
and respiratory rate according to their vital and physiologi-
cal needs [1,2].

It has been widely demonstrated that the more variable
an individual's heart rate, the better the state of health,

and numerous studies for over 20 years have shown that
heart rate variability is a very powerful and reproducible
indicator of the general health of the human being, and
could even predict their future state of health [3]. The fetus
and later baby from birth are no exception to this rule and,
fortunately, are not spared this extraordinary adaptive
capacity which gives them the possibility of precise adjust-
ment of cardiorespiratory rhythms in response to various
stimuli. In other words, the more variable its heart rate, the
more effectively it can deal with stresses and environmental
changes that could affect cardiac function, such as skin-to-
skin contact, touch, and various sounds, from the most

<footnote><sup>a</sup> Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire de Saint-Étienne, F-42023, Saint-Étienne, France</footnote>

<footnote><sup>b</sup> Université Jean Monnet Saint-Étienne, INSERM, SAINBIOSE U1059, F-42023, Saint-Étienne, France</footnote>

<footnote>* Corresponding author at: Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Universitaire de Saint-Étienne, F-42023, Saint-Étienne, France.</footnote>

<footnote>E-mail address: hugues.patural@univ-st-etienne.fr (H. Patural).</footnote>
aggressive, to the most restful and familiar, like parental voices or music [4,5].

Heart rate variability (HRV) measures the variation in time between consecutive heartbeats. HRV analysis aims to extract meaningful information from heart rate signals to understand the underlying physiological mechanisms better, and make inferences about health and well-being. Cardiac signal processing is commonly used as a marker of autonomic nervous system function and is linked to various health problems, including stress, cardiovascular disease, and mortality [6].

## Why assess ANS maturation?

### Because fetal autonomic balance is subtle and can be easily altered from birth

The process of development and autonomic physiological maturation of the fetus is essential to regulate in utero its internal environment and its vital functions such as heart rate, blood pressure, and hemodynamic redistribution. During fetal development, the ANS undergoes significant maturation and changes, which result in improved regulation and stability of these functions [6]. Overall, autonomic fetal physiological maturation is a complex process essential for fetal survival and healthy fetal development. Understanding and monitoring this process is crucial to ensuring fetal health and well-being.

Studies have shown that genetic and environmental factors affect fetal ANS maturation [7]. For example, maternal factors such as maternal stress, nutrition, and substance abuse, including high nicotine exposure, can impact fetal ANS development. Assessment of fetal ANS maturation is essential in determining fetal well-being and identifying potential risks of fetal distress or other complications. A commonly used method to assess fetal ANS maturation is to analyze fetal heart rate variation (fHRV). HRV reflects the balance between sympathetic and parasympathetic components of the ANS, and changes in HRV over time can provide insight into the autonomic maturation of the fetus. HRV is an excellent indicator to detect and monitor stress related to labor and delivery for the term newborn [8–10].

Gender-specific longitudinal studies have established that reaching satisfactory autonomic maturation at birth takes at least 37 weeks [11,12].

Thus, compared to healthy full-term neonates, preterm neonates, regardless of their gestational age (GA), show altered cardiac reactivity and baroreflex loop, even if we consider the significant increase in postnatal HRV parameters in particular for the high frequency (HF) parasympathetic index [13–16].

After birth, the autonomic balance changes significantly from the first day of life. The slight sympathetic preponderance linked to the stress of birth decreases in a few days in favor of the parasympathetic system, whose reactivity quickly becomes predominant [17]. During this initial period of life, the very rapid cholinergic synaptic response (in milliseconds) must be considered the first to appear in response to stimuli. In contrast, the accelerating adrenergic response is delayed and a thousand times slower (in seconds).

This physiological state of vagal predominance in the neonatal period lasts several months and explains the frequent initial cardiac decelerations in response to extrinsic stress [18] (noise, pain, gastroesophageal reflux). Subsequently, this sympathovagal balance, specific to each individual, evolves slowly during the first months of life as described in the AuBE (Autonomic Baby Evaluation) longitudinal cohort [19]. During the first two years of life, global autonomic maturation gradually reaches a new balance, resulting in predominant parasympathetic activity over sympathetic activity and, therefore, a gain in fine regulation.

This essential balance for cardiorespiratory control and homeostasis depends on the state of wakefulness (wakefulness, calm sleep, active sleep) and postnatal age.

Later in childhood, sympathetic and parasympathetic cardiac activities follow different matrational trajectories marked by large individual differences, even within narrow age ranges. There is, however, a general trend of maturation with a cubic trend, and a phase of stagnation in middle childhood for the vagal branch and a more gradual decrease from early childhood until adolescence for the sympathetic branch of the ANS [20].

### Because life-threatening events and sudden infant death can be induced by an ANS dysfunction

Sudden infant death syndrome (SIDS) is the sudden and unexpected death of an infant under one year old, usually while sleeping. The cause remains unknown in about half of cases, despite a systematic etiological assessment integrated with biological and radiological examinations and the performance of a scientific autopsy [21,22].

There are three main types of risk, often combined, favoring the occurrence of SIDS.

The first relates to the potential vulnerability of the baby due to the history of the pregnancy (premature birth, in utero nicotine exposure, malformation). In the case of prematurity and/or maternal smoking, a perfect correlation exists between the different experimental conditions of sleep-wakefulness, ventral decubitus, and the multiparametric indices of HRV [23–25]. Based on an epidemiological survey of 20,000 children, Kato et al. reported an association between central abnormalities of the cardiorespiratory response on awakening and transmitted events involving life prognosis and sudden death [26].

The second concerns a particular period of the baby's life, between birth and four months, when the mechanisms of autonomic cardiorespiratory maturation and the sleep-wake cycles progress and can malfunction. In this case, the immaturity or maladaptive response of the cardiorespiratory control centers at the level of the brainstem, including adrenergic hyporesponsiveness, minimal sensitivity to hypercapnia, and abnormal arousal responses, could be important risk factors [27,28]. Cardiorespiratory modulations during wakefulness are mediated by the cortico-hypothalamic pathways and the cardiorespiratory nuclei of the brainstem (nucleus ambiguus, dorsal vagus nerve, nucleus of the solitary tract). Possibly due to genetic polymorphisms, the involvement of active neurotransmitters such as GABA (γ-aminobutyric acid), serotonin, adenosine, prostaglandins, and endorphins has been proposed as an element favoring the occurrence of apnea and bradycardia in patients with
SIDS [29–31]. Finally, the possibility of overexpression of muscarinic M2 receptors in the brain, serum and heart, or of an abnormal increase in the enzymatic activity of acetylcholinesterase has been proposed [32,33].

The third and perhaps most crucial risk relates to environmental and external factors. Thus, infants who sleep prone on their stomachs are at an extremely high risk of thermal dysregulation and SIDS through asphyxia. Especially at this level, the prevention of unexpected infant death is essential. Nowadays, at least one-half of deaths would be preventable if safe sleeping rules were respected! Reducing the risk of SIDS must involve combining safe sleep practices and efforts to identify and treat any underlying health conditions [34]. So, to limit the risk of death from underlying congenital or acquired autonomic dysfunction, the neonatologist would be well advised to test the state of equilibrium of the autonomic regulatory function of the baby because all these neurobiological considerations converge towards autonomic dysfunction as a preponderant element in the occurrence of SIDS.

## Because inflammation increases the risk of acquired dysautonomia

The function of the autonomic nervous system of the child is not only dependent on its degree of prematurity, and could be altered in other clinical situations observed in the neonatal period: this is the case after deep anoxia [35], sepsis [36,37] or an inflammatory cascade.

Systemic inflammation could explain the link between infection and acquired dysautonomia in the neonatal period. Numerous data from the literature provide evidence of essential interactions of pro and anti-inflammatory cytokines at the level of the brainstem [38–40]. Inflammation is a defense reaction initiated by the immune system, involving several mechanisms, particularly the production of pro-inflammatory cytokines in response to a pathogenic agent or cell invasion. The most important of these cytokines is TNFα (tumor necrosis factor), produced by activated macrophages. The accumulation of TNFα is responsible for the local inflammatory reaction and stimulates the release of other pro-inflammatory cytokines, such as IL-1 or HMGB1. TNFα is secreted in large quantities in the event of a significant presence of the pathogenic agent, accumulating in the systemic circulation, and is responsible for manifestations of sepsis, up to septic shock. At the same time, inflammation is slowed down by other cytokines (IL-10, TGF-β, TNF binding protein, IL-1Rα), hormones (glucocorticoids, adrenaline, noradrenaline, α-MSH), and other locally acting molecules (spermine, prostaglandin E2).

The ANS is also widely involved in regulating the inflammatory response. It receives information about ongoing inflammation via the humoral response (accumulation of TNF and the cytokines IL-1 and IL-6 in the systemic circulation, which cross the blood-brain barrier and are assimilated at the cerebral level), but also neuronally (vagus nerve afferent pathway, activated by IL-1 and other endotoxins with very sensitive detection capability, even in the absence of systemic inflammation) [41].

The ANS is then activated to play its role in the mediation of the inflammatory reaction in particular:

The secretion of noradrenaline and adrenaline by the sympathetic system, interacts with the adrenergic receptors of immune cells, stimulating the production of anti-inflammatory cytokines such as IL-10, and inhibiting the production of pro-inflammatory cytokines TNF [38,42], IL-1 and IL-12 [39].

The release of acetylcholine by the parasympathetic system interacts with acetylcholine receptors of macrophages, inhibiting the secretion of TNF, IL-1, HMGB1, and other pro-inflammatory cytokines [43–46].

This sympathovagal coactivation in the face of inflammation has been described by K. Tracey et al. under the term “Cholinergic anti-inflammatory pathway” [47,40] or “Inflammatory reflex” [40]. The ANS, by reflex, regulates the inflammatory response in real-time, just as it controls heart rate and other vital functions.

## When to assess the ANS maturation level?

### Before discharge from the neonatal unit to guide when to stop cardiorespiratory monitoring

Cardiorespiratory monitoring in neonatology is crucial to guarantee the neonate's safety and stability, especially in the event of prematurity, respiratory or cardiac diseases, and other medical problems. It aims to monitor in real-time the cardiac and respiratory function of the newborn to detect any potential problem quickly. The most common techniques are continuous cardiac monitoring using heart rate sensors, pulse oximeters, and oxygen saturation monitoring.

In the neonatal unit, stopping cardiorespiratory monitoring before discharge is a risky activity that requires careful monitoring of the daily cardiorespiratory events observed, particularly regarding bradycardia and desaturation [48]. An understanding of the mechanisms and integral self-regulatory capacities of neonates is essential to secure the discontinuation of monitoring. In this case, an objective analysis of the basal autonomic control and the possibility of the ANS reactivity, is very useful.

We have observed that at the time of the corrected term, the cholinergic response is adequate, robust, and, above all, faster than the adrenergic response. This singularity, specific to all newborns, implies a daily presence of numerous physiological bradycardias at the slightest stimulus. However, since assessing the degree of maturation and responsiveness is more relevant than the cardiac event itself [22,19], it becomes more efficient to assess the capacity for sympathetic autoregulation (response), which should not be impaired, rather than counting the daily bradycardias which are physiological.

In other words, considering this vagal predominance as a pathological element is a misunderstanding of neonatal physiology when approaching the theoretical term. More important is to look for a lack of sympathetic reactivity, which can increase the risk of maladaptive cardiorespiratory responses following constant or environmental stress. It is now recognized that this immaturity, or this lack of sympathetic stress response, is the leading risk factor for
unexpected infant death syndrome (SIDS), particularly in premature infants [18,28].

A simple way to reduce the risk of discharging babies from the neonatal unit, and stopping cardiorespiratory monitoring is to consider this capacity for self-regulation of the cardiac and respiratory rhythm [18].

In clinical practice, when the baby reaches its theoretical term, the presence of daily bradycardias should not justify continued monitoring if these events remain isolated, asymptomatic, brief (<10 s), shallow (>70 bpm), and are followed by a rapid heart rate acceleration indicating an adapted sympathetic activity. Complementary assessment of the ANS total power and autonomic reactivity of the newborn facilitates the identification of rare children with a high potential for life-threatening events, which should be the only ones to benefit from home cardiorespiratory monitoring (Fig. 1).

Careful observation of heart rate variability and complexity of cardiorespiratory rhythms, either in real-time or delayed from a 24-h cardiac Holter recording, is a valuable tool for neonatologists [49,50].

## To take into account a risk of dysautonomia during infection or immunization

In adults, in the event of sepsis, several studies have shown an alteration in cardiac variability [51,52]. This alteration of the integral cardiac regulation of the individual may even be a predictive criterion of organ dysfunction and death in adults [53]. In children, alteration of the ANS has been well studied in neonatology: newborns also present with dysautonomia, which sometimes precedes clinical signs of sepsis, and monitoring can therefore be used as a predictive tool for neonatal morbidity [54–57]. On the other hand, few studies have focused on older children in sepsis, although a few older studies and case reports also show that dysautonomia is present during septic shock in children.

The situations of acquired dysautonomia occurring during the neonatal period justify the study of heart rate variability as a tool to understand this potential for regulating cardio-respiratory cycles. It is the case with a number of infectious diseases:

* During neonatal botulism after poisoning with *Clostridium botulinum* toxin present in honey, the child develops neuromuscular paralysis but also a blockage of the cholinergic autonomic neurotransmission system [58].

* During bronchiolitis due to respiratory syncytial virus (RSV) [59], H1N1 flu [60], SARS-CoV-2 [61] infection, we observe prolonged central apnea due to brainstem dysfunction, especially in infants. Their capacity for cardiorespiratory adaptation is then significantly impaired and recovers only slowly, potentially putting them at risk of severe life-threatening events during this period. The recovery mechanisms and the time required to achieve long-term recovery are not well understood. This post-viral dysfunction could explain the physio-pathogenesis of certain SIDS.

After vaccination, a cytokine response partly explains the occurrence of apneic respiratory disorders in premature infants. In clinical practice, apnea and bradycardia occurring in premature infants within 48 h following vaccination justify performing the first injection under cardio-respiratory monitoring [62,63].

## To consider HRV as a biomarker for brain injury and prognosis in neonates

In a clinical situation of perinatal anoxia occurring in the early postnatal period, an alteration in cardiac variability has been recognized as an indirect predictive marker of the severity of the underlying hypoxic-ischemic brain damage. Non-invasive heart variability assessment, readily available, inexpensive and performed early within 12 h after birth, could be useful to target indications for hypothermia in case of difficulty in accessing continuous EEG monitoring [64,65].

## How to assess ANS maturation?

It is important to note that the interpretation of HRV signals can be complex and may require an in-depth understanding of physiology and signal processing. There are several methods for processing HRV signals, including time domain, frequency domain, and non-linear analysis.

The choice of method and specific parameters used will depend on the objectives of the analysis and the specific population being studied [19,66].

## With linear analysis of HRV [50,66]

- Time domain analysis (Fig. 2)

Time domain analysis involves calculating various measures based on the differences between consecutive heart-beats, such as the mean of the difference and the standard deviation.

It is thus possible to calculate various indices such as the standard deviation of the RR intervals (SDNN), the standard deviation of the average of all the RR intervals for the 5-min segments (SDANN), and the average of the standard deviation of all 5-min RR intervals (SDNNindex) which can be considered as the global long-term variations. Other indices like the difference between adjacent normal RR intervals greater than 50 ms (pNN50) or 20 ms (pNN20) in percent, the square root of the mean of the sum of the differences between squared normal RR intervals (rMSSD) reflect rapid variations. They are representative of parasympathetic activity, whose main neuromediator is acetylcholine. Other geometric indices in the time domain are calculated from the density distribution of the RR intervals.

Also representing the time domain, the Poincaré diagram is an index of cardiac variability, expressed as a cloud of points obtained by plotting each RR interval to its previous one. This quantitative diagram is represented by an ellipse whose shape is defined from the average RR interval (center of the ellipse). The index SD1 (standard deviation of the Poincaré diagram perpendicular to the identity line) represents the short-term variability. In contrast, SD2 (standard deviation of the plot along this identity line) reflects the long-term variability.

- Frequency domain analysis (Fig. 3)

This analysis consists of converting the signal from the time domain into the frequency domain using a technique
<figure><img src="image_4.png" /><figcaption>**Figure 1** proposition of a decision-making algorithm taking into account the type of cardiac events observed on the scope and an evaluation of time-domain heart rate variability indices/24 h.
OSAS: obstructive sleep apnea syndrome, HRV: heart rate variability, HR: heart rate (bpm), SDNN: standard deviation normal to normal R (ms).</figcaption></figure>

called fast Fourier transform (FFT). It allows information to be extracted about the distribution of power over different frequency bands, which can provide insight into the dynamics of HRV.

The HRV frequency spectrum, standardized in 1996 by the Reference Task Force, is characterized in newborns and human infants by an amplitude of 0 to 2 Hz that is more extensive than for adults due to the higher respiratory frequency of newborns and can be segmented into three leading bands: very low frequencies (VLF) from 0 to 0.04 Hz or long-term regulation (thermoregulation,

peripheral vasomotor tone, renin-angiotensin system), low frequencies (LF) from 0.04 to 0.15 Hz mainly reflect sympathetic activity and more subsidiary to the parasympathetic system, and high frequencies (HF) from 0.15 to 2 Hz correspond to the ventilatory component under the exclusive control of the parasympathetic system. The total power (Ptot) or "Area under the spectrum curve" represents the integral variability. Using standardized indices such as LFnu, HFnu, or the LF/HF ratio makes it possible to estimate the sympathetic component of autonomic modulation.
<figure><img src="image_5.png" /><figcaption>**Figure 2** 24-hour tachogram representing heart rate variability of RR intervals (ms) and standard deviation of RR intervals per 5 min periods (SDNN, ms), of a full-term healthy neonate (left) and a premature 34 GA healthy neonate (right).</figcaption></figure>

The real-time segmentation of the signal is best achieved by the wavelet transform method, which makes it possible to isolate the transition periods and evaluate the non-stationary signals better.

## - Geometric analysis

Also derived from a linear signal, these indices quantify the overall heart rate variability influenced by the slow oscillations of the RR intervals. This is the triangular index (integral of the density distribution divided by the maximum

of this distribution), the triangular interpolation index of the histogram or width of the base of this triangle (TINN).

## With non-linear analysis of HRV [50,66]

The choice of method and specific parameters used will depend on the objectives of the analysis and the specific population being studied.

Non-linear analysis, often used in addition to other HRV assessment techniques, uses mathematical algorithms such as fractal dimension, entropy, and chaos analyses to analyze

<figure><img src="image_6.png" /><figcaption>**Figure 3** Maturation of the heart rate variability (HRV) of a full-term healthy newborn, between birth (left) and 24 months of life (right), from a 24-h tachogram representing the RR variability (ms) (upper part) and the frequency-domain analysis (lower part) including the total power of the spectrum (PSD, $ms^2$/Hz) and each individualized indices [parasympathetic HF ($ms^2$/Hz, green), ortho-sympathetic LF ($ms^2$/Hz, red) and VLF ($ms^2$/Hz, light blue)].</figcaption></figure>
the complex and non-linear properties of the cardiovascular system and can help assess physiological responses to stressful situations.

The indices give information on the complexity of autonomic regulation:

Fractal values based on the analysis of trend fluctuations (Detrend Fluctuation Analysis, $\alpha1$, $\alpha2$, H), slope (1/f), and exponent (Hurst, Higuchi, Katz, Lyapunov), which quantify at different scales the repetition of patterns. These indices will give information on the degree of fractality of the RR signal, with two extreme values, one indicating a purely random signal (no adaptation capacity of the SNA), the other due to a completely harmonic signal (stereotype regulations always in the same frequency bands). In general, the analysis of RR intervals series shows a mixture of harmonic (VLF, LF, HF) and fractal components. Entropy values (Shanon indices and its derivatives, conditional entropy, sampled and approximate entropy) estimate the regularity and complexity of a pattern over different lengths.

Capacity for deceleration (DC) and acceleration (AC) of two successive sequences of RR beats to dissociate vagal and sympathetic characteristics.

The non-linear analysis is an advanced technique that involves expertise in data analysis for a proper interpretation of results.

## Concomitant cardiac and respiratory analysis

Cardiac autonomic regulation is closely linked to respiratory regulation, at all ages of life.

Real-time coupling analysis approaches explore the link between instantaneous heart rate and respiratory rate fluctuations. This synchronous coupling is called “cardiorespiratory coherence” [67]. The most prominent representation in neonatal physiology is represented by the physiological sinus arrhythmia caused by the respiratory cycle in healthy infants [68,3]. During inspiration, the heart rate accelerates instantaneously, whereas it decreases during expiration and prolonged apnea.

In immaturity or stress, this coupling between heart rate and respiration can be altered and generate central apnea and bradycardia, inversely correlated with gestational age. Pharmacological strategies based on caffeine citrate and non-pharmacological (non-invasive respiratory assistance) most of the time make it possible to limit the impact of this immaturity of coupling until it is definitively effective as the baby approaches its adjusted age of term.

In clinical practice, cardiorespiratory coherence analysis is mainly concerned with perioperative anesthesia and analgesia and is rarely used in neonatology units.

## Simple use of HRV in clinical practice and conclusion

Once these different HRV analysis tools are well understood, they must be available at the patient's bedside. This is simple and possible either through a central monitoring unit equipped with such analysis algorithms or by performing a 24-h cardiac Holter afterwards [49]. This will determine whether the autonomic equilibrium is normal or abnormal at any given time. As the adjusted age approaches term, this

non-invasive tool and indicator of good central neurological regulation will make it possible to stop cardiorespiratory monitoring without risk in the vast majority of cases [69].

By integrating this automatic regulation mechanism, it is easier to understand that neonatal bradycardias do not justify continued monitoring if, even several times a day, they remain isolated and asymptomatic, brief (<10 s), and followed by a rapid cardiac acceleration as evidence of an adapted sympathetic response.

Only a proven alteration of this physiological adaptation capacity should justify continued monitoring in the Neonatal Unit. This alteration will be defined by an overall decrease in sympathovagal power (decrease in Ptot and abnormally low SDNN < 25 ms), a defect in sympathetic reactivity (decrease in the LF index and LF/HF ratio), a decrease in the properties fractals and cardiac entropy of rhythm.

Such an autonomic imbalance increases the risk of an unsuitable cardiorespiratory response during permanent or environmental stress and, ultimately, the risk of SIDS (odds ratio x 5). To date, only the real-time or delayed evaluation of the infant's automatic regulation can answer this legitimate question. It should become a tool that is integrated into clinical care. The use of artificial intelligence and machine learning technology in the near future to search for congenital or acquired dysautonomia of the child could play a crucial role, not only for managing the risk of severe life-threatening events but perhaps also for targeting children with risk of serious neurodevelopmental disorders in order to start interventions earlier [68].

## Declaration of Competing Interest

The authors have no competing interests to declare.

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