Correlation of a new index reflecting the fluctuation of parasympathetic tone and fetal acidosis in an experimental study in a sheep model.

The autonomic nervous system plays a leading role in the control of fetal homeostasis. Fetal heart rate variability (HRV) analysis is a reflection of its activity. We developed a new index (the Fetal Stress Index, FSI) reflecting parasympathetic tone. The objective of this study was to evaluate this index as a predictor of fetal acid-base status. This was an experimental study on chronically instrumented fetal lambs (n = 11, surgery at 128 +/- 2 days gestational age, term = 145 days). The model was based on 75% occlusion of the umbilical cord for a maximum of 120 minutes or until an arterial pH ≤ 7.20 was reached. Hemodynamic, gasometric and FSI parameters were recorded throughout the experimentation. We studied the FSI during the 10 minutes prior to pH samplings and compared values for pH>7.20 and pH≤ 7.20. In order to analyze the FSI evolution during the 10 minutes periods, we analyzed the minimum, maximum and mean values of the FSI (respectively FSImin, FSImax and FSImean) over the periods. 11 experimentations were performed. During occlusion, the heart rate dropped with an increase in blood pressure (respectively 160(155-182) vs 106(101-120) bpm and 42(41-45) vs 58(55-62) mmHg after occlusion). The FSImin was 38.6 (35.2-43.3) in the group pH>7.20 and was higher in the group pH less than 7.20 (46.5 (43.3-52.0), p = 0.012). The correlation of FSImin was significant for arterial pH (coefficient of -0.671; p = 0.004) and for base excess (coefficient of -0.632; p = 0.009). The correlations were not significant for the other parameters. In conclusion, our new index seems well correlated with the fetal acid-base status. Other studies must be carried out in a situation close to the physiology of labor by sequential occlusion of the cord.

Review shows that using surfactant a number of times or as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia.

AIM: Bronchopulmonary dysplasia (BPD) remains the most common respiratory morbidity in immature infants. This review describes the diagnosis of BPD has evolved and summarises the therapeutic approaches that have made it possible to limit the incidence of BPD. METHOD: We reviewed the literature from the first definition of BPD by Northway in 1967 to the surfactant treatment policies that are currently in use, drawing on more than 50 papers up to 2017. RESULTS: Our review showed that improvements in neonatal survival have been associated with an increased risk of severe BPD, significant levels of long-term morbidity and the increased use of healthcare resources. These issues have encouraged researchers to explore potential new treatments that limit the incidence of BPD. Repeated surfactant instillation and the use of surfactant as a vehicle for budesonide are promising strategies for alleviating the burden of chronic lung disease. Ongoing research on surfactant or stem cell therapy may further improve the respiratory prognosis for prematurely born children. CONCLUSION: Considerable research has been carried out into the increase in BPD, which has resulted from improvements in neonatal survival. Key areas of research include repeated surfactant administration, using surfactant as a vehicle for budesonide and stem cell therapy.

Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension.

BACKGROUND: Prolonged pulmonary hypertension (PH) is highly predictive for pulmonary morbidity and death in infants with congenital diaphragmatic hernia (CDH). OBJECTIVES: To report the effects and tolerability of subcutaneous treprostinil in newborns with severe CDH and late life-threatening PH. METHODS: We recorded clinical and echocardiography data before and after starting subcutaneous treprostinil, on patients with severe CDH and late PH, refractory to inhaled nitric oxide and oral sildenafil. RESULTS: 14 patients were treated with treprostinil (gestational age: 39.1±2.0weeks; birth weight: 3200±600g). Prior to treatment, the pre- and post-ductal SpO2 difference (Δ SpO2) was 14±10%. Treprostinil was initiated at a median age of 12days [5-157]. After starting treprostinil, ΔSpO2 decreased to 3% at day 7 (p<0.05), and the mean blood flow velocities in the right pulmonary arteries increased by 110% (p<0.05). 2 of the 14 patients died. At the age of follow up (12months to 3years), the 12 surviving infants were all weaned from respiratory support and discharged home. CONCLUSION: The subcutaneous treprostinil improves pulmonary hemodynamics and outcomes in infants with CDH and life-threatening PH. We suggest that the treatment should be considered in infants with severe CDH and late PH. TYPE OF STUDY: Case series with no comparison group. LEVEL OF EVIDENCE: Level IV.

[Esophageal atresia]. / Devenir à moyen et long terme des enfants atteints d'atrésie de l'œsophage.

Most of the children operated for esophageal atresia will survive the neonatal period. However, medium-term and late complications are frequent in this population. Gastroesophageal reflux disease is observed in 26 to 75% of the cases and can be responsible for peptic esophagitis, anastomotic stenosis, and Barrett esophagus, which is a risk factor for adenocarcinoma of the esophagus. Dysphagia is frequently observed, sometimes several years after the surgery, affecting up to 45% of children at the age of 5 years. Growth retardation is present in nearly one-third of children at the age of 5 years. Ear, nose, and throat and respiratory complications are also very frequent but tend to improve with time. Tracheomalacia is found in 75% of these children at birth, sometimes responsible for severe complications (malaise, bradycardia). Respiratory symptoms are dominated by chronic cough, wheezing, and infections reported in 29% of the children by the age of 5 years. Restrictive, obstructive syndromes and bronchial hyperactivity can be observed, but usually remain moderate. All these complications can influence the patient's quality of life, which is moderately impaired compared to healthy controls. The high frequency of late sequelae in esophageal atresia justifies regular and multidisciplinary follow-up through adulthood.

[Congenital diaphragmatic hernia: respiratory and vascular outcomes]. / Hernie de coupole diaphragmatique : devenir respiratoire et vasculaire pulmonaire.

Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly associated with a variable degree of pulmonary hypoplasia (PH) and persistent pulmonary hypertension (PPH). Despite remarkable advances in neonatal resuscitation and intensive care, and new postnatal treatment strategies, the rates of mortality and morbidity in the newborn with CDH remain high as the result of severe respiratory failure secondary to PH and PPH. Later, lung function assessments show obstructive and restrictive impairments due to altered lung structure and lung damage due to prolonged ventilatory support. The long-term consequences of pulmonary hypertension are unknown. Other problems include chronic pulmonary aspiration caused by gastro-oesophageal reflux and respiratory manifestations of allergy such as asthma or rhinitis. Finally, failure to thrive may be caused by increased caloric requirements due to pulmonary morbidity. Follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols.

[Congenital diaphragmatic hernia: antenatal care]. / Hernie congénitale du diaphragme : prise en charge anténatale.

The prenatal evaluation of the postnatal prognosis of fetuses displaying congenital diaphragmatic hernia (CDH) has improved over the past five years. Although the accuracy of these outcome predictions remains a matter of debate, it seems important that all teams in charge of those fetuses use the same prognostic factors in order to be able to improve and compare their practice. Prediction will be based on Lung over Head Ratio (LHR) between 22 and 28 weeks or the LHR observed/expected whatever the gestational age, (the measurement of which relies on very strict criteria), the position of the liver and lung volumes measured by MRI. These factors allow the identification of a group of fetuses likely to have a poor outcome. In the group with LHR less than 1 or LHR o/e less than 25% and where the liver is in the thorax, survival is less than 20%. In utero treatment could be offered to these fetuses. A balloon can be placed in the trachea, under the vocal cords, by foetoscopy between 28 and 30 weeks of pregnancy. The balloon is retrieved at 34 weeks. The preliminary results show that survival in this group increases from 20% to up to 50%. The morbidity does not seem to be increased but is currently under evaluation.

[Very premature births: Dilemmas and management. Part 1. Outcome of infants born before 28 weeks of postmenstrual age, and definition of a gray zone]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Première partie : pronostic des naissances avant 28 semaines, identification d'une zone grise.

With very preterm deliveries, the decision to institute intensive care, or, alternatively, to start palliative care and let the baby die, is extremely difficult, and involves complex ethical issues. The introduction of intensive care may result in long-term survival of many infants without severe disabilities, but it may also result in the survival of severely disabled infants. Conversely, the decision to withhold resuscitation and/or intensive care at birth, which is an option at the margin of viability, implies allowing babies to die, although some of them would have developed normally if they had received resuscitation and/or intensive care. Withholding intensive care at birth does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. The likelihood of survival without significant disabilities decreases as gestational age at birth decreases. In addition to gestational age, other factors greatly influence the prognosis. Indeed, for a given gestational age, higher birth weight, singleton birth, female sex, exposure to prenatal corticosteroids, and birth in a tertiary center are favorable factors. Considering gestational age, there is a gray zone that corresponds to major prognostic uncertainty and therefore to a major problem in making a "good" decision. In France today, the gray zone corresponds to deliveries at 24 and 25 weeks of postmenstrual age. In general, babies born above the gray zone (26 weeks of postmenstrual age and later) should receive resuscitation and/or full intensive care. Below 24 weeks, palliative care is the only option offered in France at the present time. Decisions within the gray zone will be addressed in the 2nd part of this work.

[Very premature births: Dilemmas and management. Second part: Ethical aspects and recommendations]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Seconde partie : enjeux éthiques, principes de prise en charge et recommandations.

In the first part of this work, the outcome following very premature birth was assessed. This enabled a gray zone to be defined, with inherent major prognostic uncertainty. In France today, the gray zone corresponds to deliveries occurring at 24 and 25 weeks of postmenstrual age. The management of births occurring below and above the gray zone was described. Withholding intensive care at birth for babies born below or within the gray zone does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. Given the high level of uncertainty, making good decisions within the gray zone is problematic. Decisions should be based on the infant's best interests. Decisions should be reached with the parents, who are entitled to receive clear and comprehensive information. Possible decisions to withhold intensive care should be made following the procedures described in the French law of April 2005. Guidelines, based on gestational age and the other prognostic elements, are proposed to the parents before birth. They are applied in an individualized fashion, in order to take into account the individual features of each case. At 25 weeks, resuscitation and/or full intensive care are usually proposed, unless unfavorable factors, such as severe growth restriction, are associated. A senior neonatologist will attend the delivery and will make decisions based on both the baby's condition at birth and the parents' wishes. At 24 weeks, in the absence of unfavorable associated factors, the parents' wishes should be followed in deciding between initiating full intensive care or palliative care. Below 24 weeks, palliative care is the only option to be offered in France at the present time.

[Consequences of premature rupture of the membranes in the perinatal lung]. / Physiopathologie des conséquences respiratoires néonatales de la rupture prématurée des membranes: application à la prise en charge néonatale.

Early premature rapture of the membranes (PROM) during pregnancy is associated with a high risk of perinatal morbidity and mortality. Early PROM impairs lung structures and function through 3 mechanisms : 1) oligo-hydramnios ; 2) fetal inflammatory syndrome ; and 3) prematurity. Thus, the related causes of respiratory failure at birth after PROM are: hyaline membrane disease, persistent pulmonary hypertension induced by impaired endothelial function and/or lung hypoplasia, materno-fetal infection, and bronchopulmonary dysplasia resulting at least in part from the fetal inflammatory syndrome. Severity of the respiratory morbidity is largely unpredictable. Even if gestational age at PROM is considered as a prognostic factor, survival without morbidity exist after PROM as early as 18 weeks GA. Better knowledge of the pathophysiology improved the outcome of the preterm infants born after early PROM. Optimal management of the respiratory failure including minimizing barotrauma is required to prevent from bronchopulmonary dysplasia.

Effects of antenatal glucocorticoids on circulatory adaptation at birth in the ovine fetus.

OBJECTIVE: Adaptation to extra-uterine life requires dramatic increase in pulmonary blood flow. Mechanisms that induce pulmonary vasodilatation at birth are incompletely understood but include alveolar ventilation, increase in PaO2, and production of vasoactive mediators. We hypothesized that antenatal glucocorticoids (GC) increase pulmonary vasodilatation to birth-related stimuli. STUDY DESIGN: To test this hypothesis, we studied the pulmonary hemodynamic response at birth to mechanical ventilation with low (<10%) and then with high (100%) FiO2 in chronically prepared late-gestation fetal lambs treated or not by antenatal maternal steroids. RESULTS: Basal mean aortic and pulmonary artery pressure (PAP), left pulmonary blood flow, pulmonary vascular resistance (PVR), and blood gas were similar between control and dexamethasone-treated animals (GC group). During mechanical ventilation with low FiO2, mean PVR decreased by 40% in the control group (from 0.44 +/- 0.01 to 0.25 +/- 0.01 mm Hg/ml/min) and by 60% in the GC group (from 0.44 +/- 0.02 to 0.19 +/- 0.02 mm Hg/ml/min) (p < 0.01). When subsequently ventilated with 100% O2, there was no difference in PVR decrease between groups (0.15 +/- 0.02 mm Hg/ml/min in the GC group vs. 0.14 +/- 0.01 mm Hg/ml/min in the control group). CONCLUSION: Antenatal GC enhance pulmonary vasodilatation induced by alveolar ventilation at birth but do not alter the pulmonary vascular response to O2. We speculate that antenatal steroids exposure improve adaptation at birth through acceleration of both parenchymal and vascular lung maturation.

Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs.

BACKGROUND: This experimental study was performed to determine the effects of norepinephrine on: (i) the pulmonary vascular tone during the development of pulmonary hypertension (PH) in the fetus and (ii) the circulatory adaptation at birth after chronic intrauterine PH. METHODS: Chronically instrumented fetal lambs were randomized into two groups: (i) a group with PH obtained by antenatal partial ligation of the ductus arteriosus (DA) (n=9) and (ii) a control group without DA ligation (n=6). Pulmonary vascular responses to norepinephrine (1.5 microg min(-1)) were measured in utero 7 days after surgery. At day 8 post-surgery, after delivery, animals were ventilated for 3 h with oxygen 100%. The group with PH was randomly assigned to receive norepinephrine or saline. RESULTS: Mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were higher in the PH group (P<0.01). Norepinephrine-induced decrease in PVR was more pronounced in the PH group than in the control group (63 vs 35%, respectively; P<0.01). In the PH group, the decrease in PVR during mechanical ventilation was greater in the animals receiving norepinephrine than in the animal receiving saline (from 1.05 (0.12) to 0.1 (0.02) vs from 1.04 (0.1) to 0.2 (0.04) mm Hg ml(-1) min(-1), respectively; P<0.01). After 3 h of ventilation, mean PVR in the PH lambs treated by norepinephrine was similar to those measured in the control lambs. Aortic pressure was higher in the group treated with norepinephrine. CONCLUSION: The data suggest that norepinephrine may improve post-natal pulmonary adaptation in the newborn with persistent PH both by increasing systemic vascular pressure and by increasing pulmonary blood flow.

Successful management of severe chylothorax with argon plasma fulguration and fibrin glue in a premature infant.

Post-traumatic neonatal chylothorax is a rare entity. Management includes medical and surgical treatment. We describe here a newborn who developed a severe chylothorax after repair of an oesophageal atresia. The chylothorax was treated successfully by a combination of argon beam coagulation of the mediastinum and fibrin glue application. However, the patient developed complete thrombosis of the left femoral vein with clot extension to the inferior vena cava which resolved after infusion of recombinant tissue plasminogen activator (rt-PA). The use of argon plasma coagulation and mediastinal fibrin glue application for treating postoperative chylothorax appears to be attractive and is easy to perform even in small premature infants and may replace a more extensive surgical procedure. However, the coagulation profile should be monitored and special care should be taken to prevent vascular thrombosis after surgery.

[Fetal thoracic MR imaging]. / IRM thoracique foetale.

Ultrasonography is the method of choice for prenatal malformation screening, but it does not always provide sufficient informations to allow a correct diagnosis or an adequate abnormality evaluation. Fetal MRImaging (MRI) indications are increasing in order to complete sonographic findings. It has been initially used for evaluation of cerebral abnormalities, but it is more and more applied to other fetal areas. An adequate analysis of fetal chest and abdomen can be obtained with fast T2 and T1 weighted sequences. This allows an easy diagnosis of congenital diaphragmatic hernia and an evaluation of the consequences on pulmonary growth. Other pulmonary malformations can be also easily identified (cystic adenoid malformation, sequestration, bronchogenic cyst, tracheal or bronchial atresia). Therefore, fetal thoracic MRI contributes to a better understanding and evaluation of fetal thoracic malformations, which is particularly useful for their postnatal management.

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation.

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.

Effects of catecholamines on the pulmonary circulation in the ovine fetus.

High levels of circulating catecholamines are found in the fetus, and fetal stress and birth induce a marked surge in catecholamine secretion. Little is known about the role of catecholamines on the fetal pulmonary circulation. To determine the effects of catecholamines on the pulmonary vascular tone, we tested the hemodynamic response to norepinephrine and dopamine infusion in chronically prepared late-gestation fetal lambs. We found that norepinephrine infusion (0.5 microg. kg(-1). min(-1)) increased pulmonary artery pressure (PAP) by 10 +/- 1% (P < 0.01), left pulmonary artery blood flow by 73 +/- 14% (P < 0.01), and decreased pulmonary vascular resistance (PVR) by 33 +/- 6% (P < 0.01). The pulmonary vasodilator effect of norepinephrine was abolished after nitric oxide synthase inhibition. Dopamine infusion at 5 microg. kg(-1). min(-1) did not significantly change PVR. Conversely, dopamine infusion at 10 microg. kg(-1). min(-1) increased PAP (P < 0.01) and progressively increased PVR by 30 +/- 14% (P < 0.01). These results indicate that catecholamines may modulate basal pulmonary vascular tone in the ovine fetus. We speculate that catecholamines may play a significant role in the maintenance of the fetal pulmonary circulation and in mediating changes in the transitional pulmonary circulation.

Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome.

BACKGROUND: Early use of high-frequency ventilation and exogenous surfactant is proposed as the optimal mode of ventilatory support in infants with respiratory distress syndrome. In very premature infants, we tested the hypothesis that high-frequency versus conventional ventilation could decrease exogenous surfactant requirements and improve pulmonary outcome, without altering the complication rate, including that of severe intraventricular hemorrhage. METHODS: Preterm infants with a postmenstrual age of 24 to 29 weeks, presenting with respiratory distress syndrome were randomly assigned to high-frequency oscillatory ventilation (lung volume recruitment strategy) or conventional ventilation. RESULTS: Two hundred seventy-three infants were enrolled. One hundred fifty-three had a postmenstrual age of 24 to 27 weeks, and 143 had a birth weight /=2 instillations of exogenous surfactant (30% vs 62%; odds ratio:.27; 95% confidence interval:.16-.44) and no difference in pulmonary outcome. The incidence of severe intraventricular hemorrhage was 24% in the high-frequency group and 14% in the conventional ventilation group (adjusted odds ratio: 1.50; 95% confidence interval:.68-3.30). CONCLUSION: Early use of high-frequency oscillatory ventilation in very premature infants decreases exogenous surfactant requirements, does not improve the pulmonary outcome, and may be associated with an increased incidence of severe intraventricular hemorrhage.

Two years' follow-up of newborn infants after extracorporeal membrane oxygenation (ECMO).

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is a technique of extracorporeal oxygenation used in newborn infants with refractory hypoxemia after failure of maximal conventional medical management, when mortality risk is higher than 80%. We retrospectively reviewed all the neonates treated by ECMO between October 1991 and September 1997 in our newborn intensive care unit. METHODS: Fifty-seven patients were treated with ECMO for severe respiratory failure: congenital diaphragmatic hernia (CDH) (n=23), neonatal sepsis (NS) (n=14), meconium aspiration syndrome (MAS) (n=12), and others (n=8). Mean gestational age and birth weight were 38+/-2 weeks and 3200+/-500 g, respectively. Oxygenation index was 61+/-8. Both venovenous (n=28) or venoarterial ECMO (n=29) were used. The mean time at ECMO initiation was 47 h (range 8 h-2 months). The mean duration was 134+/-68 h. In each case of VA ECMO, carotid reconstruction was performed. Survival at 2 years was 40/57 (70%) (CDH 12/23 (52%), NS 11/14 (79%), MAS 12/12 (100%), others 5/8). Follow-up at 2 years was available in 36 survivors. RESULTS: Neurodevelopmental outcome was not related to the initial diagnosis: normal neurologic development (n=30), cerebral palsy (n=5), and neurologic developmental delay (n=1). Two patients remained oxygen dependant at 2 years, and four required surgical treatment for severe gastroesophageal reflux. Respiratory and digestive sequelae were more frequent in the CDH group (P<0.01). Patency and flow of the repaired carotid artery was assessed in 20 infants at 1 year of age using Doppler ultrasonography: normal (n=10), <50% stenosis (n=9), and >50% stenosis (n=1). CONCLUSION: ECMO increased survival of newborn infants with refractory hypoxemia. However, higher a survival rate and lower morbidity were found in non-CDH infants than in congenital diaphragmatic hernia.

Effects of inhaled nitric oxide on gas exchange and acute lung injury in premature lambs with moderate hyaline membrane disease.

OBJECTIVE: The purpose of this study was to examine whether inhaled nitric oxide (iNO) may change lung injury in moderate hyaline membrane disease (HMD). METHODS: Fifteen moderately premature lambs (128 days gestation, term=147 days) were randomly assigned to treatment with 20 ppm inhaled NO (n=7) from the onset of ventilation or control (n=8). Except for inhaled NO, treatments were intentionally similar to those applied in clinical situations. After porcine surfactant administration (Curosurf, 100 mg/kg), mechanical ventilator settings were modified during the course of the study to maintain PaCO(2) between 40 and 50 mmHg and post-ductal SpO(2) between 90 and 95%. The main studied parameters were gas exchanges parameters, respiratory mechanics (static compliance and functional residual capacity) and pulmonary vascular permeability and/or filtration rate indices. RESULTS: We found that 20 ppm of inhaled NO for 5 h significantly reduce ventilatory and oxygen requirements, but only during the first hour of mechanical ventilation. No increase in extravascular lung water content (5.41+/-0.96 vs. 5.46+/-1.09 ml/g bloodless dry lung in the control group and in the NO group, respectively) and no impairment of the respiratory mechanics could be found in the NO-treated group. However, inhaled NO increased the albumin lung leak index in this model (6.09+/-1.51 in the NO-treated group vs. 4.08+/-1.93 in the control group; P<0.05). CONCLUSIONS: Our results do not therefore support a detrimental effect of short-term exposure to low doses of NO inhalation in moderate HMD. However, it may induce an increase in lung vascular protein leakage. The pathophysiological consequences of this finding remain to be elucidated.