Methemoglobin and the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn

Abstract

BACKGROUND:

We aimed to investigate whether the change in methemoglobin levels (ΔMHb) predicts oxygenation response to inhaled nitric oxide (iNO) in persistent pulmonary hypertension of the newborn (PPHN) with lung disease, with or without pulmonary hypoplasia.

METHODS:

In this prospective observational study, infants were categorized based on ΔMHb and oxygenation response (ΔPaO₂/FiO₂) following iNO: ΔMHb ≤0 or ΔMHb>0, and ΔPaO₂/FiO₂ < 20 mmHg (Non-responder) or≥20 mmHg (Responder). ΔMHb levels were compared among infants with or without pulmonary hypoplasia.

RESULTS:

Among infants with pulmonary hypoplasia (n = 28), ΔMHb was not associated with an oxygenation response to iNO or survival without ECMO. Among infants without hypoplasia (n = 29), subjects with ΔMHb>0 following iNO (n = 21) had a greater ΔPaO₂/FiO₂ (median, 64 mmHg; IQR, 127; p < 0.01) and 100% survival without extracorporeal membrane oxygenation (ECMO) when compared to infants with ΔMHb ≤0 (n = 8; median 10 mmHg; IQR, 33).

CONCLUSIONS:

PPHN secondary to lung disease without hypoplasia with increased ΔMHb following iNO was associated with better oxygenation response and survival without ECMO compared to subjects without an increase in MHb.

Keywords

Hypoxic respiratory failure oxygenation pulmonary hypertension pulmonary hypoplasia

Abbreviations

ABG

Arterial blood gas

CDH

Congenital diaphragmatic hernia

ECMO

Extracorporeal membrane oxygenation

iNO

Inhaled nitric oxide

MHb

Methemoglobin

Oxygenation index

PPHN

Persistent pulmonary hypertension of the newborn

URMC

University of Rochester Medical Center

WCHOB

Women and Children’s Hospital of Buffalo

1 Introduction

With an incidence of approximately two cases per 1,000 live births, persistent pulmonary hypertension of the newborn (PPHN) is a common problem in neonatal intensive care units [1, 2]. Conventional medical management aims to improve oxygenation by optimizing the infant’s cardiopulmonary function and acid-base status through mechanical ventilation, pressor support, surfactant, sedation and correction of acidosis as needed. For infants who do not respond to these strategies, inhaled nitric oxide (iNO) is available as a selective pulmonary vasodilator [3, 4]. However, iNO is not effective in approximately one-third of infants > 34 weeks’ gestational age, and mortality occurs in approximately 10% of infants despite medical intervention with iNO [1, 5].

Reasons why iNO fails to improve oxygenation among infants with PPHN consistently are unclear but may be related to the heterogeneity of the diseases underlying PPHN [6]. Suboptimal iNO delivery to its site of action in the pulmonary arterial smooth muscle cells in the precapillary pulmonary arterioles may impair the oxygenation response to iNO [7]. At the cellular level, iNO diffuses into pulmonary vascular smooth muscle cells to cause vasodilation through the release of cyclic guanosine monophosphate (cGMP). When NO comes in contact with hemoglobin in the vascular lumen, the heme iron is oxidized to methemoglobin (MHb) [8], offering the opportunity to possibly use an increase in MHb as an indirect measure of successful iNO delivery to the pulmonary vasculature.

In a retrospective study, infants with parenchymal lung disease who had a poor oxygenation response to iNO exhibited lower ratios of MHb/cumulative iNO when compared to infants who responded with a ≥10 mmHg increase in the PaO₂/FiO₂ ratio [9]. However, it is unclear whether a change in MHb levels during iNO therapy may also predict response in other etiologies of PPHN, such as pulmonary hypoplasia, which were excluded in the prior study. In this study, we aimed to determine prospectively the relationship between oxygenation response and the change in MHb levels in infants administered iNO therapy for PPHN due to pulmonary hypoplasia or due to lung disease without pulmonary hypoplasia.

2 Methods

2.1 Study population

This was a prospective observational study in two centers conducted during 2009–2012 in the neonatal intensive care units at the Women and Children’s Hospital of Buffalo (WCHOB) and the University of Rochester Medical Center (URMC). The Institutional Review Boards at both centers approved the study protocol. The IRB at WCHOB granted a waiver of informed consent, while URMC obtained consent from the parents of all subjects. Infants who were diagnosed with PPHN and had iNO therapy initiated at ≤1 week of age, regardless of gestational age, were enrolled into the study. The diagnosis of PPHN and the decision to initiate iNO were made by the clinical team. Clinical evidence for the diagnosis of PPHN included: hypoxemia, hypoxia and ≥10% differential gradient between pre- and post-ductal oxygen saturations. Echocardiographic findings included: right-to-left or bidirectional shunting of blood via the ductus arteriosus or foramen ovale, an elevated tricuspid regurgitation jet, and/or flattened or leftward motion of the intraventricular septum. The study team categorized infants into pulmonary hypoplasia or lung disease without pulmonary hypoplasia based on whether the etiology of PPHN may be associated with pulmonary hypoplasia [e.g., congenital diaphragmatic hernia, renal dysplasia, oligohydramnios, etc. (Fig. 1)] Infants who did not have documentation of iNO doses, arterial blood gases (ABG) or MHb levels in their medical records were excluded from the study. Guidelines for weaning iNO were similar between centers.

Fig.1

Subject enrollment. Abbreviations: ABG, arterial blood gas; iNO, inhaled nitric oxide; MHb, methemoglobin.

2.2 Study design

Protocols that guided iNO initiation, maintenance and weaning were similar at WCHOB and URMC. iNO was initiated at a maximum dose of 20 ppm. If there was no positive response in oxygenation (e.g., PaO2 or OI) within the first 2 hours, then iNO was discontinued. If there was a positive response in oxygenation, then iNO was maintained at 20 ppm for at least 4 hours. If there was a sustained positive response in oxygenation, the clinical team considered decreasing iNO in increments of 5 ppm until reaching a dose of 5 ppm, followed by increments of 1 maximum dose ppm until iNO was discontinued.

Data collection included the following baseline characteristics: gestational age, birth weight, diagnoses, echocardiogram findings, inotropic support, surfactant administration and maternal medications during pregnancy. The following data were obtained 1 hour before and 2 hours after iNO initiation: ventilator settings, pre- and post-ductal oxygen saturations, ABG results, MHb levels and hemoglobin levels. In addition, the study team noted the need for extracorporeal membrane oxygenation (ECMO), survival or death.

The Δ(PaO₂/FiO₂) ratios were calculated at 1 hour before and 2 hours after iNO initiation to differentiate between infants who showed an improvement in oxygenation with iNO therapy (“Responders”, ≥20 mmHg increase from baseline) from those who did not (“Non-responders”, <20 mmHg increase from baseline) [10]. The change in MHb levels and oxygenation indices (OI), calculated as (mean airway pressure x FiO₂×100)/PaO₂, were determined by comparing data before and after iNO initiation.

2.3 MHb concentration measurements

MHb levels were measured by the Bayer RapidLab 1265 Blood Gas Analyzer (Siemens Medical Solutions USA, Inc., Malvern, PA) at URMC and by the IL-682 Co-oximeter (Instrumentation Laboratory, Bedford, MA) at WCHOB. Both systems were calibrated on a daily basis to ensure reproducibility of results.

2.4 Sample size calculation and statistical analysis

The primary outcome was the comparison of ΔMHb levels between Responders and Non-responders at 2 hours after iNO initiation. In a previous study, the response within each subject group, represented as MHb/ΣNO ratio, was normally distributed with a standard deviation of 0.053 [9]. Since ΣNO was standardized (20 ppm for 2 hours) in this study, we expected MHb in each group to approximate the MHb/ΣNO ratio. To detect a difference in the experimental and control means similar to the 0.046 found in the previous study, an estimated sample size consisting of 33 responders and 17 Non-responders would achieve 80% power to reject the null hypothesis that the population means of the experimental and control groups were equal.

Secondary analyses were performed to determine infants’ response to iNO according to their pathophysiology of disease: pulmonary hypoplasia and lung disease without hypoplasia. Data were analyzed using the Wilcoxon rank sum test for unpaired continuous variables that were not normally distributed, and the Wilcoxon signed rank test for paired continuous variables that were not normally distributed, and either chi-square or Fisher’s exact test for categorical variables. Because we noted similar levels of ΔMHb between Responders and Non-responders (primary outcome), but there was a difference in response to iNO among infants with pulmonary hypoplasia versus lung disease without hypoplasia (secondary analyses), data are presented according to pathophysiology of disease and subcategorized by ΔMHb in tables and figures. Data are expressed as median with IQR. Significance was accepted at P < 0.05. Data analyses were performed using GraphPad Prism 7 (GraphPad Software, La Jolla, CA).

3 Results

Over the four-year study period, 64 infants with PPHN requiring iNO therapy before one week of age met eligibility criteria (Fig. 1) Seven infants were excluded, because their parents declined participation or there was no documentation of either the iNO dose or an ABG or MHb level prior to iNO initiation. The remaining 57 infants were enrolled, of which 18 (33%) were subjects at WCHOB.

Twenty-eight infants had pulmonary hypoplasia due to congenital diaphragmatic hernia, severe oligohydramnios with an amniotic fluid index ≤5 cm, or renal anomalies. The remaining 29 infants did not have pulmonary hypoplasia and had lung disease due to causes such as respiratory distress syndrome, meconium aspiration or pneumonia. None of the infants were labelled “idiopathic” or “black-lung” PPHN.

Among PPHN infants with pulmonary hypoplasia versus those without pulmonary hypoplasia, there were no significant differences in gestational age, birth weight or gender. As part of patient care, clinical teams obtained echocardiograms in 51 patients. All except one Responder showed evidence of pulmonary hypertension on echocardiogram; for this one infant, iNO was initiated based on clinical presentation before obtaining the echocardiogram. All infants started iNO therapy at 20 ppm. After 2 hours of iNO, a repeat MHb level was obtained and infants were categorized as infants with an increase in MHb following iNO (ΔMHb>0 group) or infants without an increase in MHb (ΔMHb≤0 group). With the exception of one Responder who was weaned to 15 ppm of iNO after 7 hours and one Non-responder who received 10 ppm after 5 hours, infants received 20 ppm of iNO during the first 8-hour study period.

Among infants with pulmonary hypoplasia, demographic and clinical characteristics were similar between the ΔMHb≤0 group and ΔMHb>0 groups (Table 1). Among infants without pulmonary hypoplasia, the baseline OI was higher in the ΔMHb≤0 group compared to the ΔMHb>0 group (p = 0.05). Baseline PaO2 levels, PaO2/FiO₂ ratio and MHb levels were similar between the two groups (Table 2).

Table 1
Demographic and clinical characteristics

Characteristic Pulmonary hypoplasia Lung disease without hypoplasia

ΔMHb ≤0 (n = 8) ΔMHb>0 (n = 20) P value ΔMHb ≤0 (n = 8) ΔMHb>0 (n = 21) P value

Demographic

Infant from WCHOB, n (%) 3 (38) 6 (15) 1 1 (13) 9 (43) 0.2

Gestational age, weeks (Q1, Q3) 37.9 (30.8, 39.2) 38.6 (34.8, 39.3) 0.7 39.2 (37.4, 39.7) 38.3 (35.9, 39.6) 0.4

Birth weight, g (Q1, Q3) 2365 (1606, 3086) 3060 (2123, 3514) 0.3 3483 (2913, 4036) 3068 (2093, 3590) 0.3

Male, n (%) 2 (25) 13 (65) 0.1 6 (75) 13 (62) 0.7

Maternal medications

Indomethacin, n (%) 0 (0) 0 (0) – 0 (0) 0 (0) –

SSRI, n (%) 0 (0) 1 (5) – 0 (0) 0 (0) –

Infant medications

Age of iNO onset, hours (Q1, Q3) 19.6 (7.2, 38.2) 16.4 (4.0, 29.6) 0.4 18.8 (9.7, 29.0) 39.4 (15.3, 59.8) 0.1

Surfactant, n (%) 6 (75) 12 (60) 0.7 6 (75) 15 (71) 1

Vasopressor(s), n (%) 6 (75) 17 (85) 0.6 8 (100) 16 (76) 1

Echocardiogram done, n (%)^A 6 (75) 18 (90) 0.6 8 (100) 19 (90) 1

High frequency ventilation, n (%) 5 (63) 15 (75) 0.7 6 (75) 8 (38) 0.1

Characteristic	Pulmonary hypoplasia	Lung disease without hypoplasia
Demographic
Infant from WCHOB, n (%)	3 (38)	6 (15)	1	1 (13)	9 (43)	0.2
Gestational age, weeks (Q1, Q3)	37.9 (30.8, 39.2)	38.6 (34.8, 39.3)	0.7	39.2 (37.4, 39.7)	38.3 (35.9, 39.6)	0.4
Birth weight, g (Q1, Q3)	2365 (1606, 3086)	3060 (2123, 3514)	0.3	3483 (2913, 4036)	3068 (2093, 3590)	0.3
Male, n (%)	2 (25)	13 (65)	0.1	6 (75)	13 (62)	0.7
Maternal medications
Indomethacin, n (%)	0 (0)	0 (0)	–	0 (0)	0 (0)	–
SSRI, n (%)	0 (0)	1 (5)	–	0 (0)	0 (0)	–
Infant medications
Age of iNO onset, hours (Q1, Q3)	19.6 (7.2, 38.2)	16.4 (4.0, 29.6)	0.4	18.8 (9.7, 29.0)	39.4 (15.3, 59.8)	0.1
Surfactant, n (%)	6 (75)	12 (60)	0.7	6 (75)	15 (71)	1
Vasopressor(s), n (%)	6 (75)	17 (85)	0.6	8 (100)	16 (76)	1
Echocardiogram done, n (%)^A	6 (75)	18 (90)	0.6	8 (100)	19 (90)	1
High frequency ventilation, n (%)	5 (63)	15 (75)	0.7	6 (75)	8 (38)	0.1

Abbreviations: iNO is inhaled nitric oxide; MHb is methemoglobin; OI is oxygenation index; SSRI is selective serotonin reuptake inhibitor; WCHOB is Women and Children’s Hospital of Buffalo. ^AAll echocardiograms showed evidence of pulmonary hypertension, except for 1 infant from the lung disease group who responded to iNO with an increase in the PaO₂/FiO₂ ratio.

Table 2

Response to iNO in infants categorized by etiology of PPHN and MHb response

	Pulmonary hypoplasia			Lung disease without hypoplasia
Characteristic	ΔMHb ≤0 (n = 8)	ΔMHb>0 (n = 20)	P value	ΔMHb ≤0 (n = 8)	ΔMHb>0 (n = 21)	P value
Responder vs. Non-responder
Responder, n (%)	5 (63)	8 (40)	0.4	2 (25)	17 (81)	0.04
At baseline, median (Q1, Q3)
P_aO2, mmHg	42 (35, 53)	42 (30, 48)	0.7	42 (42, 50)	55 (42, 78)	0.3
F_iO2	1 (0.86, 1)	1 (1, 1)	0.3	1 (1, 1)	1 (0.87, 1)	0.1
P_aO2/F_iO2, mmHg	44 (38, 87)	44 (30, 50)	0.5	43 (42, 53)	71 (50, 90)	0.1
OI	29 (14, 41)	38 (23, 45)	0.3	32 (29, 40)	16 (12, 28)	0.05
MHb, %	0.8 (0.6, 1)	0.8 (0.6, 1.0)	0.9	0.9 (0.7, 1.0)	0.8 (0.6, 0.9)	0.4
After iNO onset, median (Q1, Q3)
P_aO2	61 (52, 86)	43 (32, 86)	0.1	52 (39, 59)	101 (69, 231)	<0.01
F_iO2	0.82 (0.59, 1)	0.99 (0.88, 1)	0.3	0.99 (0.91, 1)	0.90 (0.69, 0.96)	0.1
P_aO2/F_iO2, mmHg	115 (54, 148)	57 (37, 105)	0.2	58 (44, 71)	122 (100, 247)	<0.001
OI	13 (7, 28)	27 (11, 43)	0.3	31 (22, 50)	10 (4, 14)	<0.0001
MHb, %	0.7 (0.6, 0.9)	1.1 (0.9, 1.3)	0.01	0.8 (0.7, 0.8)	1.1 (0.9, 1.2)	<0.01
Δ(P_aO2/F_iO2)	29 (–1, 71)	5 (–5, 64)	0.7	10 (–10, 23)	64 (27, 154)	<0.01
ΔOI	–10 (–24, –1)	–6 (–19, 6)	0.5	–6 (–8, 10)	–7 (–13, –4)	0.3
ΔMHb	–0.1 (–0.2, 0)	0.3 (0.2, 0.4)	<0.0001	–0.1 (–0.2, 0)	0.2 (0.2, 0.4)	<0.0001
Clinical outcomes
ECMO, n (%)	2 (25)	9 (45)	0.4	0 (0)	0 (0)	–
Death, n (%)	4 (50)	13 (55)	0.7	4 (50)	0 (0)	<0.01

Abbreviations: ECMO is extracorporeal membrane oxygenation; iNO is inhaled nitric oxide; MHb is methemoglobin; OI is oxygenation index.

When the entire cohort was examined, among 57 infants enrolled in the study, ΔMHb levels were similar between Non-responders (n = 25; median, 0.2; IQR, 0.3) and Responders (n = 32; median, 0.2; IQR, 0.3) despite a significant difference in ΔOI (Non-responders: median, –2; IQR, 19; Responders: median, –15; IQR, 37; p < 0.0001). Among infants with pulmonary hypoplasia, ΔMHb levels were as follows: Non-responders (n = 15, median, 0.2; IQR, 0.4) and Responders (n = 13, median, 0.1; IQR, 0.5), P = 0.2. For infants with lung disease without hypoplasia, ΔMHb levels were: Non-responders (n = 10, median, 0; IQR, 0.2) and Responders (n = 19, median, 0.2; IQR, 0.3), P = 0.04.

While there was a trend in the data toward improved PaO₂/FiO₂ ratio and OI in infants specifically with pulmonary hypoplasia, the data did not demonstrate a significant change in these markers of oxygenation response, irrespective of the ΔMHb (Fig. 2) Among infants with pulmonary hypoplasia, an increase in MHb after iNO was not associated with a statistically significant difference in the percentage of Responders or survival without ECMO (Table 2). In sharp contrast, infants with lung disease without hypoplasia who had an increase in MHb following iNO had a higher increase in the PaO₂ and PaO₂/FiO₂ ratio compared to the ΔMHb≤0 group (Table 2, Fig. 2) In addition, an increase in MHb after iNO was associated with a higher percentage of Responders (81% vs. 25% in ΔMHb≤0 group) and 100% survival without ECMO (compared to 50% death in the ΔMHb≤0 group).

Fig.2

Oxygenation response of infants to iNO therapy from baseline, categorized by etiology of PPHN. A) ΔPaO₂/FiO₂. B) ΔOI. ^*P<0.01, ^#P<0.001, before iNO vs. after 2 hrs of iNO. Data expressed as box-and-whisker plots as follows: gray plots (ν) represent before iNO initiation, black plots (ν) represent after 2 hrs of iNO exposure; central line is median, box edges are 25th and 75th percentiles, whiskers are 10th and 90th percentiles, gray dots are values < 10th or > 90th percentiles. Abbreviations: MHb, methemoglobin.

4 Discussion

In this prospective observational study, infants with PPHN with or without pulmonary hypoplasia exhibited differences in response to iNO therapy. Among infants with lung disease without hypoplasia, an increase in MHb following iNO was associated with significant improvement in oxygenation and 100% survival without ECMO. These data support findings from a retrospective study that showed an association between inadequate oxygenation response to iNO and a lower MHb-to-cumulative iNO ratio in infants with PPHN secondary to parenchymal lung disease [9]. In contrast, among infants with pulmonary hypoplasia, the change in MHb was not associated with oxygenation, need for ECMO or mortality. Pulmonary hypoplasia, as seen with congenital diaphragmatic hernia, is an important contributor to lethal and severe PPHN [11].

For infants with PPHN without pulmonary hypoplasia, both iNO inactivation and inadequate delivery of iNO to vascular smooth muscle cells contribute to the pathophysiology of PPHN. Past research has shown that optimizing lung recruitment to promote iNO delivery to the site of action in these infants improves ventilation-perfusion matching, pulmonary vasodilation, oxygenation and survival while decreasing the need for ECMO [12 –15]. Because MHb is formed after iNO comes into contact with hemoglobin [8 , 16–18], an increase in MHb may indicate successful iNO delivery to the pulmonary vasculature in this patient subpopulation (Fig. 3).

Fig.3

Nitric oxide vasodilates the pulmonary arterioles when it combines with hemoglobin to form MHb. Among infants with PPHN due to lung disease without pulmonary hypoplasia, an increase in MHb levels may indicate successful iNO delivery to the pulmonary vasculature (right schematic). These infants exhibit a response to iNO with an improvement in V-Q matching, PaO₂/FiO₂ and OI, as well as decreased need for ECMO and decreased mortality (Responders). In contrast, iNO is unable to reach the pulmonary vasculature in non-ventilated alveoli, resulting in no significant improvement in PaO₂/FiO₂ and OI (left schematic, Non-responders). Abbreviations: Hb, hemoglobin; iNO, inhaled nitric oxide; MHb, methemoglobin; PA, pulmonary arterioles; PV, pulmonary vein; V-Q, ventilation-perfusion.

In contrast, for infants with pulmonary hypoplasia, the etiology of PPHN is more complex. Limited response to iNO does not appear to be secondary to inadequate delivery of iNO to the alveoli. There is decreased cross-sectional area of lung parenchyma and pulmonary vasculature, vascular remodeling, as well as functional changes in the heart such as left ventricular systolic and diastolic dysfunction, leading to pulmonary venous hypertension [11, 19]. Past research of infants with PPHN due to congenital diaphragmatic hernia show limited clinical benefit of iNO in preventing the need for ECMO [20]. In addition, the Neonatal Inhaled Nitric Oxide Study (NINOS) Group found that infants with CDH given iNO therapy had a significantly higher need for ECMO than control infants who received 100% oxygen without iNO [21]. In this patient population, use of iNO has evolved to become a temporizing measure in selected infants to stabilize infants for ECMO rather than its use as a definitive therapeutic modality [11].

Monitoring clinical and laboratory findings, such as SPO₂, PaO₂ and the PaO₂/FiO₂ ratio, remains the mainstay of evaluating patient status during iNO therapy. We demonstrate that monitoring the change in MHb following iNO may be useful in patients with lung disease and PPHN. The lack of increase in MHb may be a sign of inadequate iNO delivery, and monitoring the adequacy of lung recruitment may be a prudent clinical maneuver prior to instituting additional vasodilator therapy.

Limitations of this study were methodological. 1) Different equipment was used to perform blood gas and MHb analyses at the two centers. To ensure quality reporting of data, both systems underwent quality assurance audits and were calibrated on a daily basis to ensure reproducibility of results. However, since we examined the change in MHb from baseline, this difference likely was not a major factor in the outcomes. 2) Six infants were diagnosed with PPHN based on clinical findings, rather than via echocardiography to confirm PPHN and exclude congenital heart disease. It is unclear why echocardiography was not obtained, but we wanted to include all patients who received iNO for suspected PPHN. Because these infants were all Responders, they may have showed clinical improvement relatively quickly. 3) Clinical practice regarding the use of vasopressors, high frequency ventilation and iNO appeared similar. However, there may have been practice variation normally found in other centers. While there were no significant differences in the use of surfactant, there may be an opportunity to further maximize its use in infants with a potential component of parenchymal lung disease. 4) We noted in our study that infants with pulmonary hypoplasia who had ΔMHb≤0 also had a nonsignificant improvement in PaO2/FiO2 and OI. This finding may have been influenced by the small size of this group. Also, while there is not a known physiologic explanation, MHb levels are influenced by factors other than iNO delivery to the vasculature, such as the levels of MHb reductase enzyme activity and changes in pulmonary blood flow. Transient decreases in right-to-left shunting can potentially result in marked changes in PaO2. The dilution or contamination of pulmonary venous return by right atrial or pulmonary arterial blood may attenuate ΔMHb. Further investigation on the nuances of MHb delivery and metabolism may provide additional insight on how different factors may affect MHb levels.

5 Conclusion

ΔMHb as an indicator of iNO delivery to the pulmonary vasculature was associated with an improved oxygenation response to iNO in infants with PPHN due to parenchymal lung disease without hypoplasia. While the range of MHb levels noted in this study limits its clinical use to help predict response to iNO therapy, further exploration of potential underlying differences in pathophysiology between infants with and without pulmonary hypoplasia may help elucidate the role of MHb in NO metabolism. We present these data to emphasize the importance of lung recruitment prior to initiation of iNO in neonates with PPHN associated with lung disease.

Disclosure statements

The authors declare no conflict of interest. No form of payment, honorarium or grant funding was given to any of the authors to produce this manuscript.

Footnotes

Acknowledgments

The authors have no acknowledgments.

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