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ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 18-26

A Retrospective study on the profile of persistent pulmonary hypertension of newborn in a tertiary care unit of Eastern India


1 Department of Neonatology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Physiology, Ananda Mohan College, University of Calcutta, Kolkata, West Bengal, India

Date of Submission08-Jun-2019
Date of Decision19-Oct-2019
Date of Acceptance09-Dec-2019
Date of Web Publication29-Jan-2020

Correspondence Address:
Dr. Somnath Pal
Assistant Professor,Department of Neonatology,Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, West Bengal; 30/1B, Old Ballygunge First Lane, P.S- Karaya, P.O- Ballygunge, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_68_19

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  Abstract 


Context: Persistent pulmonary hypertension of newborn (PPHN) is a common neonatal morbidity. There is a scarcity of data about PPHN from developing countries and the profile of babies with PPHN is different from those reported from developed countries. Aims: The aim is to study the incidence, maternal and infant risk factors, etiologies, treatment modalities, and outcome in babies with PPHN. Setting and Design: This retrospective study was conducted in the Level III neonatal unit of a referral center of Kolkata, India. Methods: This study was conducted by retrospective review of the departmental electronic database and nursing charts of the babies admitted with the diagnosis of PPHN from January 2013 to March 2019. Statistical Analysis: Chi-square test was used for categorical variable and Student's t-test was used for continuous variables to determine statistical significance. P < 0.05 was considered statistically significant. Results: A total of 86 neonates with PPHN were identified during the period, with the incidence of 3.38/1000 live births. Meconium aspiration syndrome (MAS) and transient tachypnea of newborn (TTNB) were the most common etiologies (17.44% each), followed by pneumonia, asphyxia, and congenital diaphragmatic hernia. Overall mortality rate was 29.06%. Survival in surgical cases was poor compared to medical cases (P = 0.0002). Pulmonary hypoplasia was associated with significant mortality. On the other hand, TTNB and idiopathic variety were associated with better prognosis. Use of high-frequency oscillatory ventilation without inhaled nitric oxide (iNO), milrinone, and combined use of pulmonary vasodilators and inotropes were associatedwith increased mortality, whereas use of surfactant was associated with increased survival. Conclusion: PPHN has been associated with significant mortality. In the absence of iNO, use of other drugs has not been associated with reduction of mortality.

Keywords: Developing country, newborn, persistent pulmonary hypertension of newborn, retrospective study


How to cite this article:
Sardar S, Pal S, Mishra R. A Retrospective study on the profile of persistent pulmonary hypertension of newborn in a tertiary care unit of Eastern India. J Clin Neonatol 2020;9:18-26

How to cite this URL:
Sardar S, Pal S, Mishra R. A Retrospective study on the profile of persistent pulmonary hypertension of newborn in a tertiary care unit of Eastern India. J Clin Neonatol [serial online] 2020 [cited 2020 Nov 29];9:18-26. Available from: https://www.jcnonweb.com/text.asp?2020/9/1/18/277226




  Introduction Top


Normal intrauterine to extrauterine transition of a newborn consists of a rapid fall in pulmonary vascular resistance and simultaneous rise of pulmonary blood flow along with increase in systemic vascular resistance. Persistent pulmonary hypertension of newborn (PPHN) results when these circulatory adaptation fails leading to hypoxemic respiratory failure.[1] Incidence of PPHN varies across different neonatal units, so as the mortality associated with it, depending on the patient profile, quality of care and availability of high frequency oscillatory ventilation (HFOV), inhaled nitric oxide (iNO), or extracorporeal membrane oxygenation (ECMO). Only a few neonatal units in a developing country, like India, have facilities to provide HFOV or iNO and none has the facility for neonatal ECMO. Overall, the estimated incidence of PPHN varies from 0.4 to 6.8/1000 live births and mortality ranges from 4% to 33%.[2] However, mortality in developing country is much higher, ranging from 25% to 48%.[3],[4]

The pathophysiologic mechanisms responsible for PPHN can be classified into maladaptation, maldevelopment, and underdevelopment.[5] Maladaptation of the normally developed pulmonary vasculature through excessive secretion and action of vasoactive mediators, as in sepsis, MAS, pneumonia, and asphyxia, is responsible for majority of the cases of PPHN. Maldevelopment of pulmonary vasculature is associated with chronic fetal hypoxia, fetal anemia, or intrauterine closure of ductus arteriosus from maternal medications like nonsteroidal anti-inflammatory drugs. Idiopathic PPHN also results from maldevelopment. Pulmonary hypoplasia with underdevelopment of pulmonary vasculature originates mostly from congenital diaphragmatic hernia or oligohydramnios from any cause. However, discrimination of maldevelopment from maladaptation requires histological examination and overlap between these mechanisms is a rule, rather than the exception.[6]

There is a scarcity of data about PPHN from developing countries. The incidence, diagnostic modalities, treatment options, and outcome of PPHN are different from those in the developed countries.[7] Keeping this in mind, we conducted a retrospective review on the profile of PPHN in a tertiary care neonatal unit of eastern India over a period of 6 years.


  Methods Top


Study design

This retrospective study was conducted in a Level III neonatal unit of a referral center of Kolkata, India. The obstetrics unit caters around 370 deliveries per month with full support from neonatal unit for the management of critically ill babies. Moreover, being a referral institution, critically sick outborn babies are regularly admitted in the unit. Thus, we included both inborn and outborn babies in our study. Data pertaining to the baby's details, maternal details (parity, gestational age, mode of delivery, preexisting maternal illness, illness during pregnancy, drug intake, etc.), clinical conditions (primary diagnosis, APGAR score, requirement of ventilation, type of ventilation, duration of ventilation, types of drugs, duration of neonatal intensive care unit [NICU] stay, etc.), and outcome (discharged or expired) were recorded and stored in the departmental electronic database. In addition, nursing charts of the babies were reviewed from the central medical records section of the institution. Babies with a diagnosis of PPHN were filtered from the database from January 2013 to March 2019 and relevant information were sought from the records.

Definition of persistent pulmonary hypertension of newborn

Diagnosis of PPHN was made by a combination of clinical and echocardiographic criteria.[8] Clinical criteria include labile oxygen saturation (SpO2), severe hypoxemia (SpO2 <85%), or differential cyanosis between preductal and postductal sites (more than 10% difference in SpO2). Labile SpO2 refers to fluctuating saturations with handling or agitation. Diagnosis of PPHN was confirmed by echocardiography, either by a neonatologist trained in functional echocardiography or by a cardiologist, with the help of a sonography machine, available round the clock at NICU. Suggestive echocardiography findings include right ventricular hypertrophy, deviation of interventricular septum toward left, jet of tricuspid regurgitation, and right to left or bidirectional shunting through patent foramen ovale and/or patent ductus arteriousus. As per unit protocol, none of the babies suspected of having PPHN was subjected to hyperoxia or hyperoxia-hyperventilation test. A baby was labeled as a case of PPHN, only in the presence of suggestive clinical findings along with echocardiography findings, concurred by both neonatologists and cardiologists. Although there was usually a gap of few hours between echocardiography done by neonatologist and cardiologist, treatment including pulmonary vasodilators were started as per the discretion of the treating neonatologist, even before the case seen by cardiologist.

Selection and description of participants

Both preterm and term neonates, whether outborn or inborn with the diagnosis of PPHN were included in the study. Cyanotic babies with congenital cyanotic heart disease were excluded from the study.

Babies with PPHN were managed as per unit protocol. Babies were put on some sort of respiratory support, either noninvasive ventilation (NIV) or invasive mechanical ventilation, as per existing guidelines of the unit. Those who fail conventional ventilation (FiO2@ 100%, PIP > 25, PEEP > 5) were shifted to HFOV. Our unit did not have facility for either iNO or ECMO. Choice of pulmonary vasodilators were left to the discretion of treating physician, but guided by echo parameters. Sildenafil was used if cardiac contractility was normal and baby was not hypotensive. Milrinone was started in presence of poor cardiac contractility, although there was overlap between the use of pulmonary vasodilators. If hypotensive, inotropes were added to the treating regimen. We did not use either Bosentan or MgSO4. In a few cases, vasopressin and hydrocortisone were used. Arterial lines were inserted as much as possible, either through umbilical route or radial artery, for periodic monitoring of PaO2 and blood pressure. Oxygenation index (OI) ([MAP × FiO2]/PaO2 × 100) and SpO2 index ([MAP × FiO2)/SpO2 × 100) were monitored every 12–24 hourly, depending on the clinical condition of the baby. Ventilated babies were sedated either with continuous infusion of fentanyl or morphine. Muscle relaxant was not used in any of the babies. As a adjuvant therapy, surfactant was used to optimize lung recruitment in respiratory distress syndrome (RDS), MAS, or congenital pneumonia. Antibiotics were used in clinically suspected sepsis or in confirmed sepsis. General measures included minimal handling and correction of metabolic disturbances. Ventilator parameters and investigation reports were documented in the clinical chart of each baby.

Ethics

Ethical committee of the institution approved the study protocol.

Statistical analysis

Statistical analysis was done by Statistical analysis was done by IBM SPSS software version 25 (IBM corporation, Armonk, NY, USA). Categorical variables were described as frequencies and percentages and continuous variables as mean and standard deviation or median and Interquartile range, depending on the data characteristics. Chi-square test or Fischer's exact test was used for categorical variables, and Student's t-test was used for continuous variables. P < 0.05 was considered as statistically significant.

Outcome of the study

Primary outcome of the study was to determine the incidence (per 1000 live birth for inborn babies and per 1000 NICU admissions, considering both inborn and outborn babies), risk factors (maternal and baby's characteristics), etiologies (MAS, RDS, asphyxia, idiopathic or “Black lung,” TTNB), treatment options (mechanical ventilation, pulmonary vasodilators, inotropes, surfactant, etc.) and outcome of PPHN. Idiopathic or “Black lung.” PPHN was diagnosed when PPHN was not secondary to asphyxia, cardiac dysfunction, or lung diseases. Chest X-ray should be black in idiopathic variety due to decreased pulmonary vascularity. Echocardiography in addition to PPHN should also demonstrate absence of any left ventricular dysfunction. Pathophysiologically, most cases of Idiopathic variety were due to remodeling of pulmonary vasculature in utero.[8] We also analyzed the difference in profile between those who survived and who did not and any change in the survival trend, etiologies, risk factors, and treatment modalities of PPHN over the entire period of 6 years (January 2013 to March 2019).


  Results Top


During the 6 years period, from January 2013 to March 2019, 121 neonates were diagnosed as a case of PPHN. However, 35 of them were excluded, where elevation of pulmonary pressure were attributable to associated heart disease. Thus, 86 neonates with PPHN, both inborn and outborn, were included in the study. Over the entire period, the incidence of PPHN among inborn babies were 3.38/1000 live birth. Whereas 5.49 of babies/1000 NICU admissions (inborn and outborn babies requiring admission) were diagnosed as a case of PPHN. Mean birth weight (±standard deviation [SD]) was 2281.77 ± 313.33 g and mean (±SD) gestational age was 35.74 ± 2.40 wEEks. Majority of babies were inborn (75.58%), male (54.66%), appropriate for date (AFD) (79.06%) and term (44.18%). Overall mortality rate was 29.06%. Demographic profile of neonates with PPHN is shown in [Table 1].
Table 1: Demographic characteristics of neonates with persistent pulmonary hypertension of newborn during the study period

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We divided the entire period of 6 years, in three blocks, each ranging 2 years (2013–2014, 2015–2016, and 2017–2018) to evaluate any change in the incidence, demographic profile, treatment options, and outcome of PPHN, which is shown in [Table 2] and [Table 3].
Table 2: Period wise incidence of persistent pulmonary hypertension of newborn with demographic characteristics

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Table 3: Period-wise distribution of risk factors, treatment options, and outcome in persistent pulmonary hypertension of newborn

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Although the number of live births and NICU admissions differed significantly in three periods, incidence of PPHN per 1000 live births and per 1000 NICU admissions were not significantly different. Incidence among inborn babies varied from 1.96 to 2.50/1000 live births. All other demographic parameters were comparable among three periods, with term, AFD, and male babies were predominantly affected. Although APGAR score was not available for outborn babies, 75% (2017–2018) to 90% (2013–2014) of babies with PPHN were documented to have APGAR <7 at 1 min.

Maternal and infant risk factors did not differ significantly over the whole period. Medical etiologies, such as, asphyxia, MAS, and malignant transient tachypnea of newborn (TTNB) were predominantly responsible for PPHN, with a decreasing trend in recent years. Whereas, surgical causes such as congenital diaphragmatic hernia have shown a rising trend. Although all of the babies were mechanically ventilated, mean duration of invasive ventilation varied from 6.24 ± 2.27 days (2013–2014) to 5.72 ± 2.14 days (2017–2018), which was not significantly different. Similarly, use of HFOV and NIV did not differ significantly in three periods. Sildenafil and milrinone were only used as pulmonary vasodilators. The middle period, 2015–2016, saw a significant rise in the combined use of both pulmonary vasodilators, compared to other two periods; however, use of inotrope has shown a decreasing trend. Mortality rose from 24.13% in 2013–2014 to 46.42% in 2015–2016, but came down to 18.18% in recent years, with no significant difference. Likewise, proportion of death in inborn and outborn babies was not different over the 6 year period.

Overall, malignant TTNB and MAS were the most frequent causes (17.44% each) of PPHN, followed by pneumonia (13.95%) and asphyxia and congenital diaphragmatic hernia (12.79% each). Rest of the cases were due to sepsis with shock, pulmonary hypoplasia, and idiopathic. Contribution of underlying etiologies toward the diagnosis of PPHN is shown in [Table 4]. Survival rate was worst in cases of pulmonary hypoplasia and best in TTNB and idiopathic variety. Survival in surgical cases were poor compared to medical cases (40% vs. 80.30%, P = 0.0002).
Table 4: Different etiologies of persistent pulmonary hypertension of newborn and its outcome during the study period

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The comparison between survivors and nonsurvivors is shown in [Table 5]. APGAR score at 1 min and 5 min were significantly less in nonsurvivors. Similarly, mean duration of mechanical ventilation and NIV were less in nonsurvivors, so as duration of NICU stay, because of early death in nonsurvivors. On the other hand, mean OI and SpO2 index were significantly higher in nonsurvivors, reflecting underlying severity of the disease. In univariate analysis, pulmonary hypoplasia, use of both sildenafil and milrinone, HFOV, milrinone alone, and inotropes were associated with increased mortality, whereas, use of surfactant was associated with decreased mortality. Kaplan–Meier analysis revealed no survival difference in babies receiving sildenafil from those who did not [Figure 1]. However, babies who received HFOV [Figure 2] or inotropes [Figure 3] had decreased survival chance. In contrast, babies who received surfactant had definite survival advantage over those who did not [Figure 4].
Table 5: Comparison between survivors and nonsurvivors of persistent pulmonary hypertension of newborn

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Figure 1: Survival comparison of babies with and without sildenafil therapy by Kaplan–Meier plot. Treatment with sildenafil does not have a survival advantage (P = 0.767)

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Figure 2: Survival comparison of babies with and without high-frequency oscillatory ventilation by Kaplan–Meier plot. Treatment with high-frequency oscillatory ventilation is associated with decreased survival (P = 0.0001)

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Figure 3: Survival comparison of babies with and without inotrope by Kaplan–Meier plot. Treatment with inotrope is associated with decreased survival (P = 0.001)

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Figure 4: Survival comparison of babies with and without surfactant therapy by Kaplan–Meier plot. Treatment with surfactant is associated with survival advantage (P = 0.0001)

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  Discussion Top


In this study, we attempted to evaluate the profile of newborn diagnosed with PPHN over the last 6 years. Incidence of PPHN among inborn babies was 3.38 babies/1000 live births. However, if we consider incidence among NICU admissions, incidence soared to 5.49 babies/1000 NICU admissions. To calculate the incidence of PPHN among NICU admissions, we considered both inborn and outborn babies, who required admission for their management. Being a referral center of eastern India, a formidable portion of NICU admissions are formed by outborn babies, which are often received in poor condition. Diagnosis of PPHN is not so infrequent in such sick babies. That is why PPHN incidence is higher, if we consider both inborn and outborn babies admitted in NICU (NICU admissions) compared to the incidence in inborn babies of our unit (live births at our center). Although there were not much significant differences over the entire period, some trends are worth mentioning. Incidence in the earlier years (2013–2014) was 2.5/1000 live births, which rose to 3.15/1000 live birth in 2015–2016 and then declined to 1.96/1000 live birth in 2017–2018. Overall, there was no significant change in the incidence. Increased trend of PPHN in the middle years was attributed to increase in the number of deliveries compared to other periods. There are very few studies from India and other developing countries estimating the incidence of PPHN, either retrospectively or prospectively and data from western countries differ significantly from those in the developing countries. A recent Asian multicenter retrospective study estimated PPHN incidence varying from 1.2 to 4.6/1000 live birth, which is similar to the finding in this study.[9] In developed country like USA, incidence varied from 0.4 to 6/1000 live births before the era of widespread use of inhaled NO.[10] In a recent study from California, Steurer et al. estimated the incidence of PPHN in late preterm and term infants to be 1.8/1000 live births.[11] Of the 86 babies in this study, majority were inborn (75.58%), male (54.66%), AFD (79.06%), and term (44.18%) and born through cesarian section (51.17%). Several previous studies found an increased incidence of PPHN in male, large for date, term and postterm babies, who are born through caesarian section.[12],[13],[14]

Overall mortality over the entire period was 29.06%, which varied from 24.13% (2013–2014) to 46.42% (2015–2016), but came down to 18.18% in recent years, with no significant difference. Reported mortality in PPHN varies across different institutions in different countries, such as 4%–33% in the USA, 20.6% in Asian countries, 26.6% in Pakistan, 25% in Egypt, and 32% in Portugal.[3],[4],[9],[10],[14] In this study, mortality did not differ between inborn and outborn babies (33.84% in inborn vs. 14.28% in outborn, P = 0.861); however, survival in surgical cases of PPHN were poor compared to medical cases (40% vs. 80.30%, P = 0.0002). In spite of progress in understanding the pathophysiology and treatment of PPHN, prognosis remains poor in developing countries, mostly because of nonavailability of newer treatment modalities, such as HFOV, inhaled NO, or ECMO. Although, our unit has a HFOV, there was no facility for iNO or ECMO.

Among various maternal risk factors, like pregnancy-induced hypertension or maternal intake of drugs, none are found to be significant, though these may be under estimated because of retrospective nature of the study.

Regarding etiology, MAS and TTNB (17.44% each) were the most common etiology followed by pneumonia (13.95%) and asphyxia and congenital diaphragmatic hernia (12.79% each). Rest of the cases were due to sepsis with shock (8.14%), pulmonary hypoplasia (10.46%), and idiopathic (6.97%). MAS has repeatedly been reported as the most common cause of PPHN, followed by idiopathic variety and pneumonia.[15],[16] Over the entire period, there has been a trend of increase in the surgical causes (congenital diaphragmatic hernia, pulmonary hypoplasia due to posterior urethral valve, etc.) with fall in medical causes (MAS, asphyxia, TTNB, etc.), mostly because of increased referral of surgical babies to a tertiary care neonatal unit with neonatal surgery facility but also because of improvement in obstetrics care in our unit.

We attempted to evaluate whether there was any difference between survivors and nonsurvivors of PPHN. APGAR scores, both at 1 and 5 min, were significantly lower in nonsurvivors (P < 0.001). Although APGAR score was not available for outborn babies and also for a few inborn babies, it signifies the underlying contribution of asphyxia toward PPHN in our population. In contrast, mean duration of mechanical ventilation, NIV and duration of NICU stay were significantly greater in survivors (P < 0.001), possibly reflecting early death in severely affected babies. Significantly higher OI and SpO2 index in nonsurvivors justify this explanation. Although OI requires estimation of PaO2 through arterial blood gas sampling, OSI measurement is noninvasive, simple, and reliable in clinical setting.[17] Use of OSI can predict infants with more severe disease and can be used in low-resource setting where there is lack of adequate personnel with technical expertise of arterial line placement and round the clock blood gas measurement. In our cohort, PPHN associated with TTNB had good prognosis, whereas PPHN in pulmonary hypoplasia was associated with 100% mortality. In this study, HFOV, milrinone, combined use of pulmonary vasodilators, and inotrope were all associated with increased mortality. Inhaled NO is the treatment of choice in PPHN. In the absence of iNO, other pulmonary vasodilators (sildenafil, milrinone, etc.) have been used systemically with inconsistent results. Major reason behind this is that, these pulmonary vasodilators lack selective and microselective effect of inhaled NO and thus lead to systemic adverse effects (e.g., -hypotension) and worsen the primary condition further. In our opinion, this increased mortality reflects the more severe primary disease (PPHN) of the deceased newborn which necessitate use of other drugs in the absence of iNO. However, use of other drugs was associated with hypotension which worsens the PPHN further, thus creating a vicious cycle, culminating into death of the babies. Hence, these findings imply the result of treating a more severe disease in deceased infants. Although, in developed countries, iNO delivered through HFOV is associated with better survival and less need of ECMO, this is not the case with the use of HFOV alone, where there is no facility for iNO.[18] This finding is similar to those noted by Nakwan from 6 different Asian countries.[9] Sildenafil is generally used as first-line pulmonary vasodilator in our unit, in the absence of iNO, unless contraindicated, as in concomitant hypotension. However, in case of clinical deterioration despite sildenafil or clinical indication, such as patients with left ventricular dysfunction, sildenafil is supplemented or replaced with milrinone. Inotropes are generally used in hypotensive babies. Although Cochrane meta-analysis by Kelly et al. noted decreased mortality in PPHN patients with sildenafil, data on the use milrinone in PPHN are scanty and required further evaluation.[2],[19] Use of both drugs simultaneously is associated with hypotension and increased mortality. Similarly, use of inotropes implies sicker babies who had less survival chance and thus associated with increased mortality. The only intervention that was associated with better survival was use of surfactant, which can be explained by the fact that better lung recruitment with surfactant and concomitant ventilation might result in improvement of oxygenation. It can also be explained by the fact that, the two most common etiologies in our setting were TTNB and MAS, where surfactant has a role in management and helps in recovery.[20],[21]

This study has few limitations and strengths. First, because of retrospective nature, few data were lost, particularly in outborn babies, such as APGAR scores and maternal and infant characteristics which could have an effect on the disease. On the other hand, strength being that the diagnosis of PPHN was confirmed in each and every case with echocardiography and was not solely based on clinical judgment.


  Conclusion Top


Over the last 6 years, from 2013 to 2019, 3.38 babies/1000 live births and 5.49 babies/1000 NICU admissions were diagnosed as PPHN. There have not been significant changes in the risk factors, treatment, and survival of babies with PPHN over the entire period. Overall, the most common etiology being malignant TTNB and MAS. In survival analysis, surgical cases of PPHN were associated with poor prognosis. Use of HFOV without iNO, milrinone, and inotropes all predict mortality. The conclusion from this finding is that, iNO being the drug of choice in PPHN, every tertiary care setup should have a facility for providing iNO. If this is not possible, systemic pulmonary vasodilators should be used cautiously, keeping in mind the adverse effects of such drugs, which can deteriorate the primary condition further. However, use of surfactant was associated with increased survival. In low-resource setting, PPHN is associated with high mortality, as reflected by 29.06% mortality in this study.



Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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