Is it possible to predict morbidities in neonates born to mothers with immune thrombocytopenic purpura?: A retrospective cross-sectional study.

Immune thrombocytopenic purpura (ITP) comprises ~1% to 4% of thrombocytopenia cases during pregnancy. Factors predicting neonatal thrombocytopenia and associated morbidities due to maternal ITP are unclear. The present study aimed to assess the neonatal outcomes of pregnant women with ITP. Fifty-five pregnant women with ITP and their babies, born between January/2013 and April/2021, were retrospectively reviewed. Maternal and neonatal thrombocytopenia cases other than ITP were excluded from the study. Physical examination, blood count, and cranial/abdominal ultrasonography findings of the newborns were recorded. Neonatal thrombocytopenia was defined as a platelet count < 150 × 109/L. Relationship between neonatal thrombocytopenia and maternal factors was investigated. Thrombocytopenia was detected in 17/55 babies (30.9%), and 8/17 (47.1%) had symptoms of bleeding, all but one being mild bleeding. There was a significant correlation between neonatal platelet counts of < 100 × 109/L and maternal splenectomy history. Incidence of moderate and severe thrombocytopenia was higher (statistically insignificant) in neonates of mothers with ITP. No significant correlation was determined between maternal and neonatal platelet counts. There was a weak insignificant correlation between platelet counts of neonates of mothers with or without thrombocytopenia. A significant correlation was found between the presence of splenectomy before delivery in the mother and a platelet count of < 100 × 109/L in the neonate. Moderate and severe thrombocytopenia was higher in neonates of mothers diagnosed with ITP before pregnancy and needed treatment during pregnancy and/or delivery, but the difference was insignificant. Close follow-up of babies born to mothers with ITP after birth is crucial since there is no significant prediction criterion for developing neonatal thrombocytopenia and associated morbidities.

The effect of maternal weight on neonatal cardiac functions following diabetic and non-diabetic pregnancies.

OBJECTIVE: We aimed to study myocardial functions of infants appropriate and large for gestational age (IDM-AGA, IDM-LGA) of diabetic mothers (IDM) and AGA and LGA infants of non-diabetic mothers comparatively. METHODS: Newborns were assessed between 24 and 72 h. M-Mode, pulsed wave, and tissue Doppler echocardiography were performed. RESULTS: A negative correlation was found between shortening fraction and maternal weight at delivery in the LGA group (p=0.009, r=-0.58). E/Early diastolic (E') ratio and deceleration time were increased in IDM-AGA than AGA group (p=0.02, p=0.02). There was a negative correlation between maternal blood glucose and E/A ratio (p=0.015 r=-0.63), a positive correlation between maternal blood glucose and mitral A, late diastolic (A') wave in IDM-AGA (p=0.014 r=0.63, p=0.016 r=0.62). Maternal weight gain during pregnancy was in correlation with measured and tei index in IDM-AGA group (p=0.008 r=0.72). Maternal age, pre-pregnancy weight, and weight at delivery and mitral E were higher in IDM-LGA group than IDM-AGA (p=0.03, p=0.01, p=0.003, p=0.012). CONCLUSION: We found that maternal weight has a negative effect on myocardial function in LGA newborns. Diastolic functions were found impaired in IDM-AGA infants and in infants of mothers with high blood glucose. Maternal weight gain during pregnancy has a negative effect on myocardial functions.

Coagulation parameters in very preterm infants.

The aim of this study was to define normal percentile values of coagulation parameters in preterm infants below 32 weeks of gestational age. This retrospective cohort study was conducted at Istanbul Medical Faculty. Preterm infants who were born prior to 32 weeks of gestation, between 2011 and 2021 were included and evaluated for coagulation parameters. Blood samples obtained through umbilical catheters prior to administration of heparinized flushes/fluids, vitamin K or fresh frozen plasma (FFP). Infants with a major bleeding disorder, intrapartum asphyxia or a history of familial bleeding disorders were excluded. Infants were grouped according to their gestational ages and birth weights: less than 24, 25-26, 27-28, 29-30, 31-32 weeks and <500, 500-749, 750-999, 1000-1249, 1250-1499, more than 1500 g. Third to 97th percentile values of both prothrombin time (PT) and activated partial thromboplastin time (aPTT) were defined. A total of 420 preterm infants were included. The median value and range of gestational age and birth weight of the infants were 29 (22.3-32.9) weeks and 1150 (395-2790) g, respectively. PT values were similar between subgroups according to gestational age but longer in infants with a birth weight less than 1000 g. aPTT values in infants born less than 24 weeks of gestation were found significantly longer. As maturation of the coagulation system increases by gestational age, very preterm infants (<32 gestational week (GW)) are under increased risk of bleeding. Determination of normal percentile distribution of coagulation parameters for preterm infants will shed light on the interpretation of coagulation parameters of these infants and minimize unnecessary FFP administrations.

Evaluation of babies with retinopathy of prematurity following intravitreal bevacizumab administration.

OBJECTIVE: In Turkiye, the increased likelihood of survival of small premature babies has resulted in a higher incidence of retinopathy of prematurity (ROP), which causes severe visual impairment in childhood. Early diagnosis and timely and proper treatment of ROP can prevent vision loss. This paper discusses cases of ROP treated with bevacizumab. METHODS: Patients treated with bevacizumab for ROP were evaluated retrospectively. Systolic and diastolic blood pressure values were recorded 1 day before and 2 weeks after bevacizumab administration. The Bayley III test, hearing test, eye examination, and neurological evaluation were performed. RESULTS: The mean composite Bayley III test scores for cognition, language, motor, social-emotional, and adaptive domains in 10 patients who received bevacizumab for ROP were 75±10.8, 73.4±15.4, 71.2±10.2, 88±23.7, and 65.4±13.8, respectively. The mean values of the day before the injection and the values of the 14 days after the injection were compared, it was seen that there was a significant increase in systolic blood pressure values, especially at the end of 1st day and 1st week after the surgery. Neurological examination results were abnormal in 50% of the cases. Vision problems were detected in 40% of the cases. About 30% of the babies failed the hearing test. CONCLUSION: Caution needs attention in the care of neonates until further studies of the long-term benefits and effects of bevacizumab therapy are completed.

Diagnostic Pitfalls of a Newborn with Congenital Nephrogenic Diabetes Insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is a rare cause of hypernatremia in newborns. Central diabetes insipidus (CDI) is the main differential diagnosis of NDI. NDI responds poorly to desmopressin acetate (DDAVP) treatment while this is the mainstay of CDI management. Therefore, an early and correct diagnosis of NDI is crucial to avoid the complications of inappropriate therapy. Here, we report a newborn with hypernatremia and hypotonic polyuria. The patient was initially responsive but subsequently unresponsive to intranasal DDAVP treatment in regard to urine output and serum sodium levels. A novel hemizygous missense mutation (c.632T>C, p.L211P) in the AVPR2 gene was found both in the baby and his mother, and the diagnosis of congenital NDI was established. After hydrochlorothiazide treatment and hypo-osmolar formula were given, urine volume was decreased, and serum sodium levels were normalized. Early recognition and appropriate management of NDI can prevent complications of hypernatremic dehydration in young infants.

Apnea as an isolated finding in neonatal COVID-19.

COVID-19 continues to mutate and spread rapidly. However, case reports about newborns remain rare. A male baby, born at 840 g at gestational week 28, was diagnosed with respiratory distress syndrome, sepsis, patent ductus arteriosus, and bronchopulmonary dysplasia in the neonatal intensive care unit. Refractory apnea developed on postnatal day 58, and an upper respiratory tract SARS-nCoV-2 polymerase chain reaction test was positive. A COVID test was also positive in an asymptomatic nurse who cared for the baby. This case shows that SARS-CoV-2 can cause symptoms of only apnea in newborns and that those who care for newborns should strictly comply with hygiene rules.

Intravenous Immunoglobulin Use in Hemolytic Disease Due to ABO Incompatibility to Prevent Exchange Transfusion.

Introduction: Intravenous immunoglobulin (IVIG) has been widely used to treat the hemolytic disease of the newborn (HDN). Although it has been shown that IVIG treatment reduces the duration of phototherapy and hospitalization, the use of IVIG in hemolytic disease due to ABO incompatibility has been controversial in recent years. This study aimed to investigate the role of IVIG in the prevention of exchange transfusion in infants with ABO HDN who presented with bilirubin levels at or above the level of exchange transfusion. Materials and Methods: This study evaluated the data of infants with ABO HDN in the Turkish Neonatal Jaundice Online Registry. The infants with ABO HDN who met the total serum bilirubin level inclusion criteria (within 2-3 mg/dL of exchange transfusion or even above exchange transfusion level) were included in the study according to the guidelines from the American Academy of Pediatrics and the Turkish Neonatal Society. All patients were managed according to the unit protocols recommended by these guidelines and received light-emitting diode (LED) phototherapy. Infants who only received LED phototherapy, and who received one dose of IVIG with LED phototherapy were compared. Results: During the study period, 531 term infants were included in the study according to inclusion criteria. There were 408 cases in the phototherapy-only group, and 123 cases in the IVIG group. The demographic findings and the mean bilirubin and reticulocyte levels at admission were similar between the groups (p > 0.05), whereas the mean hemoglobin level was slightly lower in the IVIG group (p = 0.037). The mean age at admission was earlier, the need for exchange transfusion was higher, and the duration of phototherapy was longer in the IVIG group (p < 0.001, p = 0.001, and p < 0.001, respectively). The rate of re-hospitalization and acute bilirubin encephalopathy (ABE) was higher in the IVIG group (p < 0.001 and p = 0.01, respectively). Conclusion: In this study, we determined that one dose of IVIG did not prevent an exchange transfusion nor decrease the duration of phototherapy in infants, who had bilirubin levels near or at exchange transfusion level, with hemolytic disease due to ABO incompatibility.

COVID-19 in perinatal period: questions and consequences.

BACKGROUND: The effect of COVID-19 infection on newborn babies is not yet clear. Babies born to pregnant women with suspected or proven COVID-19 or babies who had contact with infected people are considered to be at risk. In this review, intrauterine problems that may be caused by COVID-19 infection, delivery room approach, postnatal follow-up, precautions and controversies regarding breastfeeding and vaccination are discussed. METHODS: The articles published between March 2020 and June 2021 were searched in Pubmed, Cochrane Library and Google Scholar databases using the keywords COVID-19 and newborn, perinatal period, vertical transmission, pregnancy, breast milk and vaccines. The updated information and recommendations are presented. CONCLUSIONS: Our knowledge of the perinatal and neonatal effects of COVID-19 infection changes rapidly. Therefore, close follow-up of the mother-infant dyads is important. Larger epidemiological and clinical cohort studies are needed to better understand the possible implications and long-term outcomes of COVID-19 infection and also maternal vaccination in newborn infants.

Adrenal steroids reference ranges in infancy determined by LC-MS/MS.

BACKGROUND: Interpretation of the results of steroid hormone measurements is challenging at early infancy. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method provides a powerful tool for diagnosing steroidogenesis disorders. We aimed to develop normative data for a 14-steroid panel and four adrenal enzyme activity indices, determined by LC-MS/MS from 3 days to 6 months of age. METHODS: Age- and sex-specific plasma steroid concentrations were calculated in 324 healthy full-term neonates and infants (151 females). Percentile curves were devised. Steroid ratios were evaluated as biomarkers of adrenal enzyme activities. The steroid profiles of four patients with adrenal enzyme deficiencies were included to test the diagnostic efficiency. RESULTS: Nine steroids showed age, but none showed sex specificity. The concentrations of progestins and androgens were higher at 7-14 days than at 3-7 days. After the first month, adrenal androgen concentrations decreased significantly. Adrenal enzyme activities changed towards increasing cortisol over the first 6 months. There were several-fold differences in diagnostic steroids and related adrenal enzyme activity indices between the patients and the healthy group. CONCLUSIONS: The majority of adrenal steroids show age-related variations in the neonatal period and early infancy. Our data will enable accurate interpretation of steroid measurements for etiologic diagnosis of disorders of steroidogenesis. IMPACT: LC-MS/MS method is capable of quantitating numerous analytes simultaneously, which provides an integrated picture of adrenal steroidogenesis in a small amount of sample. The development of LC-MS/MS-based normative data of steroid hormones in healthy infants is crucial to differentiate physiologic alterations from steroidogenic defects during the first 3-6 months of infancy. Previous studies had limitations due to the small numbers of samples available by sex and by age groups. Our detailed normative data and percentile curves will enable accurate interpretation of steroid measurements for etiologic diagnosis of disorders of steroidogenesis without the need for further invasive testing.

Effect of different positions on gastric residuals in preterm infants initiating full enteral feeding.

BACKGROUND: This study was conducted to determine the effect of feeding in different positions on the gastric residual volume after feeding in preterm infants who initiated full enteral feeding. METHODS: This quasi-experimental study was conducted with the hypothesis that testing the right lateral position leads to less gastric residual than left lateral position and the prone position leads to less gastric residual than the supine position. The data were collected in four stages from 35 preterm infants. Initially, the infants were positioned in supine position and were fed. After feeding, the infant rested in the supine position for 3 h. The stomach content was aspirated, and the volume of gastric residual was measured at the 60th, 120th, and 180th min after feeding. These steps are repeated in order of in the right lateral, left lateral, and prone position. Total gastric residual volume and type of enteral feeding were evaluated. RESULTS: There was no significant difference among the positions in terms of the volume of gastric residuals in the measurements made at 60th (P = 9.552), 120th (P = .505), and 180th min (P = .430). When the amount of decrease in the gastric residual volumes was a significant difference between all measurement times in right lateral and prone positions (P < .001). CONCLUSION: Although no significant difference was determined between the positions, the smallest residual volumes were determined in the right lateral and prone positions. The amount of decrease in residual volume was significant in right lateral and prone positions.

The Evaluation of Oral Feeding in Preterm Infants: Turkish Validation of the Early Feeding Skills Assessment Tool.

OBJECTIVE: The Early Feeding Skills Assessment Tool (EFS) is a valid and reliable tool for evaluating preterm infants' oral feeding skills and readiness during the transition to oral feeding. There is currently no instrument with tested validity and reliability available to evaluate the oral feeding skills and readiness of preterm infants in Turkey. The aim of this study was to fill the need for such an instrument for use in the Turkish population by adapting and validating the EFS for the assessment of Turkish preterm infants during the transition to oral feeding. MATERIAL AND METHODS: This methodological, cross-sectional study included 107 preterm infants. Validity of the EFS-Turkish was tested with linguistic, content, and construct validity analyses, and its reliability was tested using internal consistency and item analyses. RESULTS: A panel of experts confirmed the content validity of the items in the EFS-Turkish (content validity index = 0.97). Cronbach's alpha for the total instrument was 0.95, supporting its internal consistency reliability. Item-total correlations ranged from 0.58 to 0.83 (P < .001). Confirmatory factor analysis confirmed the established EFS structure of 19 items and 5 factors. The tool demonstrated good model fit statistics (χ2/df = 2.24; P < .001). CONCLUSION: The EFS-Turkish is a valid and reliable instrument for use in neonatal intensive care units to evaluate the feeding skills of preterm infants during the transition to oral feeding. The use of the EFS-Turkish is recommended to facilitate the safe and successful development of preterm infants' oral feeding skills and to plan evidence-based initiatives.

A Multicentered Study on Epidemiologic and Clinical Characteristics of 37 Neonates With Community-acquired COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) primarily affects adults and spares children, whereas very little is known about neonates. We tried to define the clinical characteristics, risk factors, laboratory, and imagining results of neonates with community-acquired COVID-19. METHODS: This prospective multicentered cohort study included 24 neonatal intensive care units around Turkey, wherein outpatient neonates with COVID-19 were registered in an online national database. Full-term and premature neonates diagnosed with COVID-19 were included in the study, whether hospitalized or followed up as ambulatory patients. Neonates without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) via reverse transcriptase-polymerase chain reaction testing or whose mothers had been diagnosed with COVID-19 during pregnancy were excluded. RESULTS: Thirty-seven symptomatic neonates were included. The most frequent findings were fever, hypoxemia, and cough (49%, 41%, 27%, respectively). Oxygen administration (41%) and noninvasive ventilation (16%) were frequently required; however, mechanical ventilation (3%) was rarely needed. Median hospitalization was 11 days (1-35 days). One patient with Down syndrome and congenital cardiovascular disorders died in the study period. C-reactive protein (CRP) and prothrombin time (PT) levels were found to be higher in patients who needed supplemental oxygen (0.9 [0.1-8.6] vs. 5.8 [0.3-69.2] p = 0.002, 11.9 [10.1-17.2] vs. 15.2 [11.7-18.0] p = 0.01, respectively) or who were severe/critical (1.0 [0.01-8.6] vs. 4.5 [0.1-69.2] p = 0.01, 11.7 [10.1-13.9] vs. 15.0 [11.7-18.0] p = 0.001, respectively). CONCLUSIONS: Symptomatic neonates with COVID-19 had high rates of respiratory support requirements. High CRP levels or a greater PT should alert the physician to more severe disease.

Wheezing, asthma, and atopy in premature infants at 2 years of age.

BACKGROUND/AIM: We aimed to evaluate wheezing, bronchial asthma (BA), and atopy in premature infants at 2 years of age via a cross-sectional study. MATERIALS AND METHODS: Premature infants at <37 weeks of gestational age (GA) were assessed for atopy by skin-prick test and serum immunoglobulin E level at 2 years of age. The family's and infant's histories of allergy, BA, atopy, and wheezing were obtained by questionnaire and from hospital records. RESULTS: There were 98 infants, with mean birth weight (BW) 1517.4 ± 486.5 g and GA 30.8 ± 2.9 weeks. The frequencies of wheezing, asthma, and bronchopulmonary dysplasia (BPD) were 32.7%, 16.3%, and 14.3%, respectively. Skin-prick tests were positive for 11 subjects, with allergy to cereals for 7 infants, egg for 3, and peanut for 1. Wheezing was related to GA, BW, respiratory distress syndrome, mechanical ventilation, sepsis, asphyxia, smoking, antenatal steroid, BA, palivizumab prophylaxis, number of people in the household, and duration of hospitalization (P < 0.05). Wheezing was negatively correlated to GA. Family history of BA, smoking, and number of people in the household were linked to BA (P < 0.05). CONCLUSION: Wheezing was related to degree of premature birth, but BA was linked to BA in the family and smoking. Increased gestation should improve the infant's respiratory health up to 2 years of age.

Optimal Time of Tracheotomy in Infants: Still a Dilemma.

Objective. Infants with respiratory failure may require prolonged intubation. There is no consensus on the time of tracheotomy in neonates. Methods. We evaluated infants applied tracheotomy, time of procedure, and early complications in our neonatal intensive care unit (NICU) retrospectively from January 2012 to December 2013. Results. We identified 9 infants applied tracheotomy with gestational ages 34 to 41 weeks. Their diagnoses were hypotonic infant, subglottic stenosis, laryngeal cleft, neck mass, and chronic lung disease. Age on tracheotomy ranged from 4 to 10 weeks. Early complication ratio was 33.3% with minimal bleeding (1), air leak (1), and canal revision requirement (1). We discharged 7 infants, and 2 infants died in the NICU. Conclusion. Tracheotomy makes infant nursing easy for staff and families even at home. If carried out by a trained team, the procedure is safe and has low complication. When to apply tracheotomy should be individualized, and airway damage due to prolonged intubation versus risks of tracheotomy should be taken into consideration.

Utility of peritoneal dialysis in neonates affected by inborn errors of metabolism.

AIM: Some inborn errors of metabolism induce metabolic encephalopathy through accumulation of neurotoxic metabolites. Rapid elimination of these metabolites by peritoneal or extracorporeal dialysis is crucial to prevent neuronal damage or death. In this retrospective study, we evaluated the outcomes of nine neonates with metabolic crisis treated with peritoneal dialysis. METHOD: Six neonates with hyperammonemic coma (four with organic acidemias, two with urea cycle disorders) and three with leucine accumulation due to maple syrup urine disease (MSUD) were managed with peritoneal dialysis in conjunction with dietary and pharmacological therapy. RESULTS: Three patients with organic acidemia survived. One of the patients was normal; others had moderate and severe neurological impairments. One neonate with organic acidemia and both neonates with urea cycle disorders died. Two of the three patients with MSUD survived without neurological impairment; the other had severe neurological damage and died at 9 months of age due to sepsis. CONCLUSION: Theoretically, extracorporeal dialysis should be the first dialysis treatment of choice; however, this report demonstrates that peritoneal dialysis has a chance to prevent neurological damage in some patients. Therefore, in developing countries without extracorporeal dialysis opportunities, it can be still a life-saving procedure, if it is applied with skilled staff and standard procedures.

Heparin infusion to prevent umbilical venous catheter related thrombosis in neonates.

OBJECTIVE: To investigate umbilical venous catheter (UVC) related thrombosis by Doppler echocardiographic evaluation of neonates infused with heparin or placebo. METHODS: We conducted a prospective study to determine UVC-related thrombosis in term and nearterm neonates. Heparin or placebo (0.5 IU/mL) was infused at a rate of 1 mL/hr to the study and control group. Doppler echocardiography was performed at 1, 3, and 5 days after UVC insertion. RESULTS: Forty-six neonates (63% males) with a mean gestational age of 38.2 ± 1.8 weeks, and a mean birth-weight of 2993 ± 563 grams were included. No UVC-related thrombosis was observed in the study group, which included 19 neonates. Among the 27 neonates in the control group, one neonate developed UVC-related thrombosis. There were no statistical differences between the groups for gestational age, birth weight, postnatal age, UVC duration, mortality, mechanical ventilation, and inotrope requirement, and hemagram or coagulation profile. The complications were as follows, mild pulmonary hemorrhage, 6.5% (3); leak-out, 4.3% (2); peritoneal leakage, 2.2% (1); occlusion, 2.2% (1); gastrointestinal findings, 6.5% (3); sepsis, 10.9% (5); and catheter-related thrombosis, 2.2% (1). CONCLUSION: This study demonstrated that heparin infusion of 0.5 IU/mL through the UVC had no effect on catheter-related thrombosis in term and near-term neonates. Randomized controlled trials are necessary to conclusively evaluate the effect of heparin on UVC-related thrombosis.

The implementation of neonatal peritoneal dialysis in a clinical setting.

OBJECTIVE: To investigate etiology, outcome and complications related to neonatal peritoneal dialysis (PD). METHODS: Neonates treated with PD in our neonatal intensive care unit during 2007-2010 were analyzed retrospectively. RESULTS: Among 4036 hospitalized neonates; 20 neonates (0.5%) who underwent 21 cycles of PD [7 preterm, 13 term; 13 female, 7 male] were included. The mean birth weight was 2930.2 ± 720.6 g (1120-4570), mean gestational age was 37.5 ± 3.5 weeks (27-41). The etiologic disorders included inborn errors of metabolism (propionic acidemia, methylmalonic acidemia, citrullinemia, glutaric aciduria type 2, maple syrup urine disease, 10), or acute renal failure secondary to perinatal asphyxia (4), sepsis (2), prematurity (2), hypoplastic left heart syndrome (1), kernicterus (1). The complications included peritonitis (2), early leakage (4), hemorrhage (1), catheter removal (3) and occlusion (2). The mortality rate was 50%. The gestational ages and birth weights of surviving neonates were higher (p < 0.05). Among surviving neonates, chronic renal failure (1), severe (4) and moderate neuromotor impairment (2) developed within 4-43 months. CONCLUSION: PD, although invasive, is an effective therapy in neonates. The complexity and invasiveness of the procedure is probably responsible for high rate of complications and mortality. If appropriate catheter selection and technique in the placement should be done, PD might improve outcome.

Morbidity in early adulthood among low-risk very low birth weight children in Turkey: a preliminary study.

The objective of this study was to assess low-risk very low birth weight (VLBW) children, before the era of modern neonatal intensive care in Turkey, during adolescence. Forty-one VLBW adolescents were compared with 40 adolescents who had normal birth weight. The physical and neuromotor development, educational achievement and psychosocial status were assessed at a mean age of 17 +/- 1.6 years. VLBW adolescents were shorter than normal birth weight adolescents (p = 0.01). A major neurological abnormality (cerebral palsy) was seen in 12% and a minor neurological abnormality (tremor, coordination, behavioral and speech disorders) in 17%. VLBW adolescents had higher rates of visual problems (56% vs. 5%). School failure was present in 27%. There were no differences in behavioral problems or quality of life between the two groups, but VLBW adolescents did have a lower self-esteem score. Neurodevelopment and growth sequelae were a significant problem in VLBW adolescents. As early intervention might help to prevent or ameliorate potential problems, long-term follow-up is essential.