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Shu Yang Dai, Yu Qi Sun, Ying Wu, Gong Chen, Song Sun, Rui Dong,
Published: 17 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.625451

Abstract:
Objectives: Biliary atresia (BA) is a rare neonatal liver disease of which the early diagnosis remains a challenge for clinicians. Our center has established a nomogram diagnostic model based on clinical characteristics and liver function characteristics. We aim to develop and validate a nomogram that includes additional ultrasound and finds hepatobiliary abnormality with better BA early screening performance. Methods: In this single-center, retrospective cohort analysis, 1,001 neonatal obstructive jaundice (NOJ) patients between 2012 and 2015 were enrolled. Multivariable analysis was used to identify clinical characteristics, laboratory liver function characteristics, and ultrasonic features that may early screen BA. A nomogram was developed to predict the probability of BA using multiple logistic regression analysis. This nomogram was subsequently validated using another cohort of 501 NOJ patients between 2015 and 2017. Calibration curve analysis and decision curve analyses were performed to evaluate and interpret the nomogram's clinical benefits. Results: Gender, direct bilirubin (DB), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), fasting gallbladder visibility, fasting gallbladder filling, and common bile duct visibility were found to have profound statistical significance between the BA and non-BA groups (P < 0.05). The significant features were used to build the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) value of the novel nomogram (0.87) was superior to those of the former nomogram (0.83) and GGT alone (0.81) in the prediction of BA. The calibration curve revealed a close resemblance between the predicted and actual BA probabilities. Also, the net benefit from the decision curve analysis (DCA) of the nomogram (0.54) was superior to those of the former nomogram (0.49) and GGT alone (0.45) at 80% of threshold possibility. Conclusions: The nomogram has demonstrated better performance for BA screening by including additional information of the US finding, holding a promising future as a non-invasive method for BA patients.
Blandine Bianco, Bérengère François-Garret, Marine Butin, Cyril Dalmasso, Florence Casagrande, Mostafa Mokhtari,
Published: 17 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.623043

Abstract:
Objectives: To evaluate the positive threshold of PCT for neonates of <32 weeks of gestation for the diagnosis of early-onset sepsis and to determine if the level of PCT collected within 6 h of life could be used. Design: Retrospective and bicentric study from May 2016 to April 2018. Setting: Two groups were established, neonates evaluated for PCT at birth (CordPCT) and within 6 h of life (delPCT). Patients: Two hundred and sixty neonates of <32 weeks of gestation born in Nice and South Paris (Bicêtre) University Hospitals, had been evaluated for PCT level. Main Outcomes Measures: The value of the PCT positive threshold was determined for the total population and each groups thanks ROC curves. Results: The threshold level of PCT for the total population was 0.98 ng/mL. The threshold value of cordPCT group was 1.00 vs. 0.98 ng/mL for delPCT group. The area under the Receiver Operating Characteristics curve for PCT sampled in delPCT group was significantly higher than in cordPCT group (0.94 compared to 0.75). Conclusions: The threshold level of PCT was higher in this cohort of neonates of <32 weeks of gestation compared to the value generally described for term neonates. The secondary sampling PCT level seems to be usable in screening algorithm for early-onset neonatal sepsis.
Rosemary Bauer, Katherine W. Timothy,
Published: 17 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.668546

Abstract:
Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.
, Rohit Pinto, Niranjan Kissoon, Youssef E. Ahmed, Pia Daniel, Mitchell Hamele
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.665350

Abstract:
Objective: The ongoing coronavirus 2019 (COVID-19) pandemic is disproportionally impacting the adult population. This study describes the experiences after repurposing a PICU and its staff for adult critical care within a state mandated COVID-19 hospital and compares the outcomes to adult patients admitted to the institution's MICU during the same period. Design: A retrospective chart review was performed to analyze outcomes for the adults admitted to the PICU and MICU during the 27-day period the PICU was incorporated into the institution's adult critical care surge plan. Setting: Tertiary care state University hospital. Patients: Critically ill adult patients with proven or suspected COVID-19. Interventions: To select the most ideal adult patients for PICU admission a tiered approach that incorporated older patients with more comorbidities at each stage was implemented. Measurements and Main Results: There were 140 patients admitted to the MICU and 9 patients admitted to the PICU during this period. The mean age of the adult patients admitted to the PICU was lower (49.1 vs. 63.2 p = 0.017). There was no statistically significant difference in the number of comorbidities, intubation rates, days of ventilation, dialysis or LOS. Patients selected for PICU care did not have coronary artery disease, CHF, cerebrovascular disease or COPD. Mean admission Sequential Organ Failure Assessment (SOFA) score was lower in patients admitted to the PICU (4 vs. 6.4, p = 0.017) with similar rates of survival to discharge (66.7 vs. 44.4%, p = 0.64). Conclusion: Outcomes for the adult patients who received care in the PICU did not appear to be worse than those who were admitted to the MICU during this time. While limited by a small sample size, this single center cohort study revealed that careful assessment of critical illness considering age and type of co-morbidities may be a safe and effective approach in determining which critically ill adult patients with known or suspected COVID-19 are the most appropriate for PICU admission in general hospitals with primary management by its physicians and nurses.
Hsiao-Wen Chu, Chien-Heng Lin, , Ya-Chi Hsu
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.659598

Abstract:
Introduction: Genetic susceptibility and immune dysregulation play important roles in the pathogenesis of Kawasaki disease (KD). However, it is still unclear whether KD causes immune disorder later in life or whether inherited susceptibility to immune disorders causes KD. The aim of this study was to elucidate whether inherited immune disease properties from mothers increase the risk of KD from a population-based perspective. Method: Taiwan's National Health Insurance Research Database was the main data source in this study. Parents and children were linked using the Taiwan Maternal and Child Health Database. Patients diagnosed with KD and younger than 18 years from 2004 to 2015 were enrolled as the study population. The control group was randomly selected from individuals without the diagnosis of KD matched by age, index year, sex, and urbanization level at a ratio of 1 to 10. The prevalence of maternal autoimmune and allergic diseases was compared between groups. Results: In total, 7,178 children were found to have been diagnosed with Kawasaki disease. Then 71,780 children matched by index year, gender, and urbanization were randomly selected to serve as the control group. Children born from mothers with asthma and allergic rhinitis had a higher risk of developing KD. Children of mothers with an autoimmune disorder had a significantly increased tendency to develop KD. Maternal numbers of autoimmune disorders showed a dose-dependent relationship with KD incidence. Conclusion: This is the first population-based study to investigate maternal immune diseases and the risk of KD in their children. Children of mothers with immune disorders tend to have a higher risk of KD.
Brett Plouffe, Tamara Van Hooren, Michelle Barton, Nancy Nashid, Erkan Demirkaya, Kambiz Norozi, Irina Rachinsky, Johan Delport, Michael Knauer, Soumitra Tole, et al.
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.669453

Abstract:
Renal infarction is a rare finding in children. Associations between SARS-CoV-2 infections and thromboembolic events including renal infarcts have been described in adults. Although a similar association in children has not yet been described with this pandemic, the pediatric literature is still evolving with the recognition of new manifestations including the post-infectious Multisystem Inflammatory Syndrome in Children (MIS-C). We report the rare event of multiple renal infarcts in a 6-year-old boy manifesting several features of MIS-C 9 weeks following a self-limiting febrile illness characteristic of COVID-19. An underlying Factor V Leiden mutation was identified in this child but felt to be insufficient on its own to explain his clinical presentation. As SARS-CoV-2 testing was delayed, the failure to identify viral RNA or antibodies may not exclude the virus' potential role in precipitating the infarct in this host. Given that renal infarcts have been described in adult patients with COVID-19, reporting this perplexing case where SARS-CoV-2 may have played a role, may help identify this potential complication.
Qu-Ming Zhao, Ling-Yu Lai, Lan He,
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.660519

Abstract:
Aortic valve rupture (AVR) due to blunt chest trauma is extremely rare in the pediatric population, and little attention has been paid to such damages. Early diagnosis of AVR may not be easy in patients with multiple competing injuries and poor acoustic windows. We report a case of delayed diagnosis of AVR in a 12-year-old boy after falling from a height of 15 meters, who presented with recurrent hemoptysis and ventilator dependence. This rare case highlights the importance of performing transesophageal echocardiography in trauma patients when the images of transthoracic echocardiography are suboptimal, especially for those presenting with signs and symptoms suggestive of heart failure. The overall prognosis of aortic valve replacement is good.
Jennifer K. Straughen, Alexandra R. Sitarik, Christine Cole Johnson, Ganesa Wegienka, Dennis R. Ownby, Tisa M. Johnson-Hooper, Ghassan Allo, Albert M. Levin, Andrea E. Cassidy-Bushrow
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.601092

Abstract:
Background: Few studies have examined if maternal allergic disease is associated with an offspring's neurodevelopment. We hypothesized that Th-2 biased maternal immune function assessed as total serum immunoglobulin (Ig) E is associated with attention deficit hyperactivity disorder (ADHD). Methods: Data are from the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study (WHEALS), a racially and socioeconomically diverse birth cohort in metropolitan Detroit, Michigan. Maternal total IgE was measured prenatally and at 1-month postpartum. Child total IgE was assessed at birth, 6 months, and 2 years of age. ADHD diagnosis was based on the parental report at the 10–12-year study visits or medical chart abstraction. Total IgE was log2 transformed. Poisson regression models with robust error variance were used to calculate the risk ratios (RR). Inverse probability weighting was used to correct for potential bias due to a loss to follow-up and non-response. Results: Of the 636 maternal-child pairs in the analysis, 513 children were neurotypical and 123 had ADHD. Maternal prenatal total IgE was significantly associated with ADHD even after adjustment for potential confounders (RR = 1.08, 95% CI 1.03–1.13). Maternal and child IgE measures were positively and significantly correlated, but child total IgE was not associated with ADHD at any time point. Conclusions: Maternal prenatal IgE may influence neurodevelopment, but additional studies are needed to confirm and expand these findings.
Haibin Sheng, Qian Zhou, Qixuan Wang, Yun Yu, Lihua Liu, Meie Liang, Xueyan Zhou, , Xiangrong Tang,
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.655625

Abstract:
Objective: To compare the hearing screening results of two-step transient evoked otoacoustic emissions (TEOAE) and one-step automatic auditory brainstem response (AABR) in non-risk newborns, and to explore a more suitable hearing screening protocol for infants discharged within 48 h after birth in remote areas of China. Methods: To analyze the age effect on pass rate for hearing screening, 2005 newborns were divided into three groups according to screening time after birth: <24, 24–48, and 48–72 h. All subjects received TEOAE + AABR test as first hearing screen, and those who failed in any test were rescreened with TEOAE + AABR at 6 weeks after birth. The first screening results of AABR and TEOAE were compared among the three groups. The results of two-step TEOAE screening and one-step AABR screening were compared for newborns who were discharged within 48 h. The time spent on screening was recorded for TEOAE and AABR. Results: The pass rate of TEOAE and AABR increased significantly with the increase of first screening time (P < 0.05), and the false positive rate decreased significantly with the increase of first screening time (P < 0.05). The failure rate of first screening of AABR within 48 h was 7.31%, which was significantly lower than that of TEOAE (9.93%) (P < 0.05). The average time spent on AABR was 12.51 ± 6.36 min, which was significantly higher than that of TEOAE (4.05 ± 1.56 min, P < 0.05). The failure rate of TEOAE two-step screening was 1.59%, which was significantly lower than one-step AABR. Conclusions: Compared with TEOAE, AABR screening within 48 h after birth can reduce the failure rate and false positive rate of first screening. However, compared with TEOAE two-step screening, one-step AABR screening has higher referral rate for audiological diagnosis. In remote areas of China, especially in hospitals with high delivery rate, one-step AABR screening is not feasible, and two-step TEOAE screening protocol is still applicable to UNHS screening as more and more infants discharged within 48 h after birth.
Dandan Ke, Dajiang Lu, Guang Cai, Xiaofei Wang, Jing Zhang,
Published: 14 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.641353

Abstract:
Introduction: Physical fitness is an adaptive state that varies with an individual's growth and maturity status. Considering that the difference in skeletal maturity already existed among preschool children, this study was designed to determine the influence of skeletal age and chronological age on preschoolers' physical fitness performance. Methods: This cross-sectional study was conducted in 945 healthy preschoolers (509 males, 436 females) aged between 3.0 and 6.0 years in Shanghai, China. We used the method of TW3-C RUS to determine skeletal age. Chronological age was measured by subtracting the date of birth from the test date. Sit and reach, 2 × 10 m shuttle run test, standing long jump, tennis ball throw, 5 m jump on both feet, and balance beam walk were considered for physical fitness performance. Correlation coefficients and partial correlations adjusting height and weight were used to determine the relationships among the variables of skeletal age/ relative skeletal age, chronological age/relative chronological age, and physical fitness items. Results: Skill-related physical fitness was weakly to moderately associated with skeletal age (the absolute value of r: 0.225–0.508, p < 0.01) and was moderately to strongly associated with chronological age (the absolute value of r: 0.405–0.659, p < 0.01). Health-related physical fitness items (BMI and sit and reach) showed a fairly weak to no correlation with skeletal age and chronological age. After adjusting the height and weight, an extremely weak to no correlation was observed between skeletal age and both health- and skill-related physical fitness, and weak-moderate correlations were noted between chronological age and skill-related physical fitness (the absolute value of r: 0.220–0.419, p < 0.01). In children in Grade 1, skill-related physical fitness (except for balance beam walk) showed a weak to moderate correlation with relative chronological age (the absolute value of r: 0.227–0.464, p < 0.05). Conclusion: (1) both skeletal age and chronological age are associated with skill-related rather than health-related physical fitness performance, and after adjusting height and weight, chronological age, rather than skeletal age, is associated with skill-related physical fitness performance; (2) for preschool children, skill-related physical fitness performance is influenced by relative chronological age rather than individual differences in skeletal maturation, especially in the lower grades.
, Mohammed Almuqbil, Fuad Al Mutairi, Muhammad Umair, Mohammed Almannai, Malak Alghamdi, Hamad Althiyab, Rayyan Albarakati, Fahad A. Bashiri, Walaa Alshuaibi, et al.
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.633385

Abstract:
Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.
Yaru Wang, Yuanyuan Wang, Xueying Li, Junbao Du, , , Ying Liao
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.663016

Abstract:
Objective: This study was designed to assess the efficacy of increased salt and water intake in the treatment of pediatric vasovagal syncope (VVS) based on a meta-analysis of global data. Methods: Following the established inclusion criteria, seven databases, Cochrane Library, EMBASE, PubMed, Web of Science, VIP, Wanfang, and China National Knowledge Infrastructure (CNKI), were searched using specific terms. The Cochrane Bias risk assessment tool was used as a quality assessment tool of the included studies, and publication bias was assessed by funnel plots. Review Manager 5.4 software was used to analyze the efficacy of the included studies, taking the negative changing rate of the head-up tilt test (HUTT) and recurrence rate of syncope or presyncope as therapeutic efficacy evaluations. Results: In total, 5 randomized controlled trials (RCTs) were finally obtained, using the negative changing rate of the HUTT as an efficacy evaluation, while in 4 of the studies, the recurrence rate of syncope or presyncope was also evaluated. A total of 233 children with VVS were included in the salt and water intervention group. The cases in the control group were treated with non-medicinal conventional therapy. The results revealed that the negative changing rate of the HUTT in the intervention group (144/233, 61.8%) was higher than that in the control group (48/179, 26.8%), and the difference was significant (P < 0.00001). The recurrence rate of syncope or presyncope in the intervention group (85/195, 43.6%) was lower than that in the control group (86/144, 59.7%), and the difference was significant (P = 0.002). Conclusion: The current findings suggest that increased salt and water intake may increase the negative changing rates of the HUTT and reduce syncope or presyncope recurrence rates in pediatric patients with VVS.
Yung-Chieh Chang, Wan-Hua Hsieh, Sen-Fang Huang, Hsinyi Hsiao, Ying-Wei Wang, Chia-Hsiang Chu,
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.615483

Abstract:
Background: Our study examined the age, period, and cohort effects on overweight and obesity in children using a 10-year dataset collected from schoolchildren in Hualien, Taiwan. Methods: We used data from the annual health checkup of a total of 94,661 schoolchildren in primary schools and junior high schools in Hualien from 2009 to 2018. Children were defined as overweight or obese by the gender- and age-specific norm of the body mass index. We conducted the age-period-cohort (APC) analysis in boys and girls separately. Results: From 2009 to 2018, the rates of children overweight and obese were 12.78 and 14.23%, respectively. Boys had higher rates of overweight and obesity than girls (29.73 vs. 24.03%, P < 0.001). Based on APC analysis results, positive age effect existed regardless of gender. The risk of overweight or obesity of children aged 9 or 12 years was significantly higher compared to the average rate. As for period effect, a fluctuating downward trend in overweight was evident in 2016, and a similar trend in obesity was seen in 2017 across gender groups. The birth cohort of 2007 to 2009 had a significant higher proportion of overweight and obese than other birth cohorts. This indicated that the proportion of children overweight and obese in the young generation is higher than that in the old generation. Conclusion: An increased risk of children overweight or obese was associated with age and later birth cohort. For the period effect, the trend in the prevalence of overweight and obesity fluctuated downward slowly from 2016 to 2017.
, Adnan Hadid, Khalid A. Altirkawi, Hind M. Bakheet, Aminah Mohammed Alherz, Shaik Asfaq Hussain, Badr H. Sobaih, Abdulrahman M. Alnemri, Rana Almaghrabi, Medina Ahmed, et al.
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.652857

Abstract:
Background: Vertical transmission of SARS-CoV-2 is under investigation. A few reports suggest the possibility of SARS-CoV-2 transmission from mothers to their neonates. Most neonates have mild symptoms, but some develop multisystem involvement and shock. Case Presentation: We report two cases of possible SARS-CoV-2 vertical transmission from mothers to their neonates. The first case shows maternal infection with SARS-CoV-2 in the second trimester followed by recurrent infection in the third trimester right before the delivery. The infant demonstrated respiratory distress soon after delivery along with myocardial dysfunction and multi-organ system involvement. The second case shows maternal infection with SARS-COV-2 at the time of delivery with preterm labor secondary to placental abruption, with that delivery resulting in the preterm neonate requiring non-invasive ventilation with multisystem involvement in the context of persistently positive SARS-COV-2 PCR in the neonate. Both neonates were treated with IVIG along with steroids. Both neonates recovered fully and were discharged and allowed to go home. Conclusion: In neonates, COVID-19 usually presents as an asymptomatic or mild illness; some may develop a more severe course. Our two cases, however, demonstrate that multisystem involvement, although rare, is possible. This report also supports the current evidence of possible vertical transmission from mothers to their neonates. This multisystem involvement might be underreported and should be considered in neonates with respiratory distress when born to mothers suffering of COVID-19. Clinical Trial Registration: [KSUMC], identifier [No#98763298].
, Manouk van der Steen, Abel López-Bermejo, Ekaterina Koledova, Mohamad Maghnie
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.655931

Abstract:
Children born small for gestational age (SGA) comprise a heterogeneous group due to the varied nature of the cause. Approximately 85–90% have catch-up growth within the first 4 postnatal years, while the remainder remain short. In later life, children born SGA have an increased risk to develop metabolic abnormalities, including visceral adiposity, insulin resistance, and cardiovascular problems, and may have impaired pubertal onset and growth. The third “360° European Meeting on Growth and Endocrine Disorders” in Rome, Italy, in February 2018, funded by Merck KGaA, Germany, included a session that examined aspects of short children born SGA, with three presentations followed by a discussion period, on which this report is based. Children born SGA who remain short are eligible for GH treatment, which is an approved indication. GH treatment increases linear growth and can also improve some metabolic abnormalities. After stopping GH at near-adult height, metabolic parameters normalize, but pharmacological effects on lean body mass and fat mass are lost; continued monitoring of body composition and metabolic changes may be necessary. Guidelines have been published on diagnosis and management of children with Silver-Russell syndrome, who comprise a specific group of those born SGA; these children rarely have catch-up growth and GH treatment initiation as early as possible is recommended. Early and moderate pubertal growth spurt can occur in children born SGA, including those with Silver-Russell syndrome, and reduce adult height. Treatments that delay puberty, specifically metformin and gonadotropin releasing hormone analogs in combination with GH, have been proposed, but are used off-label, currently lack replication of data, and require further studies of efficacy and safety.
Yao Huang, Qi Lu, Nan Peng, Li Wang, Yan Song, Qin Zhong, Peng Yuan
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.652139

Abstract:
Background: Neonatal gastric perforation is a rare but life-threatening issue. The aim of this study was to describe the clinical characteristics and prognosis of patients with neonatal gastric perforation and identify predictive factors for poor prognosis. Methods: This was a retrospective cohort study of patients with neonatal gastric perforation treated in a tertiary pediatric public hospital between April 2009 and October 2020. The enrolled patients were divided into survival and non-survival groups. Demographic information, clinical characteristics, laboratory and imaging features, and outcomes were collected from the electronic medical record. Univariate and multivariate logistic regression analyses were performed to obtain the independent factors associated with death risk. Additionally, we separated this population into two groups (pre-term and term groups) and explored the mortality predictors of these two groups, respectively. Results: A total of 101 patients with neonatal gastric perforation were included in this study. The overall survival rate was 70.3%. Seventy-one (70.3%) were pre-term neonates, and sixty-two (61.4%) were low-birth-weight neonates. The median age of onset was 3 days (range: 1–11 days). Abdominal distension [98 (97.0%) patients] was the most common symptom, followed by lethargy [78 (77.2%) patients], shortness of breath [60 (59.4%) patients] and vomiting [34 (33.7%) patients]. Three independent mortality risk factors were identified: shock (OR, 3.749; 95% CI, 1.247–11.269; p = 0.019), serum lactic acid > 2.5 mmol/L (5.346; 1.727–16.547; p = 0.004) and platelet count <150 × 109/L (3.510; 1.115–11.053; p = 0.032). There was a borderline significant association between sclerema neonatorum and total mortality (4.827; 0.889–26.220; p = 0.068). In pre-term infants, serum lactic acid > 2.5 mmol/L and platelet count <150 × 109/L remained independent risk factors for death. In term infants, the incidence of shock, coagulopathy, pH < 7.3, serum lactic acid > 2.5 mmol/L, and hyponatremia were statistically different between non-survival and survival groups. Conclusion: Shock, hyperlactatemia, and thrombocytopenia are independently associated with an increased risk of death in patients with neonatal gastric perforation. Identification of modifiable risk factors during the critical periods of life will contribute to the development of effective prevention and intervention strategies of neonatal gastric perforation.
Ilaria Bottino, Maria F. Patria, Gregorio P. Milani, Carlo Agostoni, Paola Marchisio, Mara Lelii, Marco Alberzoni, Laura Dell'Era, Massimo L. Castellazzi, Laura Senatore, et al.
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.621019

Abstract:
Pulmonary complications in adults who recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported even in minimally symptomatic patients. In this study, lung ultrasound (LUS) findings and pulmonary function of children who recovered from an asymptomatic or mildly symptomatic SARS-CoV-2 infection were evaluated. We prospectively followed up for at least 30 days patients younger than 18 years who recovered from SARS-CoV-2 infection at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (Italy). All enrolled patients underwent LUS. Airway resistance measured by the interrupter technique test was assessed in subjects aged 4–6 years, whereas forced spirometry and measurement of diffusing capacity of the lungs for carbon monoxide were performed in subjects older than 6 years. To evaluate a possible correlation between pulmonary alterations and immune response to SARS-CoV-2, two semiquantitative enzyme immune assays were used. We enrolled 16 out of 23 eligible children. The median age of enrolled subjects was 7.5 (0.5–10.5) years, with a male to female ratio of 1.7. No subject presented any abnormality on LUS, airway resistance test, forced spirometry, and diffusing capacity of the lungs for carbon monoxide. On the other hand, all subjects presented Ig G against SARS-CoV-2. In contrast in adults, we did not detect any pulmonary complications in our cohort. These preliminary observations suggest that children with an asymptomatic or mildly symptomatic SARS-CoV-2 infection might be less prone to develop pulmonary complications than adults.
Nellie Ide, Grace Allen, , Sara Dada
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.667404

Abstract:
Respiratory illnesses are a leading cause of death for children worldwide, with the majority of these cases occurring from preterm birth complications or acute respiratory infections. Appropriate respiratory intervention must be provided quickly to lower the chances of death or permanent harm. As a result, respiratory support given in prehospital and interfacility transport can substantially improve health outcomes for these patients, particularly in areas where transportation time to appropriate facilities is lengthy. Existing literature supports the use of non-invasive ventilation (NIV), such as nasal or bilevel continuous positive airway pressure, as a safe form of respiratory support for children under 18 years old in certain transportation settings. This mini review summarizes the literature on pediatric NIV in transport and highlights significant gaps that future researchers should address. In particular, we identify the need to: solidify clinical guidelines for the selection of eligible pediatric patients for transport on NIV; explore the range of factors influencing successful NIV implementation during transportation; and apply appropriate best practices in low and middle income countries.
Hong Cai, Shuo Wang, Runmei Zou, Fang Li, Juan Zhang, Yuwen Wang, Yi Xu,
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.644461

Abstract:
Objectives: This study aims to investigate the diurnal variability of heart rate (HR) increment after standing (ΔHR) in pediatric postural tachycardia syndrome (POTS) and explore appropriate cutoff values of ΔHR at different times for the POTS diagnosis. Materials and Methods: Seventy-eight patients (9–14 years) who presented with orthostatic intolerance symptoms were enrolled. Forty-three patients were diagnosed as POTS (ΔHR ≥40 bpm), and 35 patients were assigned to the non-POTS group (ΔHR <40 bpm). Twenty-six healthy children served as the control group. All subjects completed three standing tests in the morning, afternoon, and evening. Orthostatic HR parameters were analyzed to predict the diagnosis of POTS. Additionally, 41 patients were recruited as an external validation group. Results: Orthostatic HR increments in both the POTS and non-POTS groups exhibited diurnal variability, which was markedly larger in the morning (P < 0.05), whereas it did not differ with the time of day in the control group. Among the POTS patients, 100% met the diagnostic criteria for POTS in the morning, 44.2% in the afternoon, and 27.9% in the evening. Almost half of the POTS patients (51.2%) displayed a positive result only in the morning standing test. However, in the three standing tests at different times, ΔHR from 1 to 10 min after standing and ΔHRmax were the highest in the POTS group compared with in the non-POTS and control groups (P < 0.05). Furthermore, the maximum ΔHR (ΔHRmax) and ΔHR at 5 and 10 min in the afternoon and evening standing tests yielded moderate predictive values for the POTS diagnosis. The external validation test showed that the afternoon ΔHRmax ≥30 bpm to diagnose POTS yielded sensitivity, specificity, and accuracy of 85, 71.4, and 78%, respectively, and the evening ΔHRmax ≥25 bpm yielded sensitivity, specificity, and accuracy of 85, 76.2, and 80.5%, respectively. Conclusions: The orthostatic HR increment exhibits diurnal variability in children and adolescents with POTS that may affect the diagnosis of POTS. Supplementary criteria are proposed for the POTS diagnosis based on diurnal variability.
Dan Sun, Yan Liu, Wei Cai, Jiehui Ma, Kun Ni, Ming Chen, Cheng Wang, Yongchu Liu, Yuanyuan Zhu, Zhisheng Liu, et al.
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.635703

Abstract:
Background: Epileptic encephalopathies (EEs) are a pediatric entity with highly phenotypic and genetic heterogeneity. Both single nucleotide variants (SNVs)/Indels and copy number variations (CNVs) could be the causes. Whole exome sequencing (WES) is widely applied to detect SNVs/Indels, but the bioinformatics approach for detecting CNVs is still limited and weak. In the current study, the possibility of profiling both disease-causing SNVs/Indels and CNVs in a single test based on WES in EEs was evaluated. Methods: The infants diagnosed with EEs were enrolled from a single pediatric epilepsy center between January 2018 and February 2020. Demographic and clinical data were collected. In WES data, the pathogenic SNVs were identified through an in-house pipeline, and pathogenic CNVs were identified by CNVkit. The diagnostic rate was evaluated, and the molecular findings were characterized. Results: A total of 73 infants were included; 36 (49.32%) of them were males. The median age was 7 months. Thirty-two (43.84%) infants had been diagnosed with epilepsy syndrome. The most common type of syndrome was West syndrome (22/73, 30.1%), followed by Dravet syndrome (20/77, 27.4%). Fifty-four (73.97%) had intellectual development delay. The genetic cause of EEs, pathogenic or likely pathogenic variants, were successfully discovered in 46.6% (34/73) of the infants, and 29 (39.7%) infants carried SNVs/Indels, while 5 (6.8%) carried CNVs. The majority of the disease-causing variants were inherited in de novo pattern (25, 71.4%). In addition to showing that the variants in the ion channel encoding genes accounted for the main etiology, we discovered and confirmed two new disease-causing genes, CACNA1E and WDR26. Five discovered CNVs were deletions of 2q24.3, 1p36, 15q11-q13, 16p11.2, and 17p13.3, and all were confirmed by array comparative genomic hybridization. Conclusion: The application of both SNVs/Indels and CNVs detection in a single test based on WES yielded a high diagnosis rate in EEs. WES may serve as a first-tier test with cost-effective benefit in EEs.
Shen Yang, Siqi Li, Zhi Yang, Junmin Liao, Kaiyun Hua, Yanan Zhang, Yong Zhao, Yichao Gu, Shuangshuang Li, Jinshi Huang
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.645511

Abstract:
Background: To determine the possible risk factors of recurrent tracheoesophageal fistula (rTEF) after Gross type C esophageal atresia (EA) and tracheoesophageal fistula (TEF) repair. Methods: The medical records of 343 pediatric patients with Gross type C EA/TEF who underwent surgical repair were retrospectively analyzed. The patients were retrospectively divided into two groups according to whether they had rTEF. Univariate and multivariable logistic regression analysis were performed to identify risk factors for rTEF. Results: After the diagnosis of EA/TEF, 343 patients (221 boys) underwent primary repairs after birth. According to the follow-up results (257 patients survived, 42 died, and 43 were lost to follow-up), 259 patients (257 survived and two died after rTEF repair) were included in the analysis. rTEF occurred in 33 patients (33/259, 12.74%), with a median onset time to recurrence of 3.8 (2.2, 8.2) months. Multivariate analysis showed that closing the original TEF with ligation and hospital stay ≥ 28.5 days were significant risk factors of rTEF with OR of 4.083 (1.481, 11.261) and 3.228 (1.431, 7.282). Conclusions: Surgical closure technique of original TEF and the length of initial stay could influence the occurrence of rTEF after Gross type C EA/TEF repair.
Katharina Bibl, Michael Wagner, Philipp Steinbauer, Peter Gröpel, Sabrina Wimmer, Monika Olischar, Angelika Berger,
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.675742

Abstract:
Background: This randomized interventional study evaluated the impact of a 1-day experiential communication skills training on neonatologists' performance in doctor-parents-communication. Methods: 17 neonatologists with different levels of professional experience from the Medical University of Vienna were randomized into one of two study groups: The intervention group (IG) as opposed to the control group (CG) participated in a 1-day experiential communication training. Eight weeks after the training, participants' communication skills were assessed during an objective structured clinical examination (OSCE). Neonatologists were assessed in a simulated conversation by how effectively they performed when conveying complex health-related information to parents of ill infants. Participants in the control group (CG) were assessed first during the OSCE and received their communication training later on. Self-assessment questionnaires before and after the workshop and OSCE were completed. Results: The study determined that neonatologists in the IG subjectively perceived that their competence level regarding their communication skills had increased after the workshop, while this was not reflected by their performance during the OSCE assessment. Discussion: A 1-day experiential communication skills training significantly increased physicians' self-evaluation concerning their communicative competence. This perceived competence did not manifest itself in increased communication skills during the OSCE. Conclusion: Repeated training is needed.
Lin Wan, Xinting Liu, Linyan Hu, Huimin Chen, Yulin Sun, Zhichao Li, Zhenfang Wang, Zhi Lin, ,
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.664449

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Aim: MEF2C haploinsufficiency syndrome (MCHS) is a severe neurodevelopmental disorder. We describe the clinical phenotypes and genotypes of seven patients with MCHS to enhance the understanding of clinical manifestations and genetic alterations associated with MCHS. Method: Seven patients (6 females and 1 male, aged between 2 years 5 months and 6 years) who had MEF2C mutations, and their parents underwent trio-based whole-exome sequencing; subsequently, their clinical features were assessed. A literature review of patients with MCHS was performed by searching the PubMed and Online Mendelian Inheritance in Man databases. Results: Seven mutations were identified, of which six were unreported in the past; of the reported cases, five patients had de novo mutations but two had an undefined inheritance pattern. All patients presented delays in developmental milestones, severe intellectual disabilities and lack of speech. Six patients exhibited infantile hypotonia, five patients experienced stereotypic movements and were unable to walk, four patients exhibited poor eye contact indicative of autism and two showed poor performance. While six patients experienced seizure, five among them became seizure free after receiving anti-seizure medicine. Three patients showed a regression in their development, whereas the mothers of two patients exhibited mosaicism but were healthy without any abovementioned symptoms. Interpretation: Regression was not a common phenomenon but occurred in MCHS. The prognosis of MCHS patients with epilepsy was good, but most patients can achieve a seizure-free status. Healthy people may have low-level mosaicism and carry a pathogenic MEF2C mutation.
, Beatriz Fernández Bautista, Alberto Parente Hernández, Ruben Ortiz Rodríguez, Jose María Angulo Madero
Published: 13 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.609664

Abstract:
Background: Extracorporeal shock wave lithotripsy (ESWL) is nowadays the first choice for the treatment of upper urinary tract stones smaller than 2 cm, considering its low complications and high success rate. Aim: To present an update of the current situation of ESWL treatment and to analyse our series of patients and the efficacy of combined lithiasis treatment in different locations and sizes. Patients and Method: Retrospective study including patients with urolithiasis treated with ESWL between 2007 and 2019. Collected data included: gender and age at treatment, presentation symptoms, imaging studies, stone location and size, complications and stone clearance. Success was defined as stone-free status or the presence of clinically insignificant residual fragments (<4 mm after 3 months follow-up). Patients with residual stones larger than 4 mm after 3 months were programmed for another ESWL session or received a combined sandwich therapy, followed by URS or percutaneous approach. Results: Between 2007 and 2019, 37 patients presented a total of 41 lithiasis episodes that were treated with ESWL sessions. Median age at first procedure was 9 years old (1–17) and median follow-up time was 6 years (3–12). Stones were located in the renal pelvis, followed by the lower, middle and upper calyx, proximal ureter, and 51% of our patients had multiple lithiasis. Median stone size was 12 mm (5–45), the main component being calcium oxalate (34%). During immediate postoperative period, 8 patients (19%) presented complications: renal colic, hematuria and urinary tract infection. After the first ESWL, 41% of the patients (n = 17) were stone-free. Out of the 24 residual lithiasis episodes (58%), three patients (7%) underwent a second ESWL session. In the remaining 19 patients, ESWL was combined with URS or percutaneous approach to achieve complete stone clearance. Overall stone free status after combined therapy was 95% (n = 39). Conclusion: These data support that ESWL is an effective minimally invasive technique, with low cost and morbidity, reproducible and safe for the treatment of stone disease in children. Even though lithiasis size seems to be a significant factor in ESWL success, in combination with other lithotripsy procedures it can reach very high rates of stone clearance.
Tian Zhang, Ying Song, Haoyue Teng, Yue Zhang, Jianan Lu, Linghua Tao, Yanjie Jin, Jieyun Yin, Danhong Zhou
Published: 12 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.665655

Abstract:
Objective: The purpose of this study was to identify trajectories of body mass index (BMI) in toddlers from birth to 2 years old and examine their association with infantile overweight/obesity. Methods: Data were collected from 19,054 children born in any hospital or community healthcare center in Taizhou, China from 2018 to 2019 with at least three BMI measurements after birth. The Latent Class Growth Mixture Model was used to identify distinct BMI trajectories during the first 2 years of infants. Multiple logistic regression models were conducted to explore the associated factors of different BMI trajectories, and log-binomial regression was performed to assess the association between the trajectories and overweight/obesity. Results: Three heterogeneous BMI trajectories were identified and labeled as “lower” (36.21%, n = 6,899), “middle” (53.15%, n = 10,128) and “upper” (10.64%, n = 2,027), respectively. Several characteristics of infants and their corresponding mothers were found to be correlated with infant BMI trajectories, including infant sex, mode of delivery and weight at birth, as well as maternal parity, early pregnancy BMI and status of gestational diabetes mellitus. Furthermore, compared with those in the lower trajectory, infants in the middle [prevalence ratio (PR) = 2.63, 95% confidence interval (95%CI) = 2.17–2.63] or upper (PR = 2.98, 95%CI = 1.51–2.98) trajectory groups were prone to be overweight/obesity at their final observation. Conclusion: Heterogeneous BMI trajectories were observed in our study. Characteristics of both infants and their corresponding mothers could be potential determinants of infant growth. Moreover, infants in the middle and upper trajectory groups were more likely to suffer overweight/obesity.
Valentina Härter, Claus Barkmann, Christian Wiessner, Martin Rupprecht, Konrad Reinshagen,
Published: 12 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.640236

Abstract:
Objective: Audio-visual interventions have been used to provide relevant patient information to reduce pre-operative anxiety in children. The aim of the study was to investigate whether self-reported state anxiety in children could be reduced by presenting a child-friendly educational video on the day of surgery. Methods: A prospective, single-blinded, two-armed, randomized controlled study was designed with three measurement time points including 90 children (6–17 years) and their parents. In the intervention group (IG), the children and their parents were shown a child-friendly video explaining the perioperative procedures that would be applied during the hospital stay, in addition to receiving standard information. In the control group (CG), children and parents received standard information provided by the nursing staff. The primary outcome was any change in the children's pre-operative state anxiety levels, as measured by the State-Trait Operation Anxiety Inventory (STOA). A secondary outcome was patient satisfaction regarding the received information. Results: Anxiety was significantly reduced in both groups after receiving either the intervention plus standard information or the standard information only. No significant difference in anxiety reduction was observed between the IG and the CG. However, the children and parents in the IG reported fewer worries than those in the CG. Conclusion: A child-friendly, educational video can be an additional tool for providing patient information and reducing pre-operative anxiety in children and their parents. Further studies should focus on the timing of the intervention and on age- and developmentally appropriate information formats and contents to address children's pre-operative anxiety. Clinical Trial Registration: Patient Anxiety Reduction in Children by Using Simple Explanation Videos, ID: NCT0441377; www.clinicaltrials.gov, Data Sharing Statement: Deidentified individual participant data will not be made available.
Esha Brar, Anish Saxena, Claudia Dukler, Fangxi Xu, Deepak Saxena, Preneet Cheema Brar, Yuqi Guo, Xin Li
Published: 12 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.647925

Abstract:
The use of electronic cigarettes (e-cigarettes) and vaping among adolescents has risen exponentially in the last decade. E-cigarette flavors has driven adolescents to use these convenient, USB-like devices, designed to create a desired social image, while being seemingly unaware of the serious health consequences of their behavior. Vaping impacts protective pulmonary barriers by attenuating the mucociliary clearance and by increasing peribronchial inflammation and fibrosis. The recent SARS-CoV-2 (COVID-19) pandemic has been characterized by a plethora of unusual disease presentations. Among them, a unique presentation seen exclusively in children and adolescents was multisystem inflammatory syndrome (MIS-C). Seventy percent of adolescents who had MIS-C also had acute respiratory distress syndrome (ARDS), and we speculate that there may exist common denominator that links MIS-C and adolescents: the use of e-cigarettes. The virus targets the angiotensin converting receptor (ACE receptor), and studies have shown nicotine-based e-cigarettes or vaping cause oxidative stress and resulting in the upregulation of ACE2, which might worsen ARDS in MIS-C. Our mini-review highlights that adolescents using e-cigarette have alterations in their pulmonary defenses against SARS-CoV-2: an upregulation of the ACE2 receptors, the primary target of SARS-CoV-2. Their compromised immune system makes them more uniquely vulnerable to Covid-19 related MIS-C, increasing their risk for ARDS and related morbidities. Currently, studies have shown an association between MIS-C and vaping, we speculate that adolescents who vape/smoke might be especially vulnerable to serious respiratory symptoms if they develop a hyper-inflammatory state MIS-C.
Keishiro Amano, , Kouhei Nishikawa, Tomohiro Murata, Masahiro Hirayama
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.550158

Abstract:
Secondary hyperparathyroidism (HPT) is a common complication of end-stage renal disease (ESRD) and may be an important precipitating factor for the development of myelofibrosis. However, there have been only a few reports on myelofibrosis caused by secondary HPT in children. We describe a case of a 15-year-old boy with myelofibrosis due to secondary HPT who was successfully treated with hemodialysis, erythropoietin, phosphate binders, and activated vitamin D agents. The patient had no past medical history and had been admitted to the hospital for abdominal pain. Routine blood examination revealed pancytopenia combined with renal impairment. Hyperphosphatemia, decreased 1,25-dehydroxyvitamin D, decreased serum calcium, and increased parathyroid hormone (PTH) levels were observed. Bone marrow biopsy confirmed myelofibrosis and renal biopsy revealed nephronophthisis (NPHP). The possibility of renal osteodystrophy and myelofibrosis due to secondary HPT was considered. Hemodialysis and erythropoietin were initiated and combined therapy with a phosphate binder and an active vitamin D agent achieved greater reduction of PTH levels, along with improvement of pancytopenia. As medical treatment for secondary HPT can lead to a reversal of myelofibrosis and avoid parathyroidectomy in children, prompt recognition of this condition has major implications for treatment. Therefore, despite its rarity, pediatricians should consider myelofibrosis due to secondary HPT as a cause of pancytopenia in patients with chronic kidney disease.
Łukasz Dembiński, Gottfried Huss, Igor Radziewicz-Winnicki, Zachi Grossman, Artur Mazur, Stefano del Torso, Shimon Barak, Angel Carrasco Sanz,
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.679803

Abstract:
The COVID-19 pandemic and global lockdown have had drastic socioeconomic and psychological effects on countries and people, respectively. There has been limited access to health care and education. These negative consequences have had a significant impact on the well-being of children and adolescents. Therefore, the EAP and the ECPCP are requesting state, health, and education authorities as well as European pediatric societies and the healthcare professionals that special attention be given to this population and the problems they face as a result of the pandemic.
, Daniela Loconsole, Elisabetta Pandolfi, Marta Luisa Ciofi Degli Atti, Jojanneke van Summeren, John Paget, Luisa Russo, Ilaria Campagna, Ileana Croci, Francesco Gesualdo, et al.
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.620598

Abstract:
Background: In December 2019, a novel coronavirus named SARS-CoV-2 started circulating in China and this led to a major epidemic in Northern Italy between February and May 2020. Young children (aged <5 years) seem to be less affected by this coronavirus disease (COVID-19) compared to adults, although there is very little information on the circulation of this new virus among children in Italy. We retrospectively tested nasopharyngeal swabs for SARS-CoV-2 in samples collected in young children between November, 2019 and March, 2020 in the context of the RSV ComNet study. Methods: Two networks of primary care pediatricians in Lazio (Central Italy) and Puglia (Southern Italy) collected nasopharyngeal swabs from children, aged <5 years, presenting with symptoms for an acute respiratory infection (ARI). The RSV ComNet study is a multicenter study implemented to estimate the burden of RSV in young children (aged <5 years) in the community. Swabs were sent to a central reference laboratory and tested for 14 respiratory viruses through RT-PCR. All collected samples were retrospectively tested for SARS-CoV-2 using RT-PCR (Istituto Superiore di Sanità protocol). Results: A total of 293 children with ARI were identified in the two participating networks. The highest number of cases were recruited in weeks 51/2019 and 3/2020. The majority of patients (57%) came from the Lazio region. All of the 293 samples tested negative for SARS-Cov2. Rhinovirus was the most frequently detected virus (44%), followed by RSV (41%) and influenza viruses (14%). Conclusions: Our study shows that in Lazio (a region of intermediate SARS-COV-2 incidence) and Puglia (a region of low incidence), the SARS-Cov2 virus did not circulate in a sample of ARI pediatric cases consulting primary care pediatricians between November 2019 and March 2020.
María Virginia Amesty, Claudia García-Vaz, Laura Espinosa, María José Martínez-Urrutia, Pedro López-Pereira
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.646923

Abstract:
Introduction: To obtain a successful renal transplant (RT) outcome in patients with posterior urethral valves (PUV), it is necessary to accomplish an adequate bladder dysfunction treatment. Our aim was to determine prognostic factors related to bladder dysfunction management in long-term RT outcome in patients with PUV. Methods: A retrospective review of patients with PUV who received a first RT after 1985 in our institution with at least 5 years of follow-up was performed. Variables analyzed included prenatal diagnosis, age of diagnosis, initial presentation and management, bladder dysfunction treatment, other surgical treatments, pre-transplant dialysis, age of transplantation, type of donor, immunosuppression regimen, vascular and urological complications, rejections episodes, and graft survival. Results: Fifty-one patients were included in the analysis. Prenatal diagnosis was done in 37.3%. Median age of diagnosis was 0.30 (0–88) months. Initial presentation was vesicoureteral reflux (VUR) in 78% and obstructive ureterohydronefrosis in 35.3%. Initial management was valve ablation (29.4%), pyelo-ureterostomy (64.7%), and vesicostomy (5.9%). In 33.3%, a type of bladder dysfunction treatment was performed: 21.6% bladder augmentation (BA), 15.7% Mitrofanoff procedure, 17.6% anticholinergic drugs, and 27.5% clean intermittent catheterization (CIC). Pre-transplant dialysis was received by 66.7%. Transplantation was performed at 6.28 ± 5.12 years, 62.7% were cadaveric and 37.3% living-donor grafts. Acute rejection episodes were found in 23.6%. Urological complications included recurrent urinary tract infections (UTIs) (31.4%); native kidneys VUR (31.4%); graft VUR (45.1%); and ureteral obstruction (2%). Vascular complications occurred in 3.9%. Mean graft survival was 11.1 ± 6.9 years. Analyzing the prognostic factor that influenced graft survival, patients with had CIC or a Mitrofanoff procedure had a significant better long-term graft survival after 10 years of follow-up (p < 0.05), despite of the existence of more recurrent UTIs in them. A better graft survival was also found in living-donor transplants (p < 0.05). No significant differences were observed in long-term graft survival regarding native kidneys or graft VUR, BA, immunosuppression regimen, or post-transplant UTIs. Conclusion: Optimal bladder dysfunction treatment, including CIC with or without a Mitrofanoff procedure, might result in better long-term graft survival in patients with PUV. These procedures were not related to a worse RT outcome in spite of being associated with more frequent UTIs.
Emanuele Monda, Juan Pablo Kaski,
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.696443

Abstract:
Editorial on the Research Topic Paediatric Cardiomyopathies Paediatric cardiomyopathies (CMPs) are rare disorders associated with significant morbidity and mortality (1). They represent a varied group of diseases, with the outcome largely dependent on phenotype, aetiology, and clinical characteristics (2, 3). Data in the literature on paediatric CMPs are scant, leading to several “gaps in knowledge.” In this Research Topic, experts in the field explored different topics contributing to increase knowledge on this challenging area. Sudden cardiac death (SCD) in paediatric CMPs is a rare but devastating event. Since SCD sometimes represents the first manifestation of the disease, the identification of the specific underlying disorder and the risk factors for SCD is crucial to prevent such event (4). However, evidence on risk stratification and preventing strategies is lacking. Furthermore, paediatric patients undergoing implantable cardioverter defibrillator (ICD) implantation show an elevated rate of short- and long-term device-related complications. In their review entitled “Sudden Cardiac Death in Children Affected by Cardiomyopathies: An Update on Risk Factors and Indications at Transvenous or Subcutaneous Implantable Defibrillators”, Rella et al. extensively discussed this topic providing an overview on risk factors for SCD and the possible indication for subcutaneous vs. transvenous ICD in patients with paediatric CMPs. Although arrhythmic complications are well-described in children with hypertrophic cardiomyopathy (HCM), their importance in paediatric dilated cardiomyopathy (DCM) is less well-understood. In the article “Correlation Between Arrhythmia and the Prognosis in Children With EFE/LVNC/DCM”, Wang et al. investigated 31 children with endomyocardial fibrosis (EFE), left ventricular non-compaction (LVNC), or DCM with tachyarrhythmias [including supraventricular tachycardia (SVT), atrial fibrillation (AF), atrial flutter (Af), ventricular tachycardia (VT), frequent premature ventricular contraction (PVC), and Wolff–Parkinson–White syndrome B (WPW-B)] or interventricular blocks (IVB) or complete left bundle branch block (CLBBB) aiming to explore the correlation between different phenotypes of arrhythmias and prognosis in these patients. Forty-two children with EFE with or without arrhythmias were also included to assess the impact of arrhythmias on prognosis. The authors showed that children with EFE and WPW-B that manifested SVT, IVB, or CLBBB carry worse outcome in terms of time to recovery of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD), compared to children with EFE and AF/Af or VT. Moreover, children with EFE and arrhythmias had worse overall outcomes compared to those without. Thus, the authors concluded that the long-term outcome of children with CMPs is associated with the type of arrhythmia, suggesting that early arrhythmia control is required to improve the prognosis of these patients. Myocarditis is an inflammatory cardiac disease that may occur as a consequence of infection, exposure to toxic substances, and immune systemic activation. It is a relatively common cause of SCD, DCM, and heart failure in children. The clinical presentation of myocarditis ranges from subclinical disease to fulminant heart failure, the latter representing a common presentation in young children. Viral infection is the main cause of myocarditis in children. In addition to direct viral infection, myocardial damage is partly mediated by immunological mechanisms both in the acute and chronic phases of the disease. Immunosuppressive therapy could therefore theoretically improve prognosis in selected cases (e.g., giant cell myocarditis, myocarditis associated with known extra-cardiac autoimmune disease) (5). In the study entitled “Immunosuppressive Treatment for Myocarditis in the Paediatric Population: A Meta-Analysis”, He et al. performed a systematic meta-analysis of studies investigating the efficacy of immunosuppressive treatment in the paediatric population with acute myocarditis. They found that short-term immunosuppressive treatment may improve LVEF, reduce LVEDD, and reduce the risk of death and heart transplantation in children with myocarditis. However, according to the authors, these results should be interpreted cautiously because of several study limitations, such as, among others, the small sample size, publication bias, lack of data on the viral genome and histologic type of myocarditis. Mutations in the LMNA gene are responsible for a wide spectrum of diseases, known as laminopathies, including peripheral neuropathy, skeletal muscle disorders, and DCM. LMNA-related CMPs are frequently associated to SVT, conduction disorders, and less commonly to VT, potentially leading to SCD. Although cardiac involvement in laminopathies is well-described in adults, there are little data on laminopathies in children. In the study entitled “Cardiovascular Involvement in Paediatric Laminopathies. Report of Six Patients and Literature Revision”, Baban et al. described six children with LMNA mutations. Arrhythmic events and/or DCM represented the most common type of myocardial involvement, while neuromuscular involvement was mild or absent. Importantly, they observe the coexistence of congenital heart defects (CHDs) and aortic involvement in four patients, suggesting for the first time a possible causative role of LMNA variant in left-sided CHDs and progressive aortopathies. However, further studies are essential to confirm this observation. The editors hope that readers of this Research Topic will find it of interest. EM, JK, and GL contributed equally to the conception and drafting of the Editorial. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial...
Hong-Min Zhu, Si-Min Zhang, Cong Yao, Meng-Qing Luo, Hui-Jing Ma, Tao Lei, Chun-Hui Yuan, Ge-Fei Wu, Jia-Sheng Hu, Chun-Quan Cai, et al.
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.655074

Abstract:
Background: Acute necrotizing encephalopathy of childhood (ANE) is a rare but rapidly progressing encephalopathy. Importantly, the exact pathogenesis and evidence-based treatment is scarce. Thus, we aimed to identify the clinical, imaging, and therapeutic characteristics that associated with prognosis of pediatric ANE patients. Methods: A retrospective study was conducted on pediatric patients with ANE who were admitted to Wuhan Children's Hospital between January 2014 and September 2019. All cases met the diagnostic criteria for ANE proposed by Mizuguchi in 1997. The clinical information and follow-up data were collected. The prognostic factors were analyzed by trend chi-square test and Goodman–Kruskal gamma test. Results: A total of 41 ANE patients ranging in age from 8.9 to 142 months were included in this study. Seven cases (17%) died, and the other 34 survivors had different degrees of neurological sequelae. Factors tested to be significantly correlated with the severity of neurological sequelae were the intervals from prodromal infection to acute encephalopathy (G = −0.553), conscious disturbance (r = 0.58), endotracheal intubation (r = 0.423), elevation of alanine aminotransferase (r = 0.345), aspartate aminotransferase (r = 0.393), and cerebrospinal fluid protein (r = 0.490). In addition, dynamic magnetic resonance imaging (MRI) evaluation on follow-up revealed that the total numbers of brain lesion location (χ2 = 6.29, P < 0.05), hemorrhage (r = 0.580), cavitation (r = 0.410), and atrophy (r = 0.602) status were significantly correlated with the severity of neurological sequelae, while early steroid therapy (r = −0.127 and 0.212, respectively) and intravenous immunoglobulin (IVIG) (r = 0.111 and −0.023, respectively) within 24 h or within 72 h after onset showed no association. Conclusions: Intervals from prodromal infection to acute encephalopathy (≤1 day), total numbers of brain lesion location (≥3), the recovery duration of hemorrhage and atrophy (>3 months), and the presence of cavitation predict severe neurological sequelae in pediatric patients with ANE. Early treatments, including steroid therapy and IVIG, had no correlation with better outcomes. Further studies are needed to establish a consensus guideline for the management of ANE.
Qinrui Li, Jingjing Liang, Na Fu, ,
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.650624

Abstract:
Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interaction. There are no curative treatments for children with ASD. The ketogenic diet (KD) is a high-fat, appropriate-protein, and low-carbohydrate diet that mimics the fasting state of the body and is proven beneficial in drug-resistant epilepsy and some other brain diseases. An increasing number of studies demonstrated that a KD improved autistic behavior, but the underlying mechanisms are not known. We reviewed the neuroprotective role of a KD in ASD, which is likely mediated via improvements in energy metabolism, reductions in antioxidative stress levels, control of neurotransmitters, inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, and modulation of the gut microbiota. A KD is likely a safe and effective treatment for ASD.
Susanne Tippmann, Martin Haan, Julia Winter, Ann-Kathrin Mühler, Katharina Schmitz, Mascha Schönfeld, Luise Brado, Seyed Hamidreza Mahmoudpour, Eva Mildenberger,
Published: 11 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.675238

Abstract:
Background: Intubation of neonates is difficult and hazardous. Factors associated with procedure-related adverse events and unsuccessful intubation attempts are insufficiently evaluated, especially during neonatal nasotracheal intubations. Objective: Aim of this study was to determine the frequency of tracheal intubation–associated events (TIAEs) during neonatal nasotracheal intubations and to identify factors associated with TIAEs and unsuccessful intubation attempts in our neonatal unit. Methods: This was a prospective, single-site, observational study from May 2017 to November 2019, performed at a tertiary care neonatal intensive care unit in a German academic teaching hospital. All endotracheal intubation encounters performed by the neonatal team were recorded. Results: Two hundred and fifty-eight consecutive intubation encounters in 197 patients were analyzed. One hundred and forty-eight (57.4%) intubation encounters were associated with at least one TIAE. Intubation inexperience (<10 intubation encounters) (OR = 2.15; 95% CI, 1.257–3.685) and equipment problems (OR = 3.43; 95% CI, 1.12–10.52) were predictive of TIAEs. Intubation at first attempt (OR = 0.10; 95% CI, 0.06–0.19) and videolaryngoscopy (OR = 0.47; 96% CI, 0.25–0.860) were predictive of intubation encounters without TIAEs. The first intubation attempt was commonly done by pediatric residents (67.8%). A median of two attempts were performed until successful intubation. Restricted laryngoscopic view (OR = 3.07; 95% CI, 2.08–4.53; Cormack-Lehane grade 2 vs. grade 1), intubation by pediatric residents when compared to neonatologists (OR = 1.74; 95% CI, 1.265–2.41) and support by less experienced neonatal nurses (OR = 1.60; 95% CI, 1.04–2.46) were associated with unsuccessful intubation attempts. Conclusions: In our unit, TIAEs and unsuccessful intubation attempts occurred frequently during neonatal nasotracheal intubations. To improve success rates, quality improvement und further research should target interprofessional education and training, equipment problems and videolaryngoscopy.
Maria Anna Siano, Claudia Mandato, Lucia Nazzaro, Gennaro Iannicelli, Gian Paolo Ciccarelli, Ferdinando Barretta, Cristina Mazzaccara, Margherita Ruoppolo, Giulia Frisso, Carlo Baldi, et al.
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.672004

Abstract:
Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.
Lorelei Charbonnier, Julie Rouprêt-Serzec, Marion Caseris, Marion Danse, Aurélie Cointe, Laure Cohen, Albert Faye, Naïm Ouldali,
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.638502

Abstract:
Background: The contact tracing and isolation of contagious individuals are cornerstones in the control of the COVID-19 pandemic. Strategies to identify household contacts who should be isolated around index children that tested positive for SARS-CoV-2 remain to be clarified. We aimed to compare contact tracing strategies around an index child positive for SARS-CoV-2 using serological rapid diagnostic testing (RDT, chromatography immunoassay). Methods: We conducted a contact tracing study in households of index cases children in the Paris region, France, between May 8 and July 27, 2020. We compared two strategies, one using SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) and one combining RT-PCR and serological RDT, initiated once RDT was available. The contacts RT-PCR–/RDT+ were considered to have been previously infected and not requiring quarantine. The primary outcome was the proportion of contacts that could avoid quarantine with the two screening strategies. Results: We included 34 children as index cases. Median age was 7 years. They generated 184 contacts (111 adults, 73 children) tested by RT-PCR: 24/184 (13%) were positive. The strategy combining RDT and RT-PCR was performed in 120/184 contacts (77 adults, 43 children) of 26 index children: 16/120 (13%) were RT-PCR+ and 47/120 (39%) were RDT+. Among the 16 individuals who were RT-PCR+, 14 (87%) were also RDT+. Among the 104 individuals who were RT-PCR–, 33 were RDT+. Hence 33/120 (27%) individuals were not isolated. Conclusions: Following the diagnosis of SARS-CoV-2 infection in children, a strategy combining serological RDT and nasopharyngeal RT-PCR enabled us to identify around one fourth of contacts with past infection and avoid unnecessary quarantine of these individuals.
, Iris E. van der Horst, Josse Wetzer, Anneloes L. van Baar, Brigitte Vugs, Peter Andriessen
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.672214

Abstract:
Aim: Long-term outcome data in preterm children is often limited to cross-sectional measurement of neurodevelopmental impairment (NDI) at the corrected age of 24-36 months. However, impairments may only become overt during childhood or resolve with time, and individual trajectories in outcome over time may vary. The primary aim of this study was to describe NDI in very preterm born children at three subsequent ages of 2, 5, and 8 years of age. As a secondary aim, a longitudinal analysis was performed on the individual longitudinal trajectories in NDI from 2 to 8 years of age. Methods: Single-center prospective cohort study including children born between 1990 and 2011 below 30 weeks' gestation and followed into 2019. The outcome measurement was NDI assessed at 2, 5, and 8 years of age. NDI is a composite score that includes cognitive, neurological, visual, and auditory functions, in which problems were categorized as none, mild, moderate, or severe. Cognitive function measured as total DQ/IQ score was assessed by standardized psychometric tests. Neurological, visual, and auditory functions were assessed by the neonatologist. Results: In total, 921 children were eligible for follow-up, of whom 726 (79%) children were assessed. No NDI was seen in 54, 54, and 62%, mild NDI was seen in 31, 36, and 30%, and moderate-to-severe NDI was seen in 15, 9.2, and 8.6% of the children at 2, 5, and 8 years, respectively. From 2 to 8 years, 63% of the children remained in the same NDI category, 20% of the children improved to a better NDI category, and 17% deteriorated toward a worse NDI category. No differences were found in baseline characteristics of infants that improved or deteriorated. Extreme prematurity, male gender and low parental education were associated with worse NDI status at all time points. Although we observed considerable individual variation over time in NDI status, the course of the trajectories in NDI were not associated with gestation, gender, and parental education. Conclusions: Continued follow-up until school life is essential in order to provide optimal and individually focused referrals and care when needed.
Federica Barbati, , Teresa Oranges, Lorenzo Lodi, Simona Barni, Elio Novembre, Ermanno Baldo, Mario Cristofolini, Stefano Stagi, Silvia Ricci, et al.
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.645259

Abstract:
Netherton syndrome (NS) is a genetic, multisystemic disease classically distinguished by a triad of clinical manifestations: congenital ichthyosiform erythroderma, hair shaft abnormalities, and immune dysregulation. Due to the complex pathogenesis of the disease, there are no specific therapies currently accessible for patients with NS. An early diagnosis is crucial to start the correct management of these patients. A multidisciplinary approach, including specialists in immunology, allergology, and dermatology, is necessary to set up the best therapeutic pathway. We conducted a review with the aim to summarize the different therapeutic strategies currently accessible and potentially available in the future for children with NS. However, given the limited data in the literature, the best-tailored management should be decided upon the basis of the specific clinical characteristics of the patients with this rare clinical condition. Further comprehension of the pathophysiology of the disease could lead to more efficacious specific therapeutic options, which could allow a change in the natural history of NS.
Marianne E. Nellis, Ljiljana V. Vasovic, Ruchika Goel, Oliver Karam
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.673613

Abstract:
Objectives: Children supported by extracorporeal membrane oxygenation (ECMO) are at high risk of bleeding. Though practitioners often prescribe blood components and/or medications to prevent or treat bleeding, the utilization of these hemostatic measures in children is not well-understood. We sought to evaluate the use of hemostatic blood products (platelet, plasma and cryoprecipitate transfusions) and medications [aminocaproic acid, tranexamic acid (TXA) and Factor VIIa] in children supported by ECMO. Design: Retrospective observational study using the Pediatric Health Information System (PHIS) database from 2011-2017. Setting: Fifty-one U.S. children's hospitals. Patients: Children (aged 0–18 years) supported by ECMO. Interventions: None. Measurements and Main Results: ECMO was employed in the care of 7,910 children for a total of 56,079 ECMO days. Fifty-five percent of the patients were male with a median (IQR) age of 0 (0–2) years. The median (IQR) length of ECMO was 5 (2–9) days with a hospital mortality rate of 34%. Platelets were transfused on 49% of ECMO days, plasma on 33% of ECMO days and cryoprecipitate on 17% of ECMO days. Twenty-two percent of children received TXA with the majority receiving it on the first day of ECMO and the use of TXA increased during the 6-year period studied (p < 0.001). Seven percent of children received aminocaproic acid and 3% received Factor VIIa. Conclusions: Children supported by ECMO are exposed to a significant number of hemostatic blood products. Antifibrinolytics, in particular TXA, are being used more frequently. Given the known morbidity and mortality associated with hemostatic blood products, studies are warranted to evaluate the effectiveness of hemostatic strategies.
Han-Yu Luo, Ling-Ling Xie, Si-Qi Hong, Xiu-Juan Li, Mei Li, Yue Hu, Jian-Nan Ma, Peng Wu, Min Zhong, Min Cheng, et al.
Published: 10 May 2021
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.676616

Abstract:
Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders. Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed. Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability. Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.
Daisuke Maruyama, Begüm Kocatürk, Youngho Lee, Masanori Abe, Malcolm Lane, Debbie Moreira, Shuang Chen, Michael C. Fishbein, Rebecca A. Porritt, Magali Noval Rivas, et al.
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.662953

Abstract:
Kawasaki disease (KD), an acute febrile childhood illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Experimental data from murine models of KD vasculitis and transcriptomics data generated from whole blood of KD patients indicate the involvement of the NLRP3 inflammasome and interleukin-1 (IL-1) signaling in KD pathogenesis. MicroRNA-223 (miR-223) is a negative regulator of NLRP3 activity and IL-1β production, and its expression has been reported to be upregulated during acute human KD; however, the specific role of miR-223 during KD vasculitis remains unknown. Here, using the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, we demonstrate increased miR-223 expression in LCWE-induced cardiovascular lesions. Compared with control WT mice, LCWE-injected miR-223-deficient mice (miR223 −/y ) developed more severe coronary arteritis and aortitis, as well as more pronounced abdominal aorta aneurysms and dilations. The enhanced cardiovascular lesions and KD vasculitis observed in LCWE-injected miR223 −/y mice correlated with increased NLRP3 inflammasome activity and elevated IL-1β production, indicating that miR-223 limits cardiovascular lesion development by downmodulating NLRP3 inflammasome activity. Collectively, our data reveal a previously unappreciated role of miR-223 in regulating innate immune responses and in limiting KD vasculitis and its cardiovascular lesions by constraining the NLRP3 inflammasome and the IL-1β pathway. These data also suggest that miR-223 expression may be used as a marker for KD vasculitis pathogenesis and provide a novel therapeutic target.
Xinjie Huang, Sarah Siyin Tan, Yajun Chen, Tian Li
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.657251

Abstract:
Background: Acquired rectourethral (RUF) or rectovaginal fistulas (RVF) in children are rare conditions in pediatric surgery. Prior literature are retrospective studies and based on a small number of patients. The managements and outcomes vary widely across different studies. No standard or recommended management has been universally adopted. The goal was to systematically summarize different causes, provide an overlook of current clinical trend and to derive recommendation from the literature regarding the etiology, managements, and outcomes of pediatric acquired RUF and RVF. Methods: PubMed, Embase, Cochrane databases were searched using terms: rectourethral fistula, recto-urethral fistula, urethrorectal fistula, urethro-rectal fistula, rectovaginal fistula. All studies were retrospective, in English, and included patients under the age of 18 years. Any series with congenital cases, adult (>18 years), <2 fistula cases less and obstetric related causes were excluded. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline was followed. Results: Of the 531 records identified, 26 articles with 163 patients (63 RUF and 100RVF) were fully analyzed. Most RUF resulted from trauma, most RVF were from infection of HIV. About 92 patients underwent 1 of 3 categories of definitive repair, including transanal (4.3%), trans-sphincteric (48.9%), and transperineal (30.4%). Tissue interposition flaps were used in 37.6% patients, while temporary fecal diversions were used in 63.9% patients. Fistula was successfully closed in 50.3% patients (98.4% RUF and 20% RVF). 89.1 and 79.7 % of surgical repair patients had optimal fecal and urinary functions, respectively. In the inflammatory bowel disease and HIV infection related RVF patient group, the closure rate was prohibitive poor. Conclusions: Most RVF are a sign of systematic diseases like HIV-infection or IBD and are associated with poor general conditions. While conservative treatment is recommended, stable patients can benefit from surgery. Further investigation is recommended if RVF are encountered without trauma or surgical history. RUF are likely to result from trauma or surgery, and transperineal or trans-sphincter approach can lead to closure and optimal function results. Fecal diversion and/or urinary diversion are helpful in some cases, while interposition technique may not be necessary. An objective scoring system for long-term follow-up and reporting consensus is needed to address treatment inconsistence.
Xueyu Chen, Junyan Zhong, Dongshan Han, Fang Yao, Jie Zhao, Gerry. T. M. Wagenaar, Chuanzhong Yang,
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.625031

Abstract:
Bronchopulmonary dysplasia (BPD) is a neonatal chronic lung disease characterized by an arrest in alveolar and vascular development. BPD is secondary to lung immaturity, ventilator-induced lung injury, and exposure to hyperoxia in extremely premature infants, leading to a lifelong impairment of lung function. Recent studies indicate that the lung plays an important role in platelet biogenesis. However, the dynamic change of platelet production during lung development and BPD pathogenesis remains to be elucidated. We investigated the dynamic change of platelet parameters in extremely premature infants during BPD development, and in newborn rats during their normal development from birth to adulthood. We further studied the effect of hyperoxia exposure on platelet production and concomitant pulmonary maldevelopment in an experimental BPD rat model induced by prolonged exposure to hyperoxia. We detected a physiological increase in platelet count from birth to 36 weeks postmenstrual age in extremely premature infants, but platelet counts in extremely premature infants who developed BPD were persistently lower than gestational age-matched controls. In line with clinical findings, exposure to hyperoxia significantly decreased the platelet count in neonatal rats. Lung morphometry analysis demonstrated that platelet counts stabilized with the completion of lung alveolarization in rats. Our findings indicate a close association between platelet biogenesis and alveolarization in the developing lung. This phenomenon might explain the reduced platelet count in extremely premature infants with BPD.
Yue Zheng, Zhou Zhang, Ling Hou, Xiuli Wang, Kailei Jiang, Shucheng Zhang, Yue Du
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.646118

Abstract:
Objective: The present study aimed to analyze the risk factors correlated with overactive bladder (OAB), observe the effects of desloratadine in the treatment of OAB, and explore the correlation between OAB and atopic constitution in children. Methods: Correlation and binary logistic regression analysis of the medical data from 447 children clinically diagnosed with OAB from June 2019 to June 2020 were conducted. The data included a history of urticaria, eczema, itchy skin, and allergic rhinitis or allergic cough. The OABSS scores before and after treatment with desloratadine were compared to evaluate the effectiveness of desloratadine for OAB. Results: The risk factors for OAB in children included eczema, allergic rhinitis or allergic cough, itchy skin, and the levels of total blood IgE. Desloratadine was 96.5% effective in treating cases with risk factors including eczema, allergic rhinitis or allergic cough, and itchy skin. There existed statistical significance in the difference in OABSS scores before and after the treatment of desloratadine (P < 0.05). Conclusion: OAB in children was correlated with atopic manifestations such as eczema, itchy skin, allergic rhinitis, or allergic cough. Desloratadine was safe and effective in the treatment of OAB in children with atopic manifestations.
Adem Karbuz, Gulsen Akkoc, Tugba Bedir Demirdag, Dilek Yilmaz Ciftdogan, Arife Ozer, Deniz Cakir, Selda Hancerli Torun, Eda Kepenekli, Tugba Erat, Nazan Dalgic, et al.
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.631547

Abstract:
Objectives: The aim of this study is to identify the epidemiological, clinical, and laboratory features of coronavirus disease 2019 (COVID-19) in children. Methods: A retrospective study was conducted by pediatric infectious disease specialists from 32 different hospitals from all over Turkey by case record forms. Pediatric cases who were diagnosed as COVID-19 between March 16, 2020, and June 15, 2020 were included. Case characteristics including age, sex, dates of disease onset and diagnosis, family, and contact information were recorded. Clinical data, including the duration and severity of symptoms, were also collected. Laboratory parameters like biochemical tests and complete blood count, chest X-ray, and chest computed tomography (CT) were determined. Results: There were 1,156 confirmed pediatric COVID-19 cases. In total, male cases constituted 50.3% (n = 582) and females constituted 49.7% (n = 574). The median age of the confirmed cases was 10.75 years (4.5–14.6). Of the total cases, 90 were younger than 1 year of age (7.8%), 108 were 1–3 years of age (9.3%), 148 were 3–6 years of age (12.8%), 298 were 6–12 years of age (25.8%), 233 were 12–15 years of age (20.2%), and 268 cases were older than 15 years of age (23.2%). The most common symptom of the patients at the first visit was fever (50.4%) (n = 583) for a median of 2 days (IQR: 1–3 days). Fever was median at 38.4°C (38.0–38.7°C). The second most common symptom was cough (n = 543, 46.9%). The other common symptoms were sore throat (n = 143, 12.4%), myalgia (n = 141, 12.2%), dyspnea (n = 118, 10.2%), diarrhea (n = 112, 9.7%), stomachache (n = 71, 6.1%), and nasal discharge (n = 63, 5.4%). When patients were classified according to disease severity, 263 (22.7%) patients were asymptomatic, 668 (57.7%) patients had mild disease, 209 (18.1%) had moderate disease, and 16 (1.5%) cases had severe disease. One hundred and forty-nine (12.9%) cases had underlying diseases among the total cases; 56% of the patients who had severe disease had an underlying condition (p < 0.01). The need for hospitalization did not differ between patients who had an underlying condition and those who do not have (p = 0.38), but the need for intensive care was higher in patients who had an underlying condition (p < 0.01). Forty-seven (31.5%) of the cases having underlying conditions had asthma or lung disease (38 of them had asthma). Conclusions: To the best of our knowledge, this is one of the largest pediatric data about confirmed COVID-19 cases. Children from all ages appear to be susceptible to COVID-19, and there is a significant difference in symptomatology and laboratory findings by means of age distribution.
Tzu-Yu Liu, Jui-Hsing Chang, Chun-Chih Peng, Chyong-Hsin Hsu, Wai-Tim Jim, Jia-Ying Lin, Chia-Huei Chen, Sung-Tse Li, Hung-Yang Chang
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.638449

Abstract:
Purpose: To assess the predictive validity of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive scores at 6 months of corrected age (CA) for cognitive outcomes at 24 months of CA in very-low-birth-weight (VLBW) infants and investigate the predictors of change in cognitive outcomes. Methods: We retrospectively evaluated VLBW children enrolled in the Taiwan Premature Infant Follow-up Network between 2010 and 2015 and completed the Bayley-III at CA of 6 and 24 months. The predictive validity of the cognitive performance at 6-month CA for the cognitive outcomes at 24-month CA was analyzed. The positive and negative predictive factors were also evaluated using logistic regression. Cut-off scores of <70 and <85 were used to identify lower functioning groups based on the Bayley-III definition. Results: A total of 2,972 VLBW children, born with a mean weight of 1116.4 ± 257.5 g and mean gestational age of 29.0 ± 2.8 weeks, were evaluated. A cognitive score of <70 at 6-month CA had a positive predictive value (PPV) of 27.4% (95% confidence interval [CI]: 19.2–35.7%) for a cognitive score of <70 at 24-month CA, while the negative predictive value (NPV) was 97.3% (95% CI: 96.7–97.9%). A cut-off score of 85 had a PPV of 33.6% (95% CI: 28.1–39.0%) and an NPV of 87.7% (95% CI: 86.4–88.9%). Abnormal muscle tone at 6 months was a risk factor for cognitive function decline at 24 months for both Bayley-III cognitive cut-off scores: scores of 70 (adjusted odds ratio [AOR]: 2.8; 95% CI: 1.5–5.5) and 85 (AOR: 2.6; 95% CI: 1.6–4.1). Lower maternal socioeconomic status was associated with a worsening of the cognitive function in infants at 24 months who scored ≥85 at 6 months (AOR: 1.6; 95% CI: 1.2–2.0). Conclusion: Subnormal Bayley-III cognitive scores at 6-month CA were not predictive of subnormal cognitive function at 24-month CA. In children with normal cognition during early infancy, abnormal muscle tone and lower maternal socioeconomic status may influence the cognitive developing process; this highlighted the importance of early identification of high risk infants and complete preterm infant-associated public health policies to promote an improved neurodevelopmental outcome.
Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo,
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.641397

Abstract:
Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown. Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility. Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them. Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.
Teiji Sawa, Atsushi Kainuma, Koichi Akiyama, Mao Kinoshita, Masayuki Shibasaki
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.654291

Abstract:
Difficult airway management (DAM) in neonates and infants requires anesthesiologists and critical care clinicians to respond rapidly with appropriate evaluation of specific situations. Therefore, organizing information regarding DAM devices and device-oriented guidance for neonate and infant DAM treatment will help practitioners select the safest and most effective strategy. Based on DAM device information and reported literature, there are three modern options for DAM in neonates and infants that can be selected according to the anatomical difficulty and device-oriented strategy: (1) video laryngoscope (VLS), (2) supraglottic airway device (SAD), and (3) flexible fiberoptic scope (FOS). Some VLSs are equipped with small blades for infants. Advanced SADs have small sizes for infants, and some effectively function as conduits for endotracheal intubation. The smallest FOS has an outer diameter of 2.2 mm and enables intubation with endotracheal tubes with an inner diameter of 3.0 mm. DAM in neonates and infants can be improved by effectively selecting the appropriate device combination and ensuring that available providers have the necessary skills.
Chih-Ching Chang, Yi-Chen Lin, Tzu-Chun Chen, Jainn-Jim Lin, Shao-Hsuan Hsia, Oi-Wa Chan, En-Pei Lee
Frontiers in Pediatrics, Volume 9; doi:10.3389/fped.2021.664180

Abstract:
Aim: High-flow nasal cannulas (HFNCs) show potential in the application of positive pressure, improving gas exchange, and decreasing work of breathing in patients with acute respiratory distress. The aims of this study were to elucidate the indications for HFNC therapy in children of all ages and diagnoses, and to evaluate the efficacy and risk factors for failure of HFNC therapy in children with acute respiratory distress with hypoxia in a pediatric intensive care unit. Methods: We conducted this retrospective cohort study at a tertiary pediatric intensive care unit between January 1, 2018 and December 31, 2020. All children, from 1 month to 18 years of age, with acute respiratory distress with hypoxia and HFNC therapy were eligible. The clinical data were reviewed. Results: One hundred and two children met the eligibility criteria for the study, of whom 57 (55.9%) were male, and the mean age was 7.00 ± 6.79 years. Seventy-eight (76.5%) of the children had underlying disorders. The most common indications for the use of HFNC therapy were pneumonia (40, 39.2%), sepsis-related respiratory distress (17, 16.7%), and bronchiolitis (16, 15.7%). The failure rate was 15.7% (16 of 102 children). Higher initial and maximum fraction of inspiration O2 levels and lower initial and lowest SpO2/FiO2 (S/F) ratio were early and possible signs of failure requiring escalation of respiratory support. Conclusion: In our population, we found that HFNC therapy could be initiated as the first-line therapy for various etiologies of acute respiratory distress with hypoxia in a pediatric intensive care unit and for all age groups.
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