European Journal of Pediatrics

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Online ISSN: 1432-1076
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Flowchart of the study population
Prevalence of functional gastrointestinal disorders (FGIDs) in the study population according to umbilical artery (UA) pH. Prevalence is expressed as percentage
Functional gastrointestinal disorders (FGIDs) are common in early childhood. It has been demonstrated that neonatal acidemia at delivery can lead to significant neonatal morbidity. The primary aim of this study was to evaluate the relationship between acidemia at birth and the development of FGIDs, as regurgitation, colic, and constipation, in term infants. Term newborns born at the Foggia University Hospital, Italy during the year 2020 were included in the study. As per routine clinical practice, a cord blood gas analysis on a blood sample drawn from the umbilical artery (UA) of each infant immediately after birth was performed, and Apgar score was recorded. One year after birth, each infant’s parents were interviewed through a phone call to investigate development of FGIDs, feeding practices, and morbidities. During the study period, 1574 term newborns met the inclusion criteria. The prevalence of infantile colic, regurgitation, and constipation was higher in infants with low UA pH (colic 51.5% vs. 25.4%, p < 0.001; regurgitation 30.6% vs. 15.2%, p < 0.001; constipation 24.6% vs. 16.0%, p = 0.015), with infants having moderate-severe acidemia facing the highest risk for all the examined FGIDs. In binary logistic regression analyses, UA pH and perinatal antibiotic exposure proved to be independently associated with the later diagnosis of each FGID. Conclusion : Newborns with acidemia at birth appear to face a higher risk of FGIDs in infancy. Avoiding low cord blood pH should continue to be the goal for obstetricians, while enhanced long-term surveillance for infants who experienced birth acidemia should be required. What is Known: • Cord blood gas analysis is recommended in all high-risk deliveries, and in some centers, it is performed after all deliveries. • Neonatal acidemia at birth has been linked to adverse outcomes, mainly neurological. Recently, perinatal asphyxia has been reported to increase the risk of developing necrotizing enterocolitis in term infants. What is New: • An association between acidemia at birth and risk of developing FGIDs such as regurgitation and colic during the first year of life had never been described so far. • An increased surveillance of infants with low UA pH at birth may be beneficial and could allow for early detection of any of the reported FGIDs.
This study aims to assess the identification rates in a developmental monitoring system (i.e., preventive child healthcare, PCH system) regarding identification of emotional, behavioral (EB) problems, cognitive developmental and family problems in children, and the contribution of such a system to referral to (specialized) mental health and social care services. Over a predetermined period of 6 months, we retrieved data from a random sample of 1370 children aged 0 to 18 years from the registries of two PCH organizations in the Netherlands. We assessed the degree to which PCH professionals identify EB and cognitive developmental and family problems and invite children with these problems for follow-up PCH assessments or refer them to (specialized) mental health and social care services. Among preschool-aged children, we identified 22% with EB problems, cognitive developmental and/or family problems (mainly EB and family problems). Among school-aged children, numbers varied from 10 to 14% (mainly EB). PCH invited 3 to 10%, varying in proportions of child age, for a follow-up assessment, and referred 0 to 4% of the children to external services. Conclusion: A developmental monitoring system with only preventive tasks may help to identify children with EB, cognitive developmental, and/or family problems. This can lead to early support for most of these children, with low referral rates to (more specialized) mental health and social care services. Our findings deserve validation in comparable settings and in other countries.What is Known: • Well-child care requires monitoring of the health and development of children for timely identification of problems and subsequent intervention. • The Dutch Preventive Child Healthcare system is an example of a developmental monitoring system with only preventive tasks. What is New: • A developmental monitoring system with only preventive tasks may help to identify children with problems, resulting in early support for the majority. • This may reduce referral rates to (more specialized) mental/social health services.
Flow chart of patient inclusions. EEAE: early empiric antibiotic exposure; GA: gestational age; h: hours
Stacked bar chart of incidence of (A) NEC and (B) LOS in the first 28 days of life, by EEAE category. EEAE, early empiric antibiotic exposure; LOS, late-onset sepsis, NEC, necrotizing enterocolitis
The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics’ effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19–0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35–0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85–0.97]; p = 0.003). Conclusion : Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. What is Known: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. What is New: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.
This observational study aimed to investigate whether predischarge cerebral oxygenation (CrSO 2 ), monitored by near-infrared spectroscopy, correlates with later psychomotor outcome in very preterm infants. Infants <32 weeks’ gestation or <1500 g without evidence of major brain lesions underwent a 3-h continuous CrSO 2 monitoring before hospital discharge. Psychomotor development was assessed at 6, 12, 18, and 24 months using the Griffiths Mental Developmental Scales. The developmental quotients (DQ) at each follow-up appointment were correlated with predischarge CrSO 2 . Significant correlations were adjusted for possible confounders. Sixty-three infants were enrolled. A significant correlation between CrSO 2 and DQ was observed at 6 months ca ( p =0.010), but not at later psychomotor assessments. This correlation was confirmed significant ( b =0.274, p =0.038) even after the adjustment for relevant covariates. Conclusion : According to these preliminary findings, the association between predischarge CrSO 2 and psychomotor development over the first 24 months in preterm infants without major brain lesions is time-limited. Hence, this parameter may not represent an effective predictor for medium-term neurodevelopment. What is Known: • Prematurity is a major risk factor for adverse neurodevelopment. • The validation of clinical tools for psychomotor outcome prediction may aid to identify high-risk preterm infants who might benefit from early interventions. What is New: • In infants without major brain lesions, predischarge CrSO 2 correlates with psychomotor outcome at 6 months ca but not later, indicating a short time predictability.
The most effective dosage of intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities (CAAs) in patients with acute Kawasaki disease (KD) remains unknown. This study aimed to identify the appropriate dose of IVIG to be administered to patients with acute KD, using a national inpatient database in Japan. We used the Diagnostic Procedure Combination database to identify KD patients treated with IVIG between 2010 and 2020. The primary outcome was the proportion of CAAs upon discharge. Secondary outcomes included IVIG resistance, length of stay, and medical costs. Data from 88,223 patients were extracted from the database. We found a U-shaped association between IVIG dose and the proportion of CAA, with the bottom of the curve at approximately 2.0 g/kg; the odds ratio (95% confidence interval [CI]) was 1.34 (1.26–1.43) for 1.8 g/kg and 1.80 (1.29–2.51) for 2.4 g/kg with reference to 2.0 g/kg for CAA. Similarly, IVIG dose had a U-shaped association with the proportion of IVIG resistance, with the bottom of the curve at approximately 2.0 g/kg; the odds ratio (95% CI) was 1.39 (1.36–1.42) for 1.8 g/kg and 8.95 (8.15–9.83) for 2.4 g/kg with reference to 2.0 g/kg for IVIG resistance. Additionally, IVIG dosage was found to have U-shaped associations with the length of stay and medical costs, with the bottom of the curve at approximately 2 g/kg. Conclusions: IVIG with a dose of 2 g/kg was considered appropriate for the initial treatment of KD. What is Known: • For treatments of acute Kawasaki Disease (KD), IVIG has been the most recommended to reduce fever early and prevent complications of CAAs. Few studies have shown the most effective dosage of IVIG to be administered to prevent CAAs. What is New: • 2 g/kg intravenous immunoglobulin was considered appropriate for the initial treatment of Kawasaki disease.
The asthma score (by Qureshi)
Flowchart inclusion
The median asthma score during PICU admission the first 24 h (Y-axis: median asthma score (5–15), X-axis: time in hours after PICU admission)
The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children’s hospitals included children (2–18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10–13) in the intervention group and 11 (9–12) in the control group ( p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups ( p = 0.508, β-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 μg/L (IQR 5–24) in the intervention group and 4 μg/L (IQR 0–7) in the control group ( p = 0.001). Side effects were comparable between both groups. Conclusion : We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. What is Known: • Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled β2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. What is New: • This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.
Study population
Comparison of distributions of ages of onset of steroid-resistant nephrotic syndrome between carriers of the NPHS2 p.V260E, INF2 p.P516L and other (CD2AP p.K633R and TRPC6 p.G162V) variants. Distribution of age of onset was significant in NPHS2 p.V260E vs. heterozygote autosomal dominant mutations (p = 0.03) and NPHS2 p.V260E vs. no mutations detected (p = 0.008). The p value was calculated using one-way analysis of variance. Horizontal bars indicate mean and SEM. AD, autosomal dominant; AR, autosomal resistant; Het, heterozygous; Hom, homozygous
There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6. Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility.
Flowchart depicting enrollment of the participants in the study. MSAF meconium-stained amniotic fluid
We aimed to evaluate the association between meconium-stained amniotic fluid during labor and offspring’s childhood wheezing. This study analyzed the data of participants enrolled in the Japan Environment and Children’s Study, a nationwide prospective birth cohort study, between 2011 and 2014. Data of women with singleton live births between 22 and 40 weeks’ gestation were analyzed. Participants were categorized into two groups according to the presence or absence of meconium-stained amniotic fluid. The primary outcome measure was the offspring’s childhood wheezing up to 3 years of age. A logistic regression model was used to calculate the adjusted odds ratio for childhood wheezing in children of women with meconium-stained amniotic fluid, considering those without meconium-stained amniotic fluid as a reference, taking into account the potential confounding factors affecting the incidence of wheezing. We analyzed data from 61,991 participants: 1796 (2.9%) participants had meconium-stained amniotic fluid during labor and 18,919 (30.5%) of the offspring had childhood wheezing. The adjusted odds ratios for the offspring’s childhood wheezing were 0.89 (95% confidence interval, 0.79–0.99) in total participants, 0.87 (95% confidence interval, 0.78–0.97) in term births, and 2.00 (95% confidence interval, 0.98–4.09) in preterm births. Conclusions: This study revealed a decreased incidence of childhood wheezing among the children of women with meconium-stained amniotic fluid in term births. By yet unknown mechanisms, meconium-stained amniotic fluid was associated with a decreased incidence of childhood wheezing in the offspring. Further studies are required to clarify the mechanism of one’s own meconium in affecting their health condition.What is Known: • Meconium-stained amniotic fluid during labor is associated with several adverse perinatal outcomes, and meconium aspiration syndrome is associated with offspring’s childhood asthma and wheezing. • Meconium-stained amniotic fluid during labor could be an independent protective factor for the offspring’s dermatitis and skin rash. What is New: • Whole cases with meconium-stained amniotic fluid during labor were associated with a decreased incidence of offspring’s childhood wheezing up to 3 years of age. • This study may shed light on the effects of simple meconium-stained amniotic fluid on offspring’s childhood health.
Diagram of included and excluded patients
The purpose of this study is to assess whether duration and size of the arterial duct were associated with severe respiratory morbidity and mortality in preterm infants. All echocardiography evaluations for patent ductus arteriosus (PDA) in a cohort of preterm infants, born at a gestational age less than 28 weeks, from birth up to 36 weeks of postconceptional age or final ductal closure were reviewed. Ductal size was measured at the pulmonary end. PDA was classified as small (E1: ductal diameter (DD) ≤ 1.5 mm), moderate (E2: 1.5 mm < DD ≤ 2.5 mm), or large (E3) (DD > 2.5 mm). The primary outcome was adverse outcome defined by the composite outcome of bronchopulmonary dysplasia (BPD) or death. Infants in whom the primary outcome occurred were classified as “high-risk” whereas patients who did not satisfy this outcome were classified as “low-risk”. Intergroup comparison (high vs. low risk) was performed using univariate and multivariate analyses. A total of 135 infants, born between 2010 and 2020, were evaluated. The primary outcome was satisfied in 46 (34.1%) patients. The high-risk group was characterized by increased duration of exposure to PDA of any (E1/E2/E3) grade (44 vs. 25.5 days, p = .0004), moderate or large (E2/E3) PDA (30.5 vs. 11.5 days, p < .0001), moderate (E2) PDA (10.8 vs.6 days, p = 0.05), and large (E3) PDA (11.5 vs.0 days, p < .0001) compared with low-risk group. Lower gestational age, prolonged duration of mechanical ventilation, higher rate of inotrope use, pharmacological therapy, and PDA ligation were also associated with development of BPD or death (high-risk group). After adjusting for confounders, the rate of inotrope use [OR 2.688, 95% CI (1.011–7.142), p = 0.047], duration of large (E3) PDA [OR 1.060, 95% CI (1.005–1.118), p = 0.03], and mechanical ventilation [OR 1.130, 95% CI (1.064–1.200), p = 0.0001] were independently associated with the composite of BPD or death. Among infants who developed BPD, 27 were classified as grade I and 18 as grade II BPD, respectively. Infants with grade II BPD had prolonged MV (20.0 vs. 9.0 days, p = 0.024), prolonged exposure to PDA of any grade (55.8 vs. 36.0 days, p = 0.03), and prolonged exposure to large (E3) PDA compared with infants with grade I BPD. Conclusion : Prolonged exposure to a large PDA was associated with severe respiratory morbidity and mortality in preterm infants. The modulator role of early intervention, in the most pathologic shunts, on severe respiratory morbidity in preterm infants should be tested in well-designed clinical trials. What is Known: • Current guidelines recommended against accelerating PDA closure of preterm infants within 2 weeks of life, with low certainty evidence indicating improved long-term outcomes. • Recent studies suggest that conservative approach regarding PDA management has detrimental effects on the respiratory outcomes in a subgroup population. What is New: • Persistent patency of significant PDA is associated with increased risk of BPD/death in extremely preterm infants. • Targeted intervention of PDA is beneficial for the at-risk preterm infants with increased PDA hemodynamic significance.
Hierarchical clustering phylogenetic dendrogram
Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants’ parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., <70). Significant correlations were found ( p <0.005) between SSP-S scores and the conceptual, social, practical, and GAC index of the ABAS-II, whereby higher SSP-S scores were associated with better skills and higher adaptive performance. The cluster analysis indicated that the group with the largest mutation size (7.23 Mb) showed the greatest sensory processing difficulties and very low adaptive skills. Conclusions : Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors. What is Known: • PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity. • Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors. What is New: • Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3 deletion patients. • Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills.
To compare patterns of sedentary (SED) time (more sedentary, SED + vs less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA + vs less active, MVPA-), and combinations of behaviors (SED-/MVPA + , SED-/MVPA-, SED + /MVPA + , SED + /MVPA-) regarding nonalcoholic fatty liver diseases (NAFLD) markers. This cross-sectional study included 134 subjects (13.4 ± 2.2 years, body mass index (BMI) 98.9 ± 0.7 percentile, 48.5% females) who underwent 24-h/7-day accelerometry, anthropometric, and biochemical markers (alanine aminotransferase (ALT) as first criterion, and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), AST/ALT ratio as secondary criteria). A subgroup of 39 patients underwent magnetic resonance imaging-liver fat content (MRI-LFC). Hepatic health was better in SED- (lower ALT, GGT, and MRI-LFC (p < 0.05), higher AST/ALT (p < 0.01)) vs SED + and in MVPA + (lower ALT (p < 0.05), higher AST/ALT (p < 0.01)) vs MVPA- groups after adjustment for age, gender, and Tanner stages. SED-/MVPA + group had the best hepatic health. SED-/MVPA- group had lower ALT and GGT and higher AST/ALT (p < 0.05) in comparison with SED + /MVPA + group independently of BMI. SED time was positively associated with biochemical (high ALT, low AST/ALT ratio) and imaging (high MRI-LFC) markers independently of MVPA. MVPA time was associated with biochemical markers (low ALT, high AST/ALT) but these associations were no longer significant after adjustment for SED time. Conclusion: Lower SED time is associated with better hepatic health independently of MVPA. Reducing SED time might be a first step in the management of pediatric obesity NAFLD when increasing MVPA is not possible. What is Known: • MVPA and SED times are associated with cardiometabolic risks in youths with obesity. • The relationships between NAFLD markers and concomitant MVPA and SED times have not been studied in this population. What is New: • Low SED time is associated with healthier liver enzyme profiles and LFC independent of MVPA. • While low SED/high MVPA is the more desirable pattern, low SED/low MVPA pattern would have healthier liver enzyme profile compared with high MVPA/high SED, independent of BMI, suggesting that reducing SED time irrespective of MVPA is needed to optimize liver health.
Study flow chart
The purpose of the study is to investigate the effects of delayed cord clamping on bilirubin levels and phototherapy rates in neonates of diabetic mothers. This was a prospective study that enrolled pregnant women without pregnancy complications and those with diabetes. Their neonates were randomized in a 1:1 ratio to delayed cord clamping. The main outcomes were the neonatal transcutaneous bilirubin values on 2–4 days postpartum and the rate of requiring phototherapy in infants. A total of 261 pregnant women were included in the final analysis (132 women with diabetic pregnancies and 129 women with normal pregnancies). In diabetic pregnancies, neonatal bilirubin levels on the 2–4 days postpartum and phototherapy rates were significantly higher in the delayed cord clamping group than in the immediate cord clamping group (7.65 ± 1.83 vs 8.25 ± 1.96, P = 0.039; 10.35 ± 2.23 vs 11.54 ± 2.56, P = 0.002; 11.54 ± 2.94 vs 12.83 ± 3.07 P = 0.024, 18.2% vs 6.3%, P = 0.042), while in normal pregnancies, there was no statistical difference in bilirubin values and phototherapy rates between the delayed cord clamping group and the immediate cord clamping group (P > 0.05). After receiving delayed cord clamping, bilirubin levels on the third postnatal day and the rate of requiring phototherapy in infants were higher in the diabetic pregnancy group than in the normal pregnancy group (10.35 ± 2.23 vs 11.54 ± 2.56, P = 0.013). Conclusion: Delayed cord clamping increased the risk of jaundice in newborns born to diabetic mothers, but had no effect in newborns from mothers with normal pregnancies. DCC may be a risk factor for increased bilirubin in infants of diabetic mothers. Trial registration: NCT04369313; date of registration: April 27, 2020 (retrospectively registered).What is Known: • Delayed cord clamping had significant benefits for newborns by increasing neonatal hemoglobin levels and reducing the risk of neonatal anemia, etc. • Delayed cord clamping may lead to neonatal hyperemia, erythrocytosis, and hyperbilirubinemia, which increases the risk of neonatal jaundice. What is New: • Our trial focused on the differential effects of delayed cord clamping on jaundice in full-term newborns between diabetic pregnancies and normal pregnancies. And newborns of diabetic mothers who received delayed cord clamping had a significantly increased risk of jaundice compared to newborns with normal pregnancy. • Delayed cord clamping may be a risk factor for increased bilirubin levels in neonates of diabetic mothers.
Distribution of time intervals between first and second seizures among children with recurrent febrile seizures during the same febrile episode and time-lapse analysis
The purpose of this study is to elucidate risk factors for central nervous system infection and early seizure recurrence in children with febrile seizures (FSs) and thus facilitate outpatient management of complex FS. This single-center, retrospective cohort study investigated 688 children (6–60 months old) with FSs in Japan during 2011–2021. We investigated the incidence and clinical manifestations of children with acute encephalitis or bacterial meningitis. Logistic regression modeling was used to examine risk factors for seizure recurrence within 24 h. Among children with recurrent FSs, the distribution of intervals between first and second FS was assessed. Among 145 children with complex FSs, 2 patients (1.4%) had acute viral encephalitis and none had bacterial meningitis. Acute encephalitis was found in 2 of 8 patients (25%) with FSs prolonged ≥30 min and 2 of 3 patients (67%) requiring ≥2 intravenous anticonvulsants to stop seizures. Seizure recurrence within 24 h was observed in 16% of participants and was independently associated with preceding use of diazepam and family history of FS. In 82% of patients with FS recurrence within 24 h, early recurrences occurred within 8 h of the first seizure. Conclusion: Patients with prolonged or refractory FSs are still indicated for hospital admission due to the risk of acute encephalitis. FS patients with a family history of FS may be managed safely by 8-h observation or single-dose rectal diazepam as prophylaxis against early recurrent seizure.What is Known: • Hospitalization has been recommended for children with complex febrile seizures due to the increased risk of central nervous infections. • Recent studies showed low incidences of bacterial meningitis (<1%) in children with complex febrile seizures in the presence of routine immunization. What is New: • Acute encephalitis was identified in 1.4% of children with complex febrile seizures, characterized by prolonged seizures ≥30 min and refractory seizures. • Early recurrent seizures may be safely managed by prophylactic diazepam or 8-h expectant observation.
The exact immunological mechanisms of post infectious bronchiolitis obliterans (PIBO) in childhood are not fully known. It has been shown that the inflammasome and IL-18 pathway play important roles in the pathogenesis of lung fibrosis. We aimed to investigate the role of caspase-1, IL-18, and IL-18 components in PIBO. From January to May 2020, children with PIBO, children with history of influenza infection without PIBO, and healthy children were asked to participate in the study in three pediatric pulmonology centers. Serum caspase-1, IL-18, IL-18BP, IL-18R, and INF-γ levels were measured by ELISA and compared between the 3 groups. There were 21 children in the PIBO group, 16 children in the influenza group, and 39 children in the healthy control group. No differences in terms of age and gender between the 3 groups were found. IL-18 and IL-18BP levels were higher in the healthy control group (p = 0.018, p = 0.005, respectively). IL-18R was higher in the PIBO group (p = 0.001) and caspase-1 was higher in the PIBO and influenza group than the healthy control group (p = 0.002). IFN-γ levels did not differ between the 3 groups. IL-18BP/IL-18 was higher in the influenza group than the PIBO group and the healthy control group (p = 0.003). Conclusions: Caspase-1 level was increased in patients with PIBO which suggests that inflammasome activation may have a role in fibrosis; however, IL-18 level was found to be low. Mediators other than IL-18 may be involved in the inflammatory pathway in PIBO. Further immunological studies investigating inflammasome pathway are needed for PIBO with chronic inflammation. What is Known: • Post infectious bronchiolitis obliterans (PIBO) is a rare, severe chronic lung disease during childhood which is associated with inflammation and fibrosis which lead to partial or complete luminal obstruction especially in small airways. • The exact immunological mechanisms of PIBO in childhood are not fully known. What is New: • Inflammasome activation persists even years after acute infection and may play a role in fibrosis in PIBO. • Mediators other than IL-18 may be involved in these inflammatory pathway.
LUS variation during neonatal transfer. Panels A and B represent the whole data with summary measures and the individual case variation, respectively. Horizontal lines and T-bars in panel A represent means and standard deviations, respectively. Connecting lines in panel B indicate the individual case variation. Timepoints are indicated as follows: T1: before transportation (i.e., in the “spoke” hospital), T2: during transportation, T3: after transportation (i.e., at the arrival to the NICU in “hub” hospital). LUS has been calculated by one operator (the attending neonatologist leading the transportation team) for T1 and T2 and by another (the attending or fellow neonatologist in the “hub” NICU). The two operators were blinded to each other’s results. LUS is a dimensionless variable. Abbreviations: LUS, lung ultrasound score; NICU, neonatal intensive care unit
Receiver operator characteristics analysis of LUS calculated during neonatal transfer to predict surfactant need. Timepoints are indicated as follows: T1 (full curve): before transportation (i.e., in the “spoke” hospital), T2 (bold hatched curve): during transportation, T3 (light hatched curve): after transportation (i.e., at the arrival to the NICU in “hub” hospital). Area under the curves is not significantly different overtime (T1 vs T2: p = 0.486; T1 vs T3: p = 0.577; T2 vs T3: p = 0.945). Diagonal line represents an area under the curve of 0.5. Abbreviations: LUS, lung ultrasound score
LUS calculated during patient transfer (dots) and upon arrival in the NICU at the tertiary referral center (triangles). Horizontal bars represent mean and standard deviation. The two LUS have been calculated by different operators blinded to each other’s results (see text for more details). LUS is a dimensionless variable. Abbreviations: LUS, lung ultrasound score; NICU, neonatal intensive care unit
Relationship between LUS calculated during transportation and upon NICU admission in the tertiary referral center. Panels A and B show the correlation and the Bland–Altman graph, respectively. In panel A, black and dotted lines represent correlation lines and 95% confidence interval, respectively. In panel B, the Y and X axes represent the difference (delta) between LUS at T1 and T3 and their mean, respectively; the line represents the best fitting data curve plotted with local regression (smoother) method. The two LUS have been calculated by different operators blinded to each other’s results (see text for more details). LUS is a dimensionless variable. Abbreviations: LUS, lung ultrasound score; NICU, neonatal intensive care unit
Lung ultrasound score (LUS) is increasingly diffused in neonatal critical care but scanty data are available about its use during transfer of severely ill neonates. We aimed to clarify the effect of ground transportation on LUS evolution, conformity of interpretation, and relationships with oxygenation and clinical severity. This is a single-center, blinded, observational, cross-sectional study. Neonates of any gestational age with respiratory distress appearing within 24 h from birth were transferred by a mobile unit towards neonatal intensive care unit (NICU) of a tertiary referral center. Calculation of LUS prior to the transportation (T1), in the mobile unit (T2), at the end of transportation (T3), and finally upon NICU admission. LUS in the mobile unit and in the NICU was performed by different physicians blinded to each other’s results. LUS did not change overtime (T1: 6.3 (3.5), T2: 6.1 (3.5), T3: 5.8 (3.4); p = 0.479; adjusted for gestational or postnatal age or transport duration: p = 0.951, p = 0.424, and 0.266, respectively) but reliably predicted surfactant need (AUC at T1: 0.833 (95%CI: 0.72–0.92); AUC at T2: 0.82 (95%CI: 0.70–0.91); AUC at T3: 0.82 (95%CI: 0.70–0.90); p always < 0.0001). There were significant agreement (ICC = 0.912 (95%CI: 0.83–0.95); p < 0.001) and correlation (r = 0.905, p < 0.001) between LUS calculated during transportation and in the NICU. LUS during transportation was also significantly correlated with oxygenation index (r = 0.321, p = 0.026; standardized B = 0.397 (95%CI: 0.03–0.76), p = 0.048) and TRIPS-II score (r = 0.302, p = 0.008; standardized B = 0.568 (95%CI: 0.04–1.1), p = 0.037). Conclusion: LUS during ground transportation of neonates with respiratory failure is suitable and not influenced by the transportation itself. It has a high agreement with that calculated in the NICU and correlates with patients’ oxygenation and severity.What is Known: • Lung ultrasound is a part of the point-of-care ultrasound, which is becoming an essential tool, to manage critically ill neonates and children in an accurate, non-invasive and quick way. What is New: • Lung ultrasound score (LUS) is suitable during transportation of critically ill neonates with respiratory failure and is not influenced by the transportation itself. • LUS has a high agreement with that calculated in the NICU and correlates with patients’ oxygenation and severity of respiratory failure.
Pictures of the Bilicocoon® Bag device
Algorithm for the management of neonatal jaundice in hospital at home
Neonatal jaundice is common and associated with delay in hospital discharge and risk of neurological sequelae if not treated. The objectives of the study were to report on our experience of the monitoring and treatment of neonatal jaundice in a home care setting and its feasibility and safety for neonates with high risk of severe hyperbilirubinemia. The 2-year study has been led in the greater Paris University Hospital At Home (Assistance Publique—Hôpitaux de Paris). The device of the intervention was the Bilicocoon® Bag, a light-emitting diode sleeping bag worn by the neonate when the total serum bilirubin value exceeds intensive phototherapy threshold, according to the guidelines from the American Academy of Pediatrics. One hundred and thirty-nine neonates had participated in the intervention and 39 (28%) were treated by phototherapy at home, as continuation of inpatient phototherapy or started at home. Seventy-five percent of the sample had more than two risk factors for development of severe hyperbilirubinemia. Twenty five percent of the cohort who received phototherapy at home had lower gestational age (p < 0.014) and had younger age at discharge from maternity (p < 0.09). Median length of stay in hospital at home was 5 days. Two patients needed readmission in conventional hospital (1%) for less than 24 h. In multivariate model, the length of stay decreased with the higher gestational age (p < 0.001) and increased significantly with the older age at discharge, the birth weight < 10th percentile, and a treatment by phototherapy at home. Conclusion: Hospital at home, which is a whole strategy using an effective and convenient phototherapy device combined with a specialized medical follow-up, could be an alternative to conventional hospitalization for neonates at high risk of severe jaundice. The maternity discharge is facilitated, the mother-infant bonding can be promoted, and the risk of conventional rehospitalization is minimal, while guaranteeing the safety of this specific care.What is Known: •Managing neonatal jaundice is provided in conventional hospital with phototherapy. • Neonatal jaundice increases the risk of prolonged hospitalization or readmission. What is New: •Phototherapy is feasible in hospital at home for neonates with high risk of severe hyperbilirubinemia. • The care pathway of neonates from conventional hospital to hospital at home is described.
Frequency of each component of the neuroendocrine cell hyperplasia of infancy (NEHI) clinical score [5] in the French pediatric cohort of 54 NEHI or NEHI syndrome patients
Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%). Conclusion: This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs.What is Known: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy. What is New: •In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.
Flow diagram of conventionally treated patients of the TISKids study. Three patients who were treated with CS, completed induction treatment with CS but started IFX as treatment escalation while tapering prednisolone. EEN, exclusive enteral nutrition; CS, corticosteroids
A Kaplan-Meier estimates of the time to treatment escalation after start of therapy. Any additional CD-related therapy or surgery during the 52 weeks was considered treatment escalation. B Proportion of patients receiving each treatment option from 6 weeks onwards, depicted per treatment group. EEN, exclusive enteral nutrition; CS, corticosteroids’; IFX, infliximab; AZA, azathioprine
To induce remission in luminal paediatric Crohn’s disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the “TISKids” study assigned to the conventional treatment arm. Patients were aged 3–17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI) > 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score < 3 without treatment escalation at week 10. Secondary outcomes included proportion of patients without treatment escalation at week 52. In total, 27/47 patients received EEN and 20/47 corticosteroids. At baseline, patient demographics and several inflammation parameters were similar between the two treatment groups. At 10 weeks, clinical remission rates were 7/23 (30%) for EEN and 7/19 (37%) for corticosteroids ( p = 0.661). Twenty-nine of 47 consented to endoscopy at 10 weeks, showing endoscopic remission rates without treatment escalation in 2/16 (13%) of EEN-treated patients and in 1/13 (8%) of corticosteroid-treated patients ( p = 1.00). At week 52, 23/27 (85%) EEN-treated patients received treatment escalation (median 14 weeks) and 13/20 (65%) corticosteroid-treated patients (median 27 weeks), p = 0.070. Conclusion : In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10. Trial registration number : NCT02517684 What is Known: • Endoscopic remission is associated with a low risk of disease progression. • FL-IFX was superior to conventional treatment in achieving and maintaining remission in paediatric patients with moderate-to-severe CD the first year from diagnosis. What is New: • In children with newly diagnosed moderate-to-severe CD, clinical remission rates and endoscopic remission rates without treatment escalation at week 10 were 30% and 13% after EEN and 37% and 8% after corticosteroid induction treatment. • The current treatment target was often not achieved by either EEN or corticosteroid induction treatment after bridging to azathioprine.
Picture of a TGDC infection (left side) and the aspect with cutaneous fistula (right side)
Multivariate analysis of the risk factors for recurrence (age, cutaneous fistula, and TGDC infection) using the Cox model to calculate the Hazard Ratio (HR)
Kaplan–Meier survival curve of the risk of postoperative recurrence in patients with and without preoperative cutaneous fistula
The aim of this study is to investigate the risk factors for recurrence after thyroglossal duct cyst (TGDC) surgery, differentiating between infections with and without a cutaneous fistula. This is a retrospective analysis of all paediatric TGDC in a tertiary care centre with at least 2 years of postoperative follow-up. One hundred and thirty-one patients met the inclusion criteria of the study. A multivariate analysis was performed to analyse the main risk factors for recurrence (presence of a fistula, infection, age). 116/131 patients were managed primarily in our institution; 15 patients had previously been operated on in another centre. The recurrence rate was 4.3% (5/116) when the patient was operated on in our institution at the first operation, and overall, recurrence of TGDC occurred in 20/131 (15.3%) patients. Age was not a risk factor for recurrence (p = 0.596). Two or more episodes of preoperative TGDC infection were a statistically significant risk factor in univariate analysis (p = 0.021) but not in multivariate analysis adjusted for age and the presence of a cutaneous fistula (p = 0.385). In multivariate analysis, cutaneous fistula formation was an independent risk factor for recurrence when adjusted for age and preoperative TGDC infection (Hazard ratio = 5.35; p = 0.011). Conclusions: A preoperative cutaneous fistula was a critical and independent risk factor for recurrence of operated TGDC, whereas age and TGDC infection were not identified as risk factors for recurrence after surgery. This information should be given to patients and parents before surgery. What is Known: • The risk factors for recurrence after thyroglossal duct cyst surgery described in the literature are preoperative infection and young age, but this is not supported by strong evidence. • The role of cutaneous fistula formation is unclear. What is New: • The main risk factor for recurrence of TGDC is the presence of a preoperative cutaneous fistula, with an estimated hazard ratio of 4.95 (p = 0.016) in multivariate analysis. • The presence of two preoperative infections was also associated with a greater risk of recurrence in univariate analysis; age and gender were not associated with an increased risk of recurrence.
Study population flowchart
In this cross-sectional study, conducted in a cohort of infants with a gestational age of < 32 weeks, we aimed to evaluate and compare resting energy expenditure (REE) and body composition between infants who developed bronchopulmonary dysplasia (BPD) and those who did not. REE and body composition were assessed at term equivalent age using indirect calorimetry and air displacement plethysmography. Anthropometric measurements (weight, head circumference, and length) were obtained and transformed into Z-scores per the Fenton (2013) growth curve, at birth and at term equivalent age. Forty-two infants were included in this study, of which 26.2% developed BPD. Infants with BPD had significantly higher energy expenditure at term equivalent age, with no difference in body composition between the two groups. Conclusion: Despite expending more energy, infants with BPD maintained a similar body composition distribution to those without BPD, and this is likely due to the recommended nutritional approach.What is Known: • Greater resting energy expenditure impairs growth of preterm infants with bronchopulmonary dysplasia. What is New: • Although preterm infants with bronchopulmonary dysplasia had a higher resting energy expenditure at the corrected term age, this did not affect their body composition and growth.
Flowchart showing selection of study patients. PICU, paediatric intensive care unit; VTE, venous thromboembolism; pTP, pharmacological thromboprophylaxis
The risk for venous thromboembolism (VTE) is considered to be low in the general paediatric intensive care unit (PICU) population, and pharmacological thromboprophylaxis is not routinely used. PICU patients considered at high-risk of VTE could possibly benefit from pharmacological thromboprophylaxis, but the incidence of VTE in this group of patients is unclear. This was an observational, prospective study at a tertiary multi-disciplinary paediatric hospital. We used comprehensive ultrasonography screening for VTE in critically ill children with multiple risk factors for VTE. Patients admitted to PICU ≥ 72 h and with ≥ two risk factors for VTE were included. Patients receiving pharmacological thromboprophylaxis during their entire PICU stay were excluded. The primary outcome of the study was VTEs not related to the use of a CVC. Ultrasonography screening of the great veins was performed at PICU discharge. Seventy patients with median (interquartile range) 3 (2–4) risk factors for VTE were evaluated. Median age was 0.3 years (0.03–4.3) and median PICU length of stay 9 days (5–17). Regarding the primary outcome, no symptomatic VTEs occurred and no asymptomatic VTEs were found on ultrasonography screening, resulting in an incidence of VTEs not related to a vascular catheter of 0% (95% CI: 0–5.1%). Conclusion: Our results indicate that VTEs not related to a vascular catheter are a rare event even in a selected group of severely ill small children considered to be at high risk of VTE. What is Known: • Children in the PICU often have several risk factors for venous thromboembolism (VTE). • The incidence of VTE in PICU patients is highly uncertain, and there are no evidence-based guidelines regarding VTE prophylaxis. What is New: • This study found an incidence of VTEs not related to a vascular catheter of 0% (95% CI: 0–5.1%). • This indicates that such VTE events are rare even in PICU patients with multiple risk factors for VTE.
Associations between childhood BMI (panels a and b) and height (panels c and d) z-scores at ages 7 and 13 years, respectively, and risks of benign breast disease. The x-axis is truncated to depict the inner 95% of the distribution. The hazard ratios are estimated by Cox regressions, and the associations are stratified by birth cohort
A high childhood body mass index (BMI) may be protective against benign breast disease (BBD), but little is known about the effects of other early life body size measures. Thus, we examined associations between birthweight, childhood BMI, height, and pubertal timing and BBD risks. We included 171,272 girls, born from 1930 to 1996, from the Copenhagen School Health Records Register, which contains information on birthweight, childhood anthropometry (7–13 years), age at onset of the growth spurt (OGS), and peak height velocity (PHV). During follow-up, 9361 BBD cases (15–50 years) were registered in the Danish National Patient Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. At all childhood ages, BMI was inversely but non-linearly associated with BBD. The association was slightly stronger in magnitude for BMI z-scores above 0 (HRage 7 = 0.86; 95%CI: 0.83–0.90 per z-score) than below 0 (HRage 7 = 0.95; 95%CI 0.91–0.99 per z-score). Associations between childhood height and BBD differed by age; at 7 years the association was an inverted U-shape, whereas at 13 years height was not associated with BBD. Ages at OGS and PHV were positively associated with BBD. Low and high birthweights were associated with lower BBD risks. Conclusion: A high childhood BMI, a short or tall stature at young childhood ages, an early pubertal onset, and low or high birthweights are associated with reduced risks of BBD. These complex associations suggest that the role of these factors in breast tissue development during early life warrants further investigation in relation to BBD etiology.What is Known: • Benign breast disease (BBD) is common and may be an intermediary marker of breast cancer risks. • Early life body size may relate to the development of BBD, but currently little is known. What is New: • Girls with a high body mass index at school ages or with an early pubertal timing have decreased risks of BBD. • Short and tall heights at young childhood ages and low and high birthweights are associated with lower BBD risks.
Flow diagram for patient inclusion. PT preterm infants
LUS score (A) and NT-proBNP (B) at birth and on the 3rd, 7th, and 14th DOLs: data are presented as medians and interquartile ranks. BPD bronchopulmonary dysplasia; DOL day of life. *p < 0.05
The N-terminal end of B-type natriuretic peptide (NT-proBNP) and lung ultrasound (LUS) score have been proven to be adequate early biomarkers of bronchopulmonary dysplasia (BPD) in preterm infants. Our aim was to study if the predictive capacity of each one is increased by analyzing them together. We included infants born before 32 weeks with NT-proBNP and LUS scores on the first day of life (DOL) and on the 3rd, 7th, and 14th DOL and compared the diagnostic ability for moderate–severe BPD (msBPD) of each biomarker and in combination. We also compared them with a multivariate model of msBPD using only clinical variables. The sample size was 133 patients, and twenty-seven (20%) developed msBPD. The LUS score on the 7th DOL had better performance than NT-proBNP at the same moment: area under the receiver operating characteristic curve (AUC) 0.83 (0.75–0.89) versus 0.66 (0.56–0.75), p = 0.003, without differences in the rest of the times studied. These values did not increase when using the combination of both. A multivariate regression model that included only clinical variables (birth weight and invasive mechanical ventilation (IMV) at the 7th DOL) predicted msBPD with the same AUC as after the addition of any of these biomarkers, neither together. Conclusion: The LUS score is a better predictor of msBPD on the 7th DOL than NT-proBNP in preterm infants born before 32 weeks, although they have similar diagnostic accuracy on the 1st, 3rd, and 14th DOL. Neither of them, nor together, have a better AUC for msBPD than a clinical model with birthweight and the need for IMV at the 7th DOL. What is Known: • NT-proBNP and LUS score are early predictors of moderate–severe bronchopulmonary dysplasia (msBPD). What is New: • The combination of both NT-proBNP and LUS score does not increase the predictive ability of each separately.
Moderator role of daily moderate-to-vigorous physical activity minutes in the association between breakfast status and body mass index (z-score). A Moderation model for boys. B Moderation model for girls. Adjusted by age, region, and socioeconomic status. BMI, body mass index; MVPA, moderate-to-vigorous physical activity
The present study aimed to test whether the daily minutes of moderate-to-vigorous physical activity (MVPA) engaged moderate the relationship between breakfast status and excess weight (i.e., overweight and/or obesity) in a Spanish sample of young people. A cross-sectional study involving a total sample of 2890 Spanish schoolchildren (46% girls) aged 6−17 years (M = 12.3 ± 2.6) was conducted. To determine the habit of having breakfast, a dichotomous item about breakfast status (yes/no) from the Mediterranean Diet Quality Index for children and teenagers (KIDMED) was used. Physical Activity Questionnaire for Older Children and the Physical Activity Questionnaire for Adolescents were fulfilled to offer an estimation of the minutes of MVPA that individuals had in the last seven days. Body mass index (BMI) was converted into z-scores and, therefore, excess weight status (i.e., overweight and/or obesity) was established according to World Health Organization criteria for sex and age. Skipping breakfast was positively related with BMI (z-score) and excess weight. Moderation analyses suggested that daily MVPA minutes moderated the association between skipping breakfast and BMI (boys: β = − 0.175; girls: β = − 0.073) or the excess weight (boys: OR = 1.10; CI 95%, 1.02 to 1.07; girls: OR = 1.14; CI 95%, 1.04 to 1.24), meaning that physical activity of sufficient intensity seems to reduce the effect of skipping breakfast on the body weight status of young people. Conclusion: Our results indicate that promotion of having breakfast should be accompanied by daily MVPA, as young participants who have breakfast and with higher daily MVPA seem to be more likely to have no excess weight. What is Known: • Some of the well-studied factors associated with childhood obesity have been skipping breakfast and insufficient physical activity. • Some studies have pointed out the association between having breakfast and both body mass index and physical activity level, in isolation. What is New: • Daily minutes of moderate-to-vigorous physical activity moderate the association between skipping breakfast and excess weight. • Breakfast promotion as a healthy eating habit should be accompanied by increases in moderate-to-vigorous physical activity, since participants who have breakfast and with higher moderate-to-vigorous physical activity seem to be more likely to have no excess weight.
Flow chart of patient enrollment
ROC curves of different transport scoring systems. The AUC of TRIPS, MINT, NICS, and TREMS were 0.827, 0.822, 0.731, and 0.643, respectively (all p < 0.05). Although the sensitivity of NCIS score was the highest (93.1%), its specificity (53.1%) was the lowest among the 4 kinds of transport scorings. When the AUCs of different transport scorings were compared with DeLong test, MINT and TRIPS score plays a better role in predicting the risk for death within the first week for full-term neonates. Abbreviations: AUC, area under curve; MINT, Mortality Index for Neonatal Transportation; NCIS, Neonatal Critical Illness Score; ROC, receiver operating characteristic; TREMS, Transport-Related Mortality Score; TRIPS, Transport Risk Index of Physiologic Stability
DCA for clinical utility Among MINT/TREMS/TRIPS/NCIS scorings. DCA was used to assess the clinical utility among four transport scores in predicting the mortality risk of full-term neonates within the 1st week after admission. The net benefit curves for the four prediction scores are shown. X-axis indicates the threshold probability for full-term mortality in the first week and Y-axis indicates the net benefit. The preferred score is the TRIPS and MINT model, the net benefit of which was larger over the range of NCIS and TREMS. Abbreviations: DCA, decision curve analysis; MINT, Mortality Index for Neonatal Transportation; NCIS, Neonatal Critical Illness Score; TREMS, Transport-Related Mortality Score; TRIPS, Transport Risk Index of Physiologic Stability
Neonatal transport scoring systems can assess severity before and after transport, improve transport efficiency, and predict the occurrence of critical illness. The aim of this study was to compare four neonatal transport scoring methods to predict mortality risk and clinical utility within the first week after transportation. This was a single-center retrospective cohort study. All patients were full-term, out-born neonates. Each patient was assessed by the Transport Risk Index of Physiologic Stability (TRIPS), Mortality Index for Neonatal Transportation (MINT), Transport-Related Mortality Score (TREMS), and Neonatal Critical Illness Score (NCIS) scoring methods. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) for each method were compared for their utility in predicting mortality risk within the 1st week after admission. In total, 368 full-term infants were included (368/770, 47.8% of all transported infants). Within the 1st week after admission, five infants (1.36%, 5/368) died while receiving advanced life support and full treatment, and 24 infants (6.52%, 24/368) died soon after they were discharged against medical advice. The areas under the curve (AUCs) for the MINT, TRIPS, TREMS, and NCIS for the prediction of mortality were 0.822, 0.827, 0.643, and 0.731, respectively (all p < 0.05). However, the clinical net benefits for the MINT and TRIPS were far superior than those for the NCIS and TREMS. Conclusion: It was concluded that the TRIPS and MINT might be more suitable for the prediction of mortality in full-term, out-born neonates in the neonatal intensive care unit (NICU) within the 1st week after transportation. What is Known: • Neonatal transport scores can assess not only the mortality risk during transportation but also the mortality risk of critically ill newborns after admission to the NICU. • The effectiveness of neonatal transport scores in predicting mortality risk is different. What is New: • Our data indicate that the diagnostic efficacy of the MINT, TRIPS, and NCIS in the prediction of full-term infant mortality was high. • The TRIPS and MINT scores had better clinical utility and could be used to predict mortality within the 1st week after transportation in full-term out-born neonates.
Frequency of use, depending on whether the medicines or supplements were taken on the basis of a prescription or recommendation by a physician or whether they were taken as self-medication. Information on 7485 recorded medicines and supplements was available. LIFE Child 2014–2019
Children and adolescents are exposed to medicines and supplements, but only a few studies have evaluated the actual intake in routine care. Thus, we performed a pharmacoepidemiological evaluation of a longitudinal population-based pediatric cohort study (LIFE Child) conducted at the University Hospital of Leipzig between 2014 and 2019. We analyzed all visits of the participants of the LIFE Child cohort between 1 January 2014 and 31 December 2019. Participants were asked to bring their medicines and supplements to their appointments at the study center. If they had not brought the preparations with them, attempts were made to obtain the relevant information during a telephone call after the visit to the study center. Furthermore, the participants and their parents were interviewed on medicine and supplement use and on sociodemographic and socioeconomic data during their visit to the study center. Associations of medicine and supplement use with age, sex, and socioeconomic status were analyzed using multivariate binary logistic regressions to obtain adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Furthermore, the number of the respective visit was included as possible confounder in the multivariate model. We included 3602 participants who visited the study center 11,906 times. The intake of 9759 medicines and supplements was recorded. Based on the evaluation of all study visits, 49% of the children and adolescents took at least one medicine or supplement. Self-medication accounted for 28% of the medicines and supplements. The prevalence of overall intake increased from 45% in 2014 to 53% in 2019 (aOR 2.63, 95% CI 2.23, 3.09). The prevalence was the highest (77%) in children aged 0– < 3 years, owing mainly to vitamin D. The prevalence of medicine use was higher in females (40%; aOR 1.18, 95% CI 1.10, 1.28) than in males (35%), owing mainly to the intake of ibuprofen and hormonal contraceptives in adolescent females. A high socioeconomic status was a predictor of lower medicine (aOR 0.80, 95% CI 0.68, 0.95) and higher supplement (aOR 1.47, 95% CI 1.09, 1.98) use. Conclusion: Half of all children and adolescents took at least one medicine or supplement. The intake varied depending on age and sex. Furthermore, high socioeconomic status was associated with a decreased probability of medicine intake. What is Known: • Half of all children and adolescents in Germany are exposed to medicines and supplements. • Data on the actual intake are scarce as most studies focus on prescribed medicines. What is New: • The prevalence of medicine/supplement use rose from 2014 (45%) to 2019 (53%). The prevalence was age-dependent: it was the highest in children aged < 3 years, and the lowest in children aged 6–< 9 years. Females took medicines more frequently than males. • High socioeconomic status was associated with lower medicine and higher supplement use. Self-medication accounted for 28% of all preparations.
Flow chart of study inclusion and exclusion criteria for acute upper respiratory tract infection (URTI) visits during the period of 2014–2020. Side arrows indicate the exclusion criteria. N, number of visits; LRTI, lower respiratory tract infection
Antibiotic prescription rates for upper respiratory tract infection (URTI) [left axis] and URTI visit rates [right axis] yearly. Other antibiotics include pivmecillinam, ceftriaxone, trimethoprim, sulfamethoxazole/trimethoprim, sulfasalazine/trimethoprim, second-generation cephalosporin, and doxycycline. Total number of visits, 1,629,187. Number of URTI visits, 156,187
Antibiotic prescription rates for upper respiratory tract infection by age group. A Children < 2 years (n = 34,844). B Children 2–4.9 years (n = 43,459). C Children 5–11.9 years (n = 45,672). D Children 12–17.9 years (n = 31,212). Other antibiotics include pivmecillinam, ceftriaxone, trimethoprim, sulfamethoxazole/trimethoprim, sulfasalazine/trimethoprim, second-generation cephalosporin, and doxycycline
Antibiotic prescription rates for upper respiratory tract infection as diagnosed by specialists. A All patients (n = 156,187). B Patients treated by paediatricians (n = 47,789). C Patients treated by general practitioners (n = 81,267). D Patients treated by ear, nose, and throat specialists (n = 20,932). Other antibiotics include pivmecillinam, ceftriaxone, trimethoprim, sulfamethoxazole/trimethoprim, sulfasalazine/trimethoprim, second-generation cephalosporin, and doxycycline. PED, paediatrician. GP, general practitioner. ENT, ear, nose, and throat specialist
Cost of prescribed antibiotics per patient treated for upper respiratory tract infection. Total annual cost, left axis. Cost per patient, right axis. n = 156,187
Upper respiratory tract infection (URTI) is a self-limiting viral infection and should not be treated with antibiotics. The aim was to evaluate antibiotic prescriptions for children with uncomplicated URTI in a large nationwide private clinic network between 2014 and 2020. Special focus was given to macrolide prescriptions and costs. The data were obtained from the electronic health records (EHR) of the largest private healthcare company in Finland (with about 250,000 paediatric visits annually across the country). The collected variables included diagnoses, age, visit year, speciality of the doctor, and prescribed antibiotics. The number of uncomplicated URTIs in < 18-year-old children was 156,187 (53.0% in boys). The prescription rate of antibiotics decreased from 18.0% in 2014 to 8.8% in 2020, and that of macrolides from 6.1 to 1.7%. The costs decreased accordingly. Paediatricians prescribed antibiotics less often than general practitioners or ear, nose, and throat specialists. Conclusion: Antibiotic prescriptions for uncomplicated URTIs, especially macrolides, decreased substantially during the 7-year surveillance period; however, 8.8% of children still received unnecessary antibiotics. To further reduce unwarranted antibiotic prescriptions, active interventions are needed that can be performed by applying the available EHR system. What is Known: • Upper respiratory tract infection (URTI) is the most common infection in children. Uncomplicated URTI is a self-limiting viral infection, and antibiotic treatment is not warranted. What is New: • Almost 9% of children with uncomplicated URTIs still received unnecessary antibiotics. Paediatricians prescribed antibiotics less often than general practitioners or ear, nose, and throat specialists. To further reduce unwarranted antibiotic prescriptions, active interventions are needed that can be performed by applying the available EHR system.
Observed neonatal magnesemia according to indication for MgSO4
Estimated geometric mean neonatal magnesemia according to indication for MgSO4
To objective of this study was to compare neonatal magnesemia in the first 15 days of neonatal life between three groups: a control group not exposed to MgSO4, a neuroprotection group, and an eclampsia prevention group, and to explore its associations with child outcomes. A retrospective single-centre cohort study was performed in a tertiary care setting. Infants admitted at the neonatal intensive care unit born between 24 and 32 weeks’ gestation, regardless of etiology of preterm birth, were included. The mean outcome measure was neonatal magnesemia (mmol/L). Linear mixed regression of neonatal magnesemia on exposure group and day of life was done. Generalised estimating equation models of child outcomes on neonatal magnesemia according to exposure group and day of life were made. The analyses showed that in neonatal magnesemia is significantly higher in the preeclampsia group compared to the control and neuroprotection groups. On the day of birth, this is irrespective of maternal magnesemia (preeclampsia vs control groups), and the maternal total dose or duration of MgSO4 administration (preeclampsia vs neuroprotection group). No differences were found in short-term composite outcome between the three groups. Conclusion: We found mean differences in neonatal magnesemia between children not exposed to MgSO4 antenatally, children exposed for fetal neuroprotection, and children exposed for maternal eclampsia prevention. A 4-g loading and 1-g/h maintenance doses, for fetal neuroprotection and eclampsia prevention, appear to be safe on the short term for the neonate. What is Known: • Magnesium sulphate is a valuable medicine in obstetrics. The main indications are prevention of eclampsia and fetal neuroprotection. The most used dosage is a 4- or 6-g loading dose and a 1- or 2-g per h maintenance dose. It reduces neuromotor disabilities in extreme-to-moderate preterm born children. What is New: • Maternal concentrations are supraphysiological and the maternal total dose can be high. Concentrations in neonates appear to remain in safe ranges. A dosage of 4-g loading and 1 g/h seems safe for the preterm neonate on the short term.
Flowchart of the study
Variations of the improvements (Δ values) in each variable
Bronchiectasis is a form of airway damage as a consequence of endobronchial infection and inflammation and may be present in different diseases. The underlying aetiologies include both cystic fibrosis (CF) and a group of non-cystic fibrosis diseases (NCFB) such as immunodeficiency, primary ciliary dyskinesia, or severe pulmonary infection. Although children with CF and non-cystic fibrosis bronchiectasis (NCFB) have many similar clinical features, their responses to exercise may be different. The aim of this study was to compare the efficacy of a comprehensive respiratory physiotherapy (CRP) home-program in children with CF and NCFB. Thirty children with CF and thirty children with NCFB were included in the study. Both groups performed the CRP home-program twice daily for 8 weeks. Pulmonary function, exercise capacity, and respiratory and peripheral muscle strength were assessed at baseline and after 8 weeks of training. Both groups experienced significant improvements in pulmonary function, exercise capacity, and respiratory and peripheral muscle strength (p < 0.001). Maximum expiratory pressure, exercise capacity, and peripheral muscle strength were further improved in NCFB group compared to CF (p < 0.05); however, there was a great variability in the improvements for each variable. Conclusion: CRP is beneficial both for children with CF and NCFB and adherence to the program was high in both groups. What is Known: • Different physiotherapy approaches in the management of non-cystic fibrosis bronchiectasis have been based on the experience gained from the research studies performed in cystic fibrosis. • Although having similar pathophysiology, these two diseases show variation in some pulmonary and extrapulmonary features. What is New: • The respiratory muscle strength and the efficacy of comprehensive respiratory physiotherapy have been compared for the first time in children with cystic fibrosis and non-cystic fibrosis bronchiectasis. • Comprehensive respiratory physiotherapy provides higher increases in children with non-cystic fibrosis bronchiectasis in exercise capacity and expiratory and peripheral muscle strength; however, there was a great variability in these improvements. Nevertheless, it can be concluded that both groups significantly benefited from the CRP program.
Number of ED presentations according to the years (data from 2019 is until July). The line graph represents the ratio of refugee to resident presentations in each year
Evaluation of emergency department (ED) presentation by Syrian refugee children might provide important information about their health care needs. For this purpose, we compared ED presentation of refugee and resident children in a tertiary university hospital in Istanbul, Turkey. Electronic medical records of Syrian refugee children ≤ 18 years old presenting to the ED between January 2013 and July 2019 were retrospectively reviewed and compared with resident children. The study population consisted of 7299 refugees and 690,127 resident children admitted to the ED. High-acuity cases were more frequent in Syrian refugees (2.2% vs 1% p < 0.001). One-third of Syrian children were under 12 months of age (31% vs 17%, p < 0.001). Syrian children were more commonly hospitalized (7.9% vs 3.1% p < 0.001). The median age (and interquartile range – IQR) was lower in hospitalized refugee than in resident children [12 (0–83) months vs 41 (8–111) months, p < 0.001]. Rate of intensive care unit hospitalization (13% vs 9.4%, p = 0.001) and neonatal hospitalization was higher in Syrians compared to resident children (29% vs 12%, p < 0.001). The median NICU stay was longer in refugees [6 (IQR 4–17) days vs 3 (IQR 1–9) days, p < 0.001]. Conclusion: Refugee children, as compared to resident children, are more likely to present to the ED with high acuity conditions and at a younger age resulting in higher rates of inpatient admissions. Strategies to increase access to preventive health care services for young refugee children should be explored to decrease ED and hospital services and improve health outcomes. What is Known: • Children are the most affected victims of armed conflicts in terms of health outcomes. • Refugees prefer to access healthcare through the emergency department. What is New: • Refugee children were more likely to present as urgent when compared to resident children. • Admission to neonatal and intensive care units was more frequent among refugee than resident children.
Flow chart of the study groups
Alpha and beta diversity plots to visualize the difference in microbiota structure between the MIS-C, SARS-CoV-2, and control groups. Simpson index comparison between the study groups. There was no significant difference in stool sample data between the groups in the study (p > 0.05). a Shannon index comparison between the study groups. Shannon index was higher in stool sample data of MIS-C cases when the control group (p < 0.01). b PCoA 2D plots of beta diversity analysis of the MIS-C, SARS-CoV-2, and control groups. Each dot represents a stool sample. Red circle, green triangle, and blue square represent control, MIS-C, and SARS-CoV-2 cases, respectively. c–f Between-sample dissimilarities were measured by Bray–Curtis distances (c), Jaccard distance (d), weighted UniFrac distances (e), and unweighted UniFrac distances (f). A statistical difference in the stool samples was found between the groups in the results of the Bray–Curtis (c), Jaccard (d), weighted UniFrac (e), and unweighted UniFrac (f) baseline coordinate analysis (PCoA) (p = 0.001)
Intestinal microbiota composition of the study groups at species and genus levels. Bacterial community relative abundance analysis at the genus (a) and species (b) levels (relative abundance > 1%; bacteria with relative abundances < 1% were pooled in the “others” category and sorted by total concentration)
LEfSe analysis graphics showing bacterial taxa that were significantly different in abundance between the study groups. a–c LefSe analysis was performed to identify differentially abundant taxa for which the LDA scores are shown. Only species and functional modules with LDA effect size > 2 and FDR-corrected p value < 0.05 were plotted. Horizontal bars represent log.10 converted LDA score indicated by vertical dotted lines. Different colors represent different groups. p—phylum, c—class, o—order, f—family, g—genus, s—species. LEfSe analysis in stool samples for the MIS-C and control groups (control group (red), MIS-C (green)). a At the genus level, in the MIS-C group, Bacteroides (LDA score = 5.162, p = 0.018), Eggerthella (LDA score = 3.297, p = 0.017), and Prevotella (LDA score = 2.514, p = 0.038) were dominant, whereas Faecalibacterium (LDA score = 5.265, p = 0.0008), Gemmiger (LDA score = 4.666, p = 0.012), Ruminococcus (LDA score = 4.368, p = 0.000), Butyricicoccus (LDA score = 3.815, p = 0.002), Collinsella (LDA score = 3.752, p = 0.045), and Dorea (LDA score = 3.608, p = 0.045) were found to be dominant in the control group. At the species level, Bacteroides uniformis (LDA score = 4.926, p = 0.023), Bacteroides plebeius (LDA score = 4.332, p = 0.046), Clostridium ramosum (LDA score = 4.160, p = 0.046), Eubacterium dolichum (LDA score = 3.401, p = 0.023), Eggerthella lenta (LDA score = 3.296, p = 0.032), Bacillus thermoaamylovorans (LDA score = 3.146, p = 0.023), Prevotella tannerae (LDA score = 2.523, p = 0.038), and Bacteroides coprophilus (LDA score = 2.460, p = 0.041) are most abundant in the MIS-C group. In the control group, Faecalibacterium prausnitzii (LDA score = 5.265, p = 0.000), Gemmiger formicilis (LDA score = 4.666, p = 0.012), Bifidobacterium adolescentis (LDA score = 4.344, p = 0.008), Ruminococcus bromii (LDA score = 4.286, p = 0.000), Lactobacillus ruminis (LDA score = 4.231, p = 0.046), Butyricicoccus pullicaerocum (LDA score = 3.815, p = 0.002), Collinsella aerofaciens (LDA score = 3.752, p = 0.045), Ruminococcus callidus (LDA score = 3.609, p = 0.008), and Dorea formicigenerans (LDA score = 3.608, p = 0.000) were found to be dominant (a). LEfSe analysis in stool samples for the SARS-CoV-2 and control groups (control group (red), SARS-CoV-2 (blue)). b At the genus level, Lachnospiraceae_Clostridium (LDA score = 2.648, p = 0.039) was dominant in SARS-CoV-2 cases, while Faecalibacterium (LDA score = 5.168, p = 0.016) and Ruminococcus (LDA score = 4.316, p = 0.037) were dominant in the control group. At the species level, in the SARS-CoV-2 group, Bacteroides coprophilus (LDA score = 3.629, p = 0.002), Eubacterium dolichum (LDA score = 3.261, p = 0.012), Bacteroides uniformis (LDA score = 4.834, p = 0.011), and Clostridium piliforme (LDA score = 2.642, p = 0.039) were dominant, while Faecalibacterium prausnitzii (LDA score = 5.168, p = 0.016), Ruminococcus callidus (LDA score = 3.632, p = 0.003), and Lactobacillus ruminis (LDA score = 4.184, p = 0.013) were dominant in the control group (b). LEfSe analysis in stool samples for the MIS-C, SARS-CoV-2, and control groups (control group (red), MIS-C group (green), SARS-CoV-2 (blue)). cBacteroides uniformis (LDA score = 4.820, p = 0.024), Bacillus thermoaamylovorans (LDA score = 3.040, p = 0.048), and Eubacterium dolichum (LDA score = 3.297, p = 0.002) were most abundant species in children with MIS-C at species level. Bacteroides coprophilus (LDA score = 3.331, p = 0.008), Bifidobacterium adolescentis (LDA score = 4.408, p = 0.016), Dorea formicigenerans (LDA score = 3.560, p = 0.000), Ruminococcus albus (LDA score = 3.049, p = 0.017), and Clostridium piliforme (LDA score = 2.450, p = 0.0130) were most abundant species in children with SARS-COV-2. In the control group, Faecalibacterium prausnitzii (LDA score = 5.201, p = 0.000), Gemmiger formicilis (LDA score = 4.524, p = 0.019), Ruminococcus bromii (LDA score = 4.169, p = 0.000), Lactobacillus ruminis (LDA score = 4.231, p = 0.046), Butyricicoccus pullicaerocum (LDA score = 3.660, p = 0.002), and Ruminococcus callidus (LDA score = 3.499, p = 0.000) were found to be dominant (c)
Microbiota composition may play a role in the development, prognosis, or post-infection of COVID-19. There are studies evaluating the microbiota composition at the time of diagnosis and during the course of COVID-19, especially in adults, while studies in children are limited and no study available in children with multisystem inflammatory syndrome in children (MIS-C). This study was planned to compare intestinal microbiota composition in children diagnosed with MIS-C and acute COVID-19 infection with healthy children. In this prospective multicenter study, 25 children diagnosed with MIS-C, 20 with COVID-19 infection, and 19 healthy children were included. Intestinal microbiota composition was evaluated by 16 s rRNA gene sequencing. We observed changes of diversity, richness, and composition of intestinal microbiota in MIS-C cases compared to COVID-19 cases and in the healthy controls. The Shannon index was higher in the MIS-C group than the healthy controls (p < 0.01). At phylum level, in the MIS-C group, a significantly higher relative abundance of Bacteroidetes and lower abundance of Firmicutes was found compared to the control group. Intestinal microbiota composition changed in MIS-C cases compared to COVID-19 and healthy controls, and Faecalibacterium prausnitzii decreased; Bacteroides uniformis, Bacteroides plebeius, Clostridium ramosum, Eubacterium dolichum, Eggerthella lenta, Bacillus thermoamylovorans, Prevotella tannerae, and Bacteroides coprophilus were dominant in children with MIS-C. At species level, we observed decreased Faecalibacterium prausnitzii, and increased Eubacterium dolichum, Eggerthella lenta, and Bacillus thermoamylovorans in children with MIS-C and increased Bifidobacterium adolescentis and Dorea formicigenerasus in the COVID-19 group. Our study is the first to evaluate the microbiota composition in MIS-C cases. There is a substantial change in the composition of the gut microbiota: (1) reduction of F. prausnitzii in children with MIS-C and COVID-19; (2) an increase of Eggerthella lenta which is related with autoimmunity; and (3) the predominance of E. dolichum is associated with metabolic dysfunctions and obesity in children with MIS-C. Conclusions: Alterations of the intestinal microbiota might be part of pathogenesis of predisposing factor for MIS-C. It would be beneficial to conduct more extensive studies on the cause-effect relationship of these changes in microbiota composition and their effects on long-term prognosis. What is Known: • Microbiota composition may play a role in the development, prognosis, or post-infection of COVID-19. • However, the number of studies on children is limited, and no study on multisystem inflammatory syndrome in children is currently available (MIS-C). What is New: • In individuals with MIS-C, the composition of the gut microbiota changed dramatically. • Decreased Faecalibacterium prausnitzii have been observed, increased Eggerthella lenta, which was previously linked to autoimmunity, and predominance of Eubacterium dolichum which was linked to metabolic dysfunction and obesity. Graphical abstract
Frequency of daily acetaminophen error by year, stratified by severity of excessive daily dose
Baseline and 14-day trend in AST (A), ALT (B), and GGT (C) in admissions with acetaminophen error (red) and no acetaminophen error (blue). Figure demonstrates box plots with median and first and third quartile (whiskers), as well as means (circles) connected with a trend line. ALT, AST, and GGT are measured in U/L
Drug-associated harm is common but difficult to detect in the hospital setting. In critically ill children, we sought to evaluate drug-associated hepatic injury following enteral acetaminophen error, defined as acetaminophen dosing that exceeds daily maximum recommendations. This retrospective cohort study took place in two pediatric intensive care units within a pediatric hospital center. The included patients are children (< 18 years of age) admitted to the pediatric and cardiac intensive care unit between January 2008 and January 2018, and receiving enteral acetaminophen. We defined acetaminophen dosing error as exceeding daily acetaminophen dosing by > 10% the upper limit of maximum recommended dose for weight and age (> 82.5 mg/kg/day or > 4400 mg/day). We included 14,146 admissions, who received 147,485 doses of acetaminophen. Acetaminophen dosing errors occurred 1 in every 9.5 patient-days on acetaminophen. ALT and AST decreased significantly over the course of ICU admission (p < 0.0001). In patients with acetaminophen errors, ALT and AST measured in the 24 to 96 h post error were not significantly different than when measured outside this window. A sensitivity analysis using > 100 mg/kg/day as the upper daily acetaminophen error cut-off did not reveal any subsequent significant increase in ALT or ALT in the 24 to 96-h post-error window, compared to measurements taken outside the window. Conclusion: Although the administration of acetaminophen in critically ill children frequently exceeds the daily recommended limit and vigilance is needed, we did not find any associated increase in liver transaminases following acetaminophen errors. What is Known: • Acetaminophen dosing errors are common in pediatric outpatients. • Excessive acetaminophen dosing can be associated with harm, including hepatic injury. What is New: • Exceeding daily acetaminophen dosing limit occurs 1 in every 9.5 patient-days in children admitted to the critical care unit. • In patients with daily dose excess of acetaminophen, we did not find a significant increase in the measured liver enzymes in the 24 to 96 h following the overdosing.
Distribution of vancomycin concentration at 24 h post initiation of treatment. Distribution of vancomycin C24h at 24 h of treatment. Y axis showed the proportion of infective episodes in %. X axis the C24h vancomycin level (mg/L). Median C24h 18.7 mg/L (IQR 15.4–22.4)
Creatinine evolution during vancomycin treatment after 24 h of therapy. Evolution of creatinine during vancomycin therapy. Y axis showed the creatinine level (µM); the X axis showed the 2 time points, therapy initiation and creatinine control. There was no significant difference in creatinine between these both time point with a Wilcoxon pair analysis, p value 0.36
Vancomycin is widely used in neonatal sepsis but proportion of newborn reaching recommended concentration is variable. Fluid status impact on vancomycin level remains understudied. We aimed to study fluid factors impacting vancomycin concentration at 24 h of treatment. We performed a prospective and retrospective observational monocentric study of NICU patients requiring a vancomycin treatment. We used a continuous infusion protocol, with age-appropriate loading and maintenance doses. Vancomycin target serum concentration after 24 h (C24h) was above 20 mg/L. Demographic, infections, and organ failure variables were analyzed as potential predictors of C24h. Over the study period, 70 infective episodes in 52 patients were included. At treatment initiation, the median post-natal age was 12.5 days (IQR 7–23), post menstrual age 30 weeks (IQR 28–35), and median weight 1140 g (IQR 835–1722). Germs isolated were mainly gram-positive with 73.5% being coagulase-negative Staphylococci. Median C24h was 18.7 mg/L (IQR 15.4–22.4). Overall, 41 (58.6%) treatments had a C24h < 20 mg/L. After multivariate analysis, higher creatinine level (OR 1.03 (95% CI 1.002–1.06)) was associated with C24h ≥ 20 mg/L; weight gain the day before infection (OR 0.21 (95% CI 0.05–0.79)) and positive biomarkers of inflammation (OR 0.22 (0.05–0.94)) were associated with C24h < 20 mg/L. Conclusion: Vancomycin C24h was underdosed in 60% of patients and factors linked to changes in vancomycin pharmacokinetic such as volume of distribution and clearance, linked to creatinine level, inflammation, or weight gain, were identified. What is Known: • Adjustment of vancomycin regimen remains difficult due to inter- and intra-individual variability of vancomycin pharmacokinetics. • Impact of fluid status on vancomycin concentration in critically ill neonates is incompletely studied. What is New: • Proportion of patients with adequate vancomycin concentration using a target adapted to nosocomial gram-positive bacteria MIC is low. • We confirmed the role of creatinine level and report two new factors associated with low vancomycin concentration: presence of systemic inflammation and weight gain.
Patient 12: a Electroencephalography (EEG) during left occipital focal non-motor to motor seizure: high pass filter: 0.530 Hz; low pass filter: 30 HZ; and gain: 200 microV/cm. b, c Electroencephalography (EEG) during sleep, bilateral high voltage occipital sub-continuous spikes and spike-and-waves activities, with bilateral diffusion, at times followed by desynchronization, spindles of sleep: high pass filter: 0.530 Hz; low pass filter: 70 HZ (B), 30 HZ (C); high pass filter: 0.530 Hz; low pass filter: 30 HZ; and gain: 400 microV/cm. d Electroencephalography (EEG) awake during clinical improvement: high pass filter: 0.530 Hz; low pass filter: 30 HZ; and gain: 400 microV/cm. e Electroencephalography (EEG) during sleep, showing spindles and vertex waves: high pass filter: 0.530 Hz; low pass filter: 30 HZ; and gain: 400 microV/cm
Patient 2: a Electroencephalography (EEG) of sleep, showing generalized paroxysmal anomalies, normal background activity with spindles of sleep, and fast activity: high pass filter: 0.530 Hz; low pass filter: 30 Hz; and amplitude: 400 microV/cm. b Electroencephalography (EEG) of sleep, with focal isolated fronto-central low-voltage sharp-waves when falling asleep: high pass filter: 0.530 Hz; low pass filter: 30 Hz; and amplitude: 200 microV/cm
Noonan syndrome (NS) and related disorders encompass a phenotypically heterogeneous group of conditions due to mutations in the Ras/Mitogen-activated protein kinase pathway. The main objective of this study was to assess the presence and characteristics of epilepsy in children and adolescents affected by NS and related disorders. The study included all the patients aged 5–21 years who had been diagnosed with NS or of one of three Noonan-like syndromes (i.e., cardio-facio-cutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan-like syndrome with loose anagen hair) at a university pediatric hospital. Clinical, EEGs, brain MRIs, and genotype data were extracted from the medical records, and follow-up telephone interviews were conducted to obtain updated information about epilepsy and its course. Out of a total of 75 patients (38 [50.7%] males, median age at assessment 12.0 years [q1 9.0–q3 17.0]; 61 [81.3%] with NS; and 14 [18.7%] with a Noonan-like syndrome), 13 (17.3%) had epilepsy, with median age at onset of 4.0 years (q1 2.0–q3 8.0, min 0.1-max 17.0). Epilepsy was more common among Noonan-like patients (50.0%) than in NS (9.8%, p < 0.001), and its presence was associated with neurodevelopmental delay (p < 0.001, OR 14.6 95% CI 3.6–59.4), cognitive impairment (p = 0.002, OR 11.2 95% CI 2.5–51.0), need for educational support (p < 0.001, OR 21.8, 95% CI 2.6–179.1), and lower adaptive functioning (median [q1–q3]: 54.0 [q1 40.0–q3 77.5] vs 97.0 [q1 76.5–q3 107.0] of the non-epileptic subgroup, p = 0.004). In 10 out of 13 cases (76.9%), the epilepsy outcome was good (i.e., seizure-free for more than 12 months with or without anti-seizure medication). Conclusion: Epilepsy was more common in NS than reported in the general population, with a significantly higher rate in Noonan-like syndromes. Epilepsy was associated with neurodevelopmental delay, cognitive impairment, and lower adaptive functioning. What is Known: • Neurological abnormalities have been reported in NS and related disorders. • There is evidence of a phenotype-genotype relationship for neurological abnormalities. What is New: • Epilepsy was found to be more common in NS and related disorders than typically reported in the general population and associated with neurodevelopmental delay, cognitive, and functional impairment. • The Noonan-like phenotype had a higher frequency of epilepsy than typical NS.
Study participant flow chart
The purpose of this study is to clarify the relationship between neonatal sepsis and future development of Kawasaki disease (KD). We analyzed data from the National Hospital Organization Neonatal Intensive Care Unit (NHO-NICU) registry study in Japan. Participants in this study were children with a history of hospitalization in the NICU at the participating institutions from 2010 to 2014. A questionnaire was administered at age 3 years to obtain information about the patient’s history of KD. There were 8275 infants who were eligible for this study. At 3 years of age, parents of 2161 children responded to the follow-up survey (follow-up rate, 26.1%). Multivariate logistic regression analysis adjusted for preterm birth, sex, use of antibiotics in the NICU, parity, and maternal smoking showed that children with neonatal sepsis were more likely to have a history of KD at 3 years of age (adjusted odds ratio [aOR]: 11.67, 95% confidence interval [CI]: 2.84–47.96). Conclusions: Among infants admitted to the NICU, neonatal sepsis might be associated with development of KD later in life. Further large studies are needed to elucidate the relationship between neonatal infections and KD development. What is Known: • Preterm birth is known to be a risk factor for Kawasaki disease. •It is not yet known which factors related to preterm birth increase the risk of developing Kawasaki disease. What is New: •Neonatal sepsis is associated with an increased risk of subsequent development of Kawasaki disease. •Antibiotic use in the neonatal intensive care unit may also be an independent risk factor for subsequent development of Kawasaki disease.
Flow chart
Age at inclusion distribution
Inner ear impairment distribution
The purpose of this study is to assess the predictive factors of both hearing and vestibular impairment in congenitally cytomegalovirus-infected children (cCMV) through a multivariate analysis of clinical and imaging characteristics collected during pregnancy and at birth. This retrospective study was conducted between March 2014 and March 2020, including confirmed congenitally CMV-infected children with a complete vestibular and hearing assessment. Data concerning pregnancy, date of infection, clinical characteristics, and symptomatology at birth were collected. In total, 130 children were included, with a median age of 21 months. Eighty-three children (64%) presented with an inner ear impairment (both cochlear and vestibular impairment). Sex, modality of maternal infection (seroconversion or reactivation), pregnancy term, weight and head circumference at birth, neonatal clinical signs of infection, and treatment were not significantly correlated with inner ear impairment. However, multivariate analysis confirmed that there are two independent predictive factors of inner ear impairment: antenatal imaging lesions (ORa = 8.02 [1.74; 60.27], p-value = 0.01) and infection during the first trimester (ORa = 4.47 [1.21; 19.22], p-value = 0.03). Conversely, infections occurring during the second trimester were rarely associated with inner ear impairment: 4/13 (31%) in our series, with vestibular impairment alone (4/4) and no hearing loss. None of the children infected during the third trimester developed inner ear dysfunction. Conclusion: Besides the symptomatic status of the CMV infection at birth, we found that antenatal imaging brain damage and early infection (mainly during the first trimester) constitute the two best independent predictive factors of inner ear involvement in congenitally CMV-infected children.What is Known: • Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children and responsible of vestibular disorders, which are probably underestimated. • No articles have yet defined the predictive factors of the entire inner ear impairment (vestibule and cochlea). What is New: • The timing of the infection during pregnancy (first and second trimester, ORa=4.47) and antenatal imaging lesions (ORa=8.02) are independently predictive (in a multivariate analysis) of inner ear involvement. • The symptomatic status at birth is a poor predictor of inner ear impairment.
Study population
Specific knowledge of the features of minor head trauma in infants is necessary to develop appropriate preventive strategies and adjust clinical management in pediatric emergency departments (PEDs). The aim of this study is to describe the epidemiology of minor blunt head trauma in infants < 3 months who present to PEDs. We performed a prospective study of infants evaluated in any of 13 Spanish PEDs within 24 h of a minor head trauma (Glasgow Coma Scale scores of 14–15) between May 2017 and November 2020. Telephone follow-up was conducted for all patients over the 4 weeks after the initial PED visit. Of 1,150,255 visits recorded, 21,981 children (1.9%) sustained a head injury, 386 of whom (0.03%) were under 3 months old. Among the 369 patients who met the inclusion criteria (0.03%), 206 (56.3%) were male. The main causes of trauma were fall-related (298; 80.8%), either from furniture (138/298; 46.3%), strollers (92/298; 30.9%), or a caregiver’s arms (61/298; 20.5%). Most infants were asymptomatic (317; 85.9%) and showed no signs of injury on physical exam (210; 56.9%). Imaging studies were performed in 195 patients (52.8%): 37 (10.0%) underwent computed tomography (CT) scan, 162 (43.9%) X-ray, and 22 (6.0%) ultrasound. A clinically important traumatic brain injury (ciTBI) occurred in 1 infant (0.3% overall; 95% CI, 0–1.5), TBI was evidenced on CT scan in 12 (3.3% overall; 95% CI, 1.7–5.7), and 20 infants had an isolated skull fracture (5.5% overall; 95% CI, 3.4–8.3). All outcomes were caused by falls onto hard surfaces. Conclusion: Most head injuries in infants younger than 3 months are benign, and the rate of ciTBI is low. Prevention strategies should focus on falls onto hard surfaces from furniture, strollers, and caregivers’ arms. Optimizing imaging studies should be a priority in this population.What is Known: • Infants younger than 3 months are vulnerable to minor blunt head trauma due to their age and to difficulties in assessing the subtle symptoms and minimal physical findings detected on examination. • A low threshold for CT scan is recommended in this population. What is New: • Most cases of blunt head trauma in infants younger than 3 months have good outcomes, and the rate of clinically important traumatic brain injury is low. • Optimizing imaging studies should be a priority in this population, avoiding X-ray examinations and reducing unnecessary CT scans.
Flow chart of the study
Pulmonary function in active video gaming group and control group pre- and post-treatment program. Abbreviations: FEV1, forced expiratory volume in one second; FVC, forced vital capacity; FEF25-75 %, forced expiratory volume from 25-75%; PEF, peak expiratory flow rate
Respiratory and peripheral muscle strength, distance of 6-min walk test, and incremental shuttle walk test in active video gaming group and control group pre- and post-treatment program. Abbreviations: MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure; QMS, quadriceps muscle strength; 6MWD, six-minute walk test distance; ISWD, incremental shuttle walk test distance
Primary ciliary dyskinesia (PCD) impairs pulmonary function, respiratory and peripheral muscle strength, and exercise capacity. We aimed to investigate the effects of active video games (AVGs) on pulmonary function, respiratory and peripheral muscle strength, exercise capacity, muscle oxygenation (SMO2), physical activity, activities of daily living (ADL), and quality of life (QOL) in PCD. Thirty-two PCD patients were randomly assigned to AVG group (n = 16) and the control group (n = 16). AVG group underwent AVGs using Xbox-Kinect-360 device for 40 min/day, 3 days/week for 8 weeks plus airway clearance techniques (ACT), and the control group was applied ACT only. Pulmonary function, respiratory and quadriceps muscle strength, exercise capacity (6-min walk test [6MWT], incremental shuttle walk test [ISWT]), and ADL (Glittre ADL test) were assessed. SMO2 during ISWT and ADL test was also recorded. Physical activity and QOL (PCD-QOL) were evaluated. Pulmonary function; respiratory and quadriceps muscle strength; 6MWT and ISWT distance; physical activity; ADL performance; SMO2; physical, emotional, and social functioning; treatment burden; and upper and lower symptom parameters of PCD-QOL significantly improved after 8 weeks in the AVG group (p < 0.05). There were no significant differences in measured parameters except emotional function and upper respiratory symptom scores of PCD-QOL in the control group (p > 0.05). Conclusion: The AVGs positively affect pulmonary (pulmonary function, respiratory muscle strength) and extrapulmonary (peripheral muscle strength, exercise capacity, SMO2, physical activity, ADL, and QOL) characteristics in children with PCD. The AVGs may be added to the pulmonary rehabilitation program as an exercise training modality in patients with PCD. Trial registration: This study registered at with NCT03832491 on February 6, 2019.What is Known: • It is indicated that exercise capacity is increased with traditional exercise-training in a case report of Kartagener Syndrome. What is New: • No randomized controlled study investigated the effects of exercise-training in PCD. • 8-week moderate-intensity active video gaming (AVGs) improves pulmonary and extrapulmonary features in children with PCD. AVGs may be preferable due to being enjoyable, providing visual and audial feedback in the pulmonary rehabilitation programs of PCD.
Community-acquired pneumonia is a common diagnosis in children. Among the many children whose symptoms and/or chest X-ray is consistent with community-acquired pneumonia, it can be difficult to distinguish the rare cases of differential diagnoses that require specific management. The aim of this educational article is to provide clinicians with a series of questions to ask themselves in order to detect a possible differential diagnosis of pneumonia in children. The value of this approach is illustrated by 13 real clinical cases in which a child was misdiagnosed as having lobar pneumonia.What is Known: • When a lobar pneumonia is diagnosed, an appropriate antibiotic treatment leads to the resolution of the clinical signs in most cases. • However, several diseases can be look-alikes for pneumonia and mislead the practitioner. What is New: • This article provides a new approach to identify differential diagnoses of pneumonia in children. • It is illustrated by 13 real-life situations of children misdiagnosed as having pneumonia.
Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease’s recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype–phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p < 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes. Conclusion: Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis. What is Known: • Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway. • Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring. What is New: • NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes. • The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.
The use of inhaled nitric oxide (iNO) in treating pulmonary hypertension in infants with congenital diaphragmatic hernia (CDH) is controversial. Our aims were to identify factors associated with survival in CDH infants and whether this was influenced by the response to iNO. Results of CDH infants treated in a tertiary surgical and medical perinatal centre in a ten year period (2011–2021) were reviewed. Factors affecting survival were determined. To assess the response to iNO, blood gases prior to and 30 to 60 min after initiation of iNO were analysed and PaO2/FiO2 ratios and oxygenation indices (OI) calculated. One hundred and five infants were admitted with CDH; 46 (43.8%) infants died. The CDH infants who died had a lower median observed to expected lung to head ratio (O/E LHR) (p < 0.001) and a higher median highest OI on day 1 (HOId1) (p < 0.001). HOId1 predicted survival after adjusting for gestational age, Apgar score at 5 min and O/E LHR (odds ratio 0.948 (95% confidence intervals 0.913–0.983)). Seventy-two infants (68.6%) received iNO; 28 survived to discharge. The median PaO2 (46.7 versus 58.8 mmHg, p < 0.001) and the median PaO2/FiO2 ratio (49.4 versus 58.8, p = 0.003) improved post iNO initiation. The percentage change in the PaO2/FiO2 ratio post iNO initiation was higher in infants who survived (69.4%) compared to infants who died (10.2%), p = 0.018. Conclusion: The highest OI on day 1 predicted survival. iNO improved oxygenation in certain CDH infants and a positive response was more likely in those who survived.
Flow chart of patient inclusion
To assess the association between postnatal growth and neurodevelopment at the age of 2 years in extremely low gestational age newborns (ELGAN, < 28 weeks’ gestation). Retrospective population-based cohort study including all live born ELGAN in 2006–2012 in Switzerland. Growth parameters (weight, length, head circumference, body mass index) were assessed at birth, at hospital discharge home, and 2-year follow-up (FU2). Unadjusted and adjusted regression models assessed associations between growth (birth to hospital discharge and birth to FU2) and neurodevelopment at FU2. A total of 1244 infants (mean GA 26.5 ± 1.0 weeks, birth weight 853 ± 189 g) survived to hospital discharge and were included in the analyses. FU2 was documented for 1049 (84.3%) infants. The mean (± SD) mental and a psychomotor development index at 2FU were 88.9 (± 18.0) and 86.9 (± 17.7), respectively. Moderate or severe neurodevelopmental impairment was documented in 23.2% of patients. Changes of z -scores between birth and discharge and between birth and FU2 for weight were − 1.06 (± 0.85) and − 0.140 (± 1.15), for length − 1.36 (± 1.34), and − 0.40 (± 1.33), for head circumference − 0.61 (± 1.04) and − 0.76 (± 1.32) as well as for BMI 0.22 (± 3.36) and − 0.006 (± 1.45). Unadjusted and adjusted analyses showed that none of the four growth parameters was significantly associated with any of the three outcome parameters of neurodevelopment. This was consistent for both time intervals. Conclusion : In the present population-based cohort of ELGAN, neither growth between birth and hospital discharge nor between birth and FU2 were significantly associated with neurodevelopment at age of 2 years. What is Known: • Studies assessing the association between growth and neurodevelopment in extremely low gestational age newborns (28 weeks’ gestation) show conflicting results. What is New: • Neither growth between birth and hospital discharge nor between birth and corrected age of 2 years were significantly associated with neurodevelopment at age of 2 years. • The role of postnatal growth as a predictor of neurodevelopmental outcome during infancy might be smaller than previously assumed.
Multisystem inflammatory syndrome in children (MIS-C) is an inflammatory condition associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is characterized by fever, gastro-intestinal symptoms, cardiovascular complications, conjunctivitis, skin involvement, elevated inflammatory markers, and coagulation abnormalities. The current ongoing COVID-19 pandemic causes an increased alertness to MIS-C. In combination with the heterogeneous clinical spectrum, this could potentially lead to diagnostic blindness, misdiagnosis of MIS-C, and overtreatment with expensive IVIG treatment. This report demonstrates the challenge of accurately distinguishing MIS-C from other more common inflammatory pediatric diseases, and the need to act with caution to avoid misdiagnoses in the current pandemic. We present a case series of 11 patients suspected of MIS-C based on the current definitions. Three of them were eventually diagnosed with a different disease. Conclusion : Current definitions and diagnostic criteria lack specificity which potentially leads to misdiagnosis and overtreatment of MIS-C. We emphasize the need to act with caution in order to avoid MIS(-C)-taken diagnoses in the current pandemic. What is Known: • A pediatric multisystem inflammatory disease associated with SARS-CoV-2 has been described (MIS-C). • There are three definitions being used for MIS-C, all including fever for at least 24 h, laboratory evidence of inflammation, clinically severe illness with multi-organ (≥ 2) involvement, and no alternative plausible diagnosis. What is New: • MIS-C has a heterogeneous clinical spectrum without distinctive features compared to more common childhood diseases. Current definitions and diagnostic criteria for MIS-C lack specificity which leads to misdiagnosis and overtreatment. • Amid the current excessive attention to COVID-19 and MIS-C, pediatricians should remain vigilant to avoid mistaken diagnoses.
Study flow chart
Electroencephalography (EEG) is an important test in the diagnosis of epilepsy. To perform the test, many electrodes are placed on the child's scalp, a stressful situation that may contribute to uncooperative behavior. The aim of our study was to investigate the effects provided by a close collaboration with medical clowns on the performance of EEG in young children. A prospective randomized control study was conducted between July 2020 and September 2021. The study included children aged 1-5 years who were scheduled to undergo EEG testing at the Bnai Zion Medical Center. The children were randomly allocated to each group (study group with medical clowns and control group without medical clowns) according to the day of the test. The medical clowns, the EEG technician, and the children's caregivers all independently rated the entire process in designated questionnaires composed of items rated on a 5-point Likert scale. In addition, the technical quality of all EEG tests was evaluated and rated by one neurologist (G.J.) in a blinded manner. One hundred children participated in the study. Fifty children underwent the EEG accompanied by one of two medical clowns (study group), and fifty children underwent routine EEG, without medical clowns (control group). The physician-rated technical score of the EEG recording was significantly higher in the study group (p < 0.001). Among parents of the study group, 96% were highly satisfied from the presence of the medical clowns during the EEG (median 5). Both the EEG technician and the parents denoted a significantly higher cooperation rate in the study group children, of 72% and 82%, respectively, compared to the control group. The rating of child/parent's cooperation was not correlated with age, sex, or ethnicity of the child. There was no need for sedation in the study group. Conclusion: Performing EEG in young children in collaboration with medical clowns can increase the quality of the EEG recording possibly due to higher cooperation rates, which in turn lead to mutual satisfaction of both parents and technicians with the procedure. Trial registration: NCT05257096. What is known: • Performing EEG in young children may be a stressful experience. • Use of sedation during EEG may cause side effects. To avoid need for sedation various methods are used to overcome the stressful experience: Natural daytime nap, partial sleep deprivation, oral melatonine and reassurance of parents. What is new: • Performing EEG in young children in collaboration with medical clowns can increase the quality of the EEG recording. • Medical clown intervention led to mutual satisfaction of both parents and technicians with the EEG test procedure.
MIRA-Ginevri lamp system used for home phototherapy
In Italy, where neonatal jaundice treatment is required, it is largely carried out in hospitals. However, it is possible to safely administer home phototherapy (HPT). We report our pilot center's experience of HPT and its potential benefits during the COVID-19-enforced national lockdown. This is an observational study performed at the Policlinic Abano Terme, a suburban hospital that covers a large catchment area near the Euganean Hills in Northeast Italy with around 1000 deliveries per year. HPT was started after regular nursery discharge, and the mothers brought the neonates back to the hospital maternity ward each day to check infants' bilirubin levels, weight, and general state of health, until it was deemed safe to stop. The efficacy of HPT in bilirubin reduction, hospital readmission rates, and parental satisfaction were evaluated. Thirty infants received HPT. In 4 of these infants, HPT was associated with total serum bilirubin (TSB) between 75 and 95th percentile (high-intermediate-risk zone) and in 26 infants HPT was associated with TSB > 95th percentile (high-risk zone) of the Bhutani nomogram. Among these 30 infants, 27 (90%) completed the HPT with a progressive decrease of TSB levels with 4 neonates requiring a second course and 3 infants requiring a third course of 24-h HPT. Three (10%) neonates failed HPT and were readmitted after one 24-h phototherapy course. No abnormalities of breastfeeding, body weight (defined as > 10% decrease), temperature, nor COVID infections were detected following HPT consultation in the neonatal ward. Home treatment efficacy with varying degrees of parental satisfaction occurred in all but 3 cases that involved difficulties with the equipment and inconsistent lamp manipulation practices. Conclusion: Our pilot study suggests that HPT for neonatal jaundice can be carried out effectively and with parental satisfaction as supported by daily back bilirubin monitoring in the maternity ward during the enforced COVID-19 national lockdown in Italy. What is known: • No high-quality evidence is currently available to support or refute the practice of phototherapy in patients' own homes. What is new: • Phototherapy can be delivered at home in a select group of infants and could be an ideal option if parents are able to return with their infants to the hospital maternity ward for daily follow-up. • It can be as effective as inpatient phototherapy and potentially helps in delivering family-centered care.
Temperature average of the groups according to the cooling time
Hemoglobin levels, white cell, and platelet counts in control and hypothermia groups at different times of the treatment. BH (before hypothermia). Hypothermia group: 48 h after therapeutic hypothermia. Control group: 48 h after diagnosis; significant difference (control and hypothermia group): hemoglobin BH: − 2.19 (LS-4.23; LI-0.07). Platelets and white blood cells showed no differences
Sodium, potassium, creatinine, and lactate levels in control and hypothermia groups 48 h after NEC diagnosis. BH (before hypothermia). Hypothermia group: 48 h after therapeutic hypothermia. Control group: 48 h after diagnosis. (Control and hypothermia group): sodium: BH (− 4.9(LS-8.5/LI-1.5); 36 h: − 4.6 (LS-8.5/LI-0.7); potassium: 36 h: − 4.6 (LS-8.5/LI-0.7])
pH, pCO2, bicarbonate, and pO2/FiO2 levels in control and hypothermia groups 48 h after NEC diagnosis. BH (before hypothermia). Hypothermia group: 48 h after therapeutic hypothermia. Control group: 48 h after diagnosis. Significant difference (control and hypothermia group). pH 48 h: − 0.15 (− 0.28/ − 0.02); PCO2, no difference; bicarbonate, no difference. PO2/FiO2 12 h: − 107.5 (− 206.7/ − 12.4)
We performed a quality improvement project to necrotizing enterocolitis (NEC) and published our results about the initiative in 2021. However, aspects on the safety of the cooling and how to do therapeutic hypothermia with low technology to preterm infants are not described in this previous reporter. Thus, we aim to describe the steps and management to apply hypothermia in preterm infants using low technology and present the safety aspects regarding the initiative. We performed a quality improvement project to NEC in a reference hospital for neonatology (intensive care unit). Forty-three preterm infants with NEC (modified Bell's stage II/III) were included: 19 in the control group (2015-2018) and 24 in the hypothermic group (2018-2020). The control group received standard treatments. The hypothermia group received standard treatment and underwent passive cooling (35.5 °C, used for 48 h after NEC diagnosis). We reported cooling safety to NEC, assessing hematological and gasometrical parameters, coagulation disorders, clinical instability, and neurological disorders. We described how to perform cooling to preterm infants using incubators' servo-control and the occurrence and management of dysthermia during the cooling. We turn-off the incubator and used the esophageal probe to monitor the temperature every 15 min; if the temperature dropped, the incubator was turned on with a rewarming speed of 0.5 °C/h. The participants' average weights and gestational ages were 1186 g and 32 weeks, respectively. There were no differences among hematological indices, serum parameters (sodium, potassium, creatinine, lactate, and bicarbonate), pH, pCO2, and pO2/FiO2 between the groups during treatment and after rewarming. We did not observe dysthermia, bradycardia, hemodynamic instability, apnea, seizure, bleeding, peri-intraventricular hemorrhage, or any alterations in ventilatory parameters due to the cooling technique in preterm babies. This simple technique was performed without intercurrences through a rigorous team evaluation, with a target cooling speed of 0.5 °C/h. The target temperature was successfully reached between the second and third hours of life with the incubator control in 21 children; ice bags were used in only three cases. The temperature was maintained at the expected level during the programmed cooling period. Conclusion: Mild controlled hypothermia for preterm infants with NEC is safe. The cooling of preterm infants could be performed through passive methods, using the servo-control of the incubators for temperature management. What is known: • Mild controlled hypothermia to NEC treatment is feasible and associated with a decrease in NEC surgery, short bowel, and death. • Mild controlled hypothermia to preterm is feasible and can be performed through low technology and passive cooling. What is new: • Mild controlled hypothermia to preterm is safe and does not associate with safety adverse effects during and after the cooling. • Preterm infants can be cooled through passive methods by just using the servo control of the incubator, presenting acceptable temperature variance, without dysthermia, achieving and remaining at the target temperature with a proper cooling speed. Mild controlled temperature for preterm infants does not need an additional cooling device.
Top-cited authors
Michel E Weijerman
  • Alrijne Hospital Leiderdorp and Amsterdam University Medical Center
Peter De Winter
  • Spaarne Gasthuis
Hania Szajewska
  • Medical University of Warsaw
Zbigniew Kułaga
  • Children's Memorial Health Institute
Beata Gurzkowska
  • Children's Memorial Health Institute