Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Drosophila Contributions towards Understanding Neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.

Genetic Obesity in Children: Overview of Possible Diagnoses with a Focus on SH2B1 Deletion.

INTRODUCTION: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity. METHODS: We describe the phenotype of 7 children (3 male; age range: 2.8-18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis. RESULTS: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease. DISCUSSION/CONCLUSION: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended.

Transient neonatal diabetes due to a disease causing novel variant in the ATP-binding cassette subfamily C member 8 (ABCC8) gene unmasks maturity-onset diabetes of the young (MODY) diabetes cases within a family.

OBJECTIVES: Neonatal diabetes mellitus (NDM) is a rare monogenic diabetes form, occurring mainly from ATP-binding cassette subfamily C member 8 (ABCC8) and KCNJ11 mutations. ABCC8 mutations have also been found to cause adult-onset diabetes. What is new?: •Novel ABCC8 mutation in an NDM case •Heterogeneous clinical presentation of diabetes and response to sulfonylurea therapy among family members with the same ABCC8 mutation. CASE PRESENTATION: We report the case of a newborn with NDM and a heterozygous ABCC8 novel variant (c.3835G>A), successfully treated with sulfonylurea. The same ABCC8 variant was found in two other family members, already treated for type 2 diabetes. CONCLUSIONS: This case demonstrates the variable phenotypic presentation of diabetes due to a novel ABCC8 mutation (c.3835G>A), ranging from transient NDM to adult-onset, insulin-demanding diabetes, among family members. Genetic testing in young individuals with a strong family history of diabetes, presenting with non-autoimmune diabetes is recommended as it can determine prognosis and treatment of affected family members.

Measles-associated pneumonia and hepatitis during the measles outbreak of 2018.

Background Between 2017 and 2018, Greece experienced a measles outbreak, affecting >3000 patients, most of which were unvaccinated. Measles-associated pneumonia (MAP) is the most common serious compilation of the disease, but very few recent reports regarding its presentation are available. Materials and Methods Between January and May 2018, 11 adult patients presented to our department with acute measles virus infection, hypoxia and findings on chest X-ray. Clinical, laboratory and radiological data were collected and assessed. Nine out of eleven patients had hypoxic respiratory failure. Other complications included hepatitis, cholestasis and myositis, which were observed in the majority of patients. All patients received supplementary oxygen administration, whereas five patients required continuous positive airway pressure ventilation. Scoring of the radiological examinations performed was most notable for the presence of reticular opacities and consolidations. Statistical analysis demonstrated a significant association between PaO2/FiO2 values and the presence of reticular opacities, with PaO2/FiO2 decreasing as the mean value of the reticular opacities score increased (P = .02). Conclusion To our knowledge, this is the first report demonstrating an association between PaO2/FiO2 values and the presence of reticular opacities in patients with MAP. MAP should be suspected in any patient presenting with acute onset hypoxaemia and a reticular pattern on radiological examination, especially in outbreak settings. What is known Measles infections are on the rise in Europe, with epidemics affecting several European countries, resulting from suboptimal immunisation. The most common serious complication of measles is pneumonia, which is more common in adult patients and can cause significant morbidity. It is the most common cause of death due to measles. What is new In this report, we present 11 adults with measles-associated pneumonia, who presented with the combination of acute measles virus infection, hypoxia and findings on chest X-ray. To our knowledge, this is the first report demonstrating an association between the severity of hypoxaemia and the presence of reticular opacities on chest imaging studies.

Subclinical arterial damage in children and adolescents with type 1 diabetes: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Type 1 diabetes is an important risk factor for the development of cardiovascular disease. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) measurements are well recognized as independent predictors for future cardiovascular disease. The aim of the present study was to systematically review the literature and conduct a meta-analysis assessing measures of subclinical arterial damage in children and adolescents with type 1 diabetes in comparison to healthy controls. METHODS: PubMed and Cochrane Library were searched to identify studies comparing cIMT and carotid-femoral PWV levels between children with type 1 diabetes and healthy controls. Meta-analysis was performed to compare the difference of overall mean cIMT and carotid-femoral PWV levels between the two groups. New Castle Ottawa quality assessment scale for case-control studies was used to assess study quality. RESULTS: Twenty-three studies were finally included in the meta-analysis (20 studies for cIMT and 4 studies for carotid-femoral PWV). Youth with type 1 diabetes had significantly higher cIMT levels than controls (mean difference [d] = 0.03, 95% confidence interval [CI] = 0.02-0.04), as well as higher carotid-femoral PWV levels (d = 0.26, 95% CI = 0.18-0.34). Heterogeneity was present only in the cIMT analysis (I2 > 90%). CONCLUSIONS: Youth with type 1 diabetes showed signs of subclinical arterial damage, as suggested by higher levels of cIMT and carotid-femoral PWV compared to healthy controls at childhood and adolescence. Preventive and therapeutic interventions early in course of disease may be further studied to decrease morbidity in this high-risk young patient group. PROSPERO registration number: 2018 CRD42018094354.

The utility of brain natriuretic peptides in septic shock as markers for mortality and cardiac dysfunction: A systematic review.

OBJECTIVE: To conduct a systematic review evaluating the utility of brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) as biomarkers in adult patients with septic shock. MATERIALS AND METHODS: Pubmed/Medline databases were searched from inception to November 2018 using the search terms: (septic[Title/Abstract] AND shock[Title/Abstract]) AND bnp[Title/Abstract]) and (septic[Title/Abstract]) AND shock[Title/Abstract]) AND natriuretic[Title/Abstract]). No restriction was applied regarding date of publication. Comparative observational studies evaluating BNP and NT-proBNP in patients with septic shock aged ≥18 years were eligible for inclusion. Bibliographies from the extracted articles were also reviewed to identify additional relevant publications. RESULTS: In total, 46 studies met all eligibility criteria and were included. A strong body of literature has demonstrated that in patients with septic shock, increased values of BNP and NT-proBNP are associated with increased mortality. An increase from baseline BNP values has also been associated with increased mortality, whereas decreases from baseline values are not related to worse outcome. Brain natriuretic peptides have also been associated with cardiac dysfunction in patients with sepsis. Moreover, BNP values have been found to be significantly elevated in septic shock, regardless of cardiac dysfunction, and have been used to distinguish between septic and cardiogenic shock. Furthermore, BNP and NT-proBNP are significantly increased in patients with septic shock, compared to patients with sepsis and severe sepsis. CONCLUSIONS: BNP and NT-proBNP appear to be reliable predictors of outcome in septic shock.

Cellular and humoral coagulation profiles and occurrence of IVH in VLBW and ELWB infants.

BACKGROUND AND STUDY PURPOSE: Intraventricular hemorrhage (IVH) is a major complication in preterm neonates with significant long-term morbidity and an increased mortality rate. The role of the immature coagulation system in the pathogenesis of IVH in these infants is still under debate. The aim of this study was to provide reference values for coagulation studies within the first 24h of life, and to relate these findings to the incidence of IVH. PATIENTS AND METHODS: In this retrospective study, a total of 250 (male: 123/female: 127; VLBW: 150 and ELBW: 100) infants were included over a 4-year-period. Coagulation studies were performed within the first 24h of life in all infants. Multiple regression analysis was employed to demonstrate a potential association between IVH and a number of known risk and protective factors for IVH (antenatal steroids, birth weight, gender, IUGR, APGAR score at 10minutes, platelet count, INR, PTT, fibrinogen). RESULTS: Mean birth weight was 1047.9±305.6 (range: 320-1490g). Both cellular (platelets, nucleated red blood cells) and plasmatic coagulation parameters (INR, fibrinogen and antithrombin III) were dependent on birth weight. Moreover, INR levels (p<0.05) were significantly increased in neonates with IVH of any grade. Also, INR was positively correlated with the severity of IVH (Spearman's correlation coefficient: 0.193; p=0.003). While overall fibrinogen levels were not associated with IVH, a fibrinogen level<100mg/dL significantly increased the risk for IVH (p<0.01). CONCLUSIONS: Our data provide a robust set of reference values for both cellular and humoral coagulation studies in VLBW and ELBW infants for the first 24h of life. The results of our study indicate that abnormal INR levels and fibrinogen levels<100mg/dL are significantly associated with the occurrence of IVH in this susceptible cohort.

Tongue fasciculations in an infant with spinal muscular atrophy type 1.

Muscular hypotonia in infants may be associated with several conditions, such as spinal muscular atrophy (SMA). We report on an infant with tongue fasciculations and a rare mutation of the SMN1 gene. The presence of tongue fasciculations in combination with a thorough history may be suggestive of SMA.

Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes.

AIMS/HYPOTHESIS: Autoantibodies that precede type 1 diabetes frequently develop in early childhood and target distinct beta cell proteins. The aim of this study was to determine the heterogeneity of islet autoantibody development and fate. METHODS: The ages of development of insulin autoantibodies (IAA) and GAD autoantibodies (GADA), followed by multiple islet autoantibodies and progression to diabetes were examined in 2,441 children participating in two German birth cohorts. RESULTS: In 218 children who developed islet autoantibodies, the first islet autoantibody-positive sample was characterised by single IAA in 80 (37%), multiple islet autoantibodies in 68 (31%) and single GADA in 63 (29%) children. Of the children who were single antibody positive at seroconversion, 35 (44%) IAA-positive and 15 (24%) GADA-positive children developed multiple islet autoantibodies. Single persistent antibodies had heterogeneous affinities; GADA were also heterogeneous in their binding to N-terminally truncated GAD65 and in an ELISA. Progression to diabetes occurred in >50% of children within 10 years in all groups that developed multiple islet autoantibodies and in 44% of children with persistent single high-affinity IAA or persistent single GADA that were positive in both a radiobinding assay and ELISA. The earliest autoantibody development was seen in children with single IAA that progressed to multiple islet autoantibodies or in those with persistent high-affinity single IAA, with a sharp peak in incidence observed at age 9 months. The peak incidence occurred at age 2 years for children who underwent seroconversion directly to multiple islet autoantibodies and at 5 years for children who first seroconverted to GADA and subsequently developed other autoantibodies. Seroconversion to low-affinity IAA or persistent single GADA occurred at a low incidence after the age of 9 months. CONCLUSIONS/INTERPRETATION: Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.

Topiramate-induced nephrolithiasis.

Nephrolithiasis is a less common side effect of the antiepileptic drug topiramate. We report the case of a 3-year-old boy who presented to the emergency department with abdominal pain; examinations revealed a large calcification in the left kidney. Regular ultrasound examinations are recommended in children using topiramate.

Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes.

AIMS/HYPOTHESIS: More than 40 regions of the human genome confer susceptibility for type 1 diabetes and could be used to establish population screening strategies. The aim of our study was to identify weighted sets of SNP combinations for type 1 diabetes prediction. METHODS: We applied multivariable logistic regression and Bayesian feature selection to the Type 1 Diabetes Genetics Consortium (T1DGC) dataset with genotyping of HLA plus 40 SNPs within other type 1 diabetes-associated gene regions in 4,574 cases and 1,207 controls. We tested the weighted models in an independent validation set (765 cases, 423 controls), and assessed their performance in 1,772 prospectively followed children. RESULTS: The inclusion of 40 non-HLA gene SNPs significantly improved the prediction of type 1 diabetes over that provided by HLA alone (p = 3.1 × 10(-25)), with a receiver operating characteristic AUC of 0.87 in the T1DGC set, and 0.84 in the validation set. Feature selection identified HLA plus nine SNPs from the PTPN22, INS, IL2RA, ERBB3, ORMDL3, BACH2, IL27, GLIS3 and RNLS genes that could achieve similar prediction accuracy as the total SNP set. Application of this ten SNP model to prospectively followed children was able to improve risk stratification over that achieved by HLA genotype alone. CONCLUSIONS: We provided a weighted risk model with selected SNPs that could be considered for recruitment of infants into studies of early type 1 diabetes natural history or appropriately safe prevention.

Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression.

AIMS/HYPOTHESIS: Vitamin D deficiency is common in people with type 1 diabetes, but its role in disease progression is unclear. Our aim was to assess the prevalence of vitamin D deficiency in prediabetes (defined as the presence of multiple islet autoantibodies), and investigate whether or not progression to type 1 diabetes is faster in children with vitamin D deficiency and multiple islet autoantibodies. METHODS: Levels of 25-hydroxyvitamin D [25(OH)D] were measured in 108 children with multiple islet autoantibodies within 2 years of islet autoantibody seroconversion, in 406 children who remained islet autoantibody-negative and in 244 patients with newly diagnosed type 1 diabetes. Children with multiple islet autoantibodies were prospectively followed for a median of 5.8 years (interquartile range 3.4-8.6 years) to monitor progression to type 1 diabetes. RESULTS: In the cross-sectional analysis, 25(OH)D levels were lower and the prevalence of vitamin D deficiency (<50 nmol/l) was higher in children with prevalent multiple islet autoantibodies than in islet autoantibody-negative children (59.9 ± 3.0 vs 71.9 ± 1.5 nmol/l; p < 0.001; 39.8% vs 28.3%; p = 0.021). The differences in vitamin D levels between the groups were greatest in summer. The cumulative incidence of type 1 diabetes at 10 years after seroconversion was similar between children with vitamin D deficiency and those with sufficient vitamin D levels (51.8% [95% CI 29.3, 74.3] vs 55.4% [95% CI 35.5, 72.3], p = 0.8). CONCLUSIONS/INTERPRETATION: Vitamin D levels were lower in children with multiple islet autoantibodies and in children with type 1 diabetes than in autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to type 1 diabetes in children with multiple islet autoantibodies.

Effect of a single autologous cord blood infusion on beta-cell and immune function in children with new onset type 1 diabetes: a non-randomized, controlled trial.

BACKGROUND: The application of autologous cord blood in children with type 1 diabetes has been found to be safe, but not to preserve beta-cell function in a previous study, which, however, had not included a control group. OBJECTIVE: To compare the changes of metabolic and immune function over time between cord blood infused children and natural controls. SUBJECTS AND METHODS: Seven children with newly diagnosed type 1 diabetes underwent a single autologous cord blood infusion and 10 children were enrolled as natural controls in a non-randomized, controlled, open label intervention trial. Primary analyses were performed 1 year following cord blood infusion. Cases and controls were compared regarding metabolic [area under the curve (AUC) and peak C-peptide, insulin use, and HbA1c] and immune outcome (islet autoantibody titer and T-cell response), adjusted for age, gender, diabetes duration, and baseline levels. RESULTS: There were no significant adverse events related to the infusion. Metabolic and immune outcomes were not significantly different at 12 months follow-up between infused children and controls (e.g., adjusted p = 0.244 for AUC C-peptide, adjusted p = 0.820 for insulin use, adjusted p = 0.772 for peripheral regulatory T cells). Six-month change of AUC C-peptide correlated significantly with the number of infused CD34+ cells (r = 0.931, p = 0.002). CONCLUSIONS: An autologous cord blood infusion does not change the natural course of metabolic and immune parameters after disease onset. However, the content of CD34+ cells in the stored blood sample might offer potential for improvement of future cell therapies.

Insulin resistance is associated with at least threefold increased risk for prothrombotic state in severely obese youngsters.

UNLABELLED: Obesity in childhood increases the risk for early adult cardiovascular disease. However, the underlying mechanism is not fully known. The aims of this study were to measure levels of prothrombotic factors and examine their possible association with obesity and insulin resistance in obese children and adolescents. A total of 313 obese children and adolescents were recruited. In a cross-sectional design, we measured anthropometric parameters, plasminogen activator inhibitor-1-antigen (PAI-1-Ag), von Willebrand factor-antigen (vWF-Ag), fibrinogen (FB), lipids, fasting glucose, and insulin (FI) levels. Insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR) index. Boys presented significantly higher PAI-1-Ag levels than girls (82.6 vs. 71.3 ng/ml, p = 0.01). Higher levels of PAI-1-Ag (96.8 vs. 69 ng/ml, p < 0.001), vWF-Ag (123.5 vs. 107.6%, p = 0.004) but not FB (353.1 vs. 337.6 mg/dl, p = 0.137) were found in insulin-resistant (IR) participants after adjusted for age, gender, and pubertal stage. IR patients were at 2.98 (CI: 1.084-8.193) and 4.86 (CI: 1.119-15.606) times greater risk for high PAI-1-Ag and vWF-Ag levels, respectively. All three prothrombotic factors were positively correlated with body mass index (BMI) and FI levels (p < 0.05), but only PAI-1-Ag and vWF-Ag were significantly correlated with HOMA-IR index (p ≤ 0.001). After adjustment for confounding factors, both BMI and HOMA-IR indices remained significantly associated with PAI-1-Ag (r2 = 0.225, p < 0.001) and vWF-Ag levels (r2 =0.077, p = 0.003). CONCLUSION: This study shows that obesity in youngsters, when accompanied with insulin resistance, is associated with at least threefold increased risk for elevated levels of prothrombotic factors, contributing to the early development of atherothrombosis. This impaired prothrombotic state may partially explain the increased risk for developing cardiovascular disease later in adulthood.