Healthy Pediatric Subjects Research Articles

Comparative analysis of a novel spectral-domain OCT biometer versus swept-source OCT or OLCR biometer in healthy pediatric ocular biometry

With the advancements in ocular biometric technology, there have been significant improvements in accurately and efficiently measuring ocular parameters. The aim of this study is to compare the reliability of biometric parameters obtained using a new frequency-domain optical coherence tomography (SD-OCT) biometer with the measurements obtained from swept-source OCT (SS-OCT) and optical low coherence reflectometry (OLCR) biometers. This study employed an observational cross-sectional design. Measurements of axial length (AL), flat and steep corneal keratometry (K1 and K2), and central corneal thickness (CCT) obtained using the The Colombo IOL were compared with those obtained with the IOLMaster 700 and SW-9000 devices. The agreement were evaluated using intraclass correlation coefficient (ICC) and Bland–Altman analyses. The differences of the measurements of the three increments were assessed by one-way ANONA. 73 right eyes of 73 healthy pediatric subjects were analyzed. The AL difference measured by Colombo IOL compared with IOLmaster700 and SW-9000 were 0.00 ± 0.02 mm and − 0.07 ± 0.05 mm, respectively (P > 0.05, ANOVA). There was no statistically significant difference in CCT, K1, and K2 among the three instruments (all P > 0.05, ANOVA). The ICC values for AL, K1, K2, and CCT were 0.999, 0.996, 0.995, and 0.998, respectively. The Bland-Altman analysis showed an agreement of AL, K1, K2, and CCT with Colombo IOL and IOLMaster 700 spanned over 0.08 mm, 0.71D, 0.69D, and 12.17 μm, respectively. The agreement of AL, K1, K2, and CCT with Colombo IOL and SW-9000 spanned approximate 0.21 mm, 0.75D, 1.06D, and 14.37 μm, respectively. The new SD-OCT biometer and the SS-OCT biometer showed strong agreement in measuring AL and CCT in healthy pediatric subjects. This supports the reliability of the new SD-OCT biometer as an alternative for assessing these parameters. However, K1 and K2 could not be used interchangeably in clinical practice. Further research is needed to explore their applicability in different clinical settings and patient populations."light" />

Mobile ECG devices in pediatric cardiology: efficacy and accuracy of smart watch and hand-held device in healthy children

Abstract Background and Aim Pediatric arrhythmias require accurate electrocardiogram (ECG) assessment for diagnosis and management. Mobile ECG devices, such as smart watch based and hand-held devices, offer potential advantages in terms of portability and accessibility. This study aimed to compare the efficancy and diagnostic accuracy of ECG tracings obtained using a smart watch and a hand-held device with standard 12-lead ECG tracings in healthy children. Methods ECG data were acquired from healthy pediatric subjects (n=30) aged 4 to 18 years using the smart watch, hand-held device, and standard 12-lead ECG. Single leads were acquired sequentially. The time required for ECG acquisition was recorded for each device. Subsequently, ECG leads were analyzed for voltage, duration, and morphology of waves and intervals, as well as ST segments. Qualitative assessment of leads included morphology comparison of waves and complexes to standard 12-lead ECG and using a physician based quality rating scale. Assessment was performed by two blinded pediatric electrophysiologists. Results We found significant differences in the time required to acquire ECG tracings between the smart watch, standard 12-lead ECG, and hand-held device, with the smart watch being notably slower (median 15 min, 4 min, 1 min, respectively). ECG leads obtained with the smart watch and hand-held device demonstrated comparability to standard 12-lead ECG tracings in terms of quantitative key parameters, including voltage (mV) and duration (ms) of waves and intervals. Qualitative assessment revealed good correlation of the hand-held device with standard 12-lead ECG, while the smart watch performed less well. Conclusions This study suggests that mobile ECG devices offer a diagnostic accuracy comparable to that of standard 12-lead ECGs in healthy children. While the smart watch may be slower in ECG acquisition, acquisition of all 12 standard ECG leads is feasible in this population. The potential of both included mobile devices for pediatric usage in specific clinical scenarios, such as remote monitoring or emergencies, is promising.Graphical Abstract

Normal Values for Echocardiographic Myocardial Work in a Large Pediatric Population.

Echocardiographic myocardial work is a new load-independent echocardiographic technique to quantify left ventricle (LV) systolic performance. Our aim was to establish normal values for echocardiographic myocardial work in a large population of healthy children. For all the subjects 4-, 2-, and 3-chamber-view videos were stored. The following parameters were obtained by offline analysis: the global myocardial work (GMW), the global myocardial constructive work (GCW), the global myocardial wasted work (GWW), and the global myocardial work efficiency (GWE). Age, weight, height, heart rate, and body surface area (BSA) were used as independent variables in the statistical analysis. In all, 516 healthy subjects (age range, 1 day-18 years; median age, 8.2 ± 5.3 years; 55.8% male; body surface area (BSA) range, 0.16 to 2.12 m2) were included. GWI, GCW, and GWW increased with weight, height, and BSA (ρ ranging from 0.635 to 0.226, p all < 0.01); GWI and GCW positively correlated with age (ρ 0.653 and 0.507). After adjusting for BSA differences, females showed higher mean GWI (p = 0.002) and GCW values (p < 0.001), thus Z-score equations for gender have been presented. We provided MW values in a large population of healthy pediatric subjects including lower ages. MW values increased with age and body size and, interestingly, were higher in females than in men. These data cover a gap in current nomograms and may serve as a baseline for the evaluation of MW analysis in children with congenital and acquired heart diseases.

AG-920 (Articaine) Ophthalmic Solution: A Masked, Active-Controlled Evaluation of Its Local Anesthetic Efficacy and Safety in Pediatric Patients.

Purpose: The safety and efficacy of a novel topical ocular anesthetic (AG-920 sterile ophthalmic solution, 8%) was previously evaluated in adults. For both clinical and regulatory purposes, this new agent was evaluated in children. Methods: This was a Phase 3, randomized, active-controlled, single-masked, parallel-group design study in healthy pediatric subjects performed at a private practice retina clinic in the United States. The safety and anesthetic efficacy of AG-920 was compared with proparacainehydrochloride ophthalmic solution 0.5% in 60 children undergoing ophthalmic examinations. The primary efficacy endpoint was whether the investigator was able to perform the eye examination. Results: In all subjects in each treatment group, the investigator was able to perform the eye examination without additional local anesthetic. There were no adverse events reported in this study. In both the study eye and fellow eye, there were no notable changes after dosing, and both treatment groups were similar. All external eye exams in all subjects in both treatment groups were normal. Conclusions: In this pediatric population aged 7 months to >11 years, AG-920 was therapeutically equivalent to marketed proparacaine with respect to having an ophthalmic examination performed without needing additional local anesthetic. Further, AG-920 was well tolerated, and there were no clinically significant safety findings.

Animal-to-Human Dose Translation of ANTHRASIL for Treatment of Inhalational Anthrax in Healthy Adults, Obese Adults, and Pediatric Subjects.

Anthrax Immune Globulin Intravenous (AIGIV [ANTHRASIL]), was developed for the treatment of toxemia associated with inhalational anthrax. It is a plasma product collected from individuals vaccinated with anthrax vaccine and contains antitoxin IgG antibodies against Bacillus anthracis protective antigen. A pharmacokinetic (PK) and exposure-response model was constructed to assess the PKs of AIGIV in anthrax-free and anthrax-exposed rabbits, non-human primates and anthrax-free humans, as well as the relationship between AIGIV exposure and survival from anthrax, based on available preclinical/clinical studies. The potential effect of anthrax on the PKs of AIGIV was evaluated and estimates of survival odds following administration of AIGIV protective doses with and without antibiotic co-treatment were established. As the developed PK model can simulate exposure of AIGIV in any species for any dosing scenario, the relationship between the predicted area under the concentration curve of AIGIV in humans and the probability of survival observed in preclinical studies was explored. Based on the simulation results, the intravenous administration of 420 U (units of potency as measured by validated Toxin Neutralization Assay) of AIGIV is expected to result in a > 80% probability of survival in more than 90% of the human population. Additional simulations suggest that exposure levels were similar in healthy and obese humans, and exposure in pediatrics is expected to be up to approximately seven-fold higher than in healthy adults, allowing for doses in pediatric populations that ranged from one to seven vials. Overall, the optimal human dose was justified based on the PK/pharmacodynamic (PD) properties of AIGIV in animals and model-based translation of PK/PD to predict human exposure and efficacy.

Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia.

The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold (p < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower (p < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Anatomic Features of the Interthalamic Adhesion in the Pediatric Population

The main goal of this retrospective study was to examine the morphology of the interthalamic adhesion (ITA) in normal children aged between 1 and 18 years. The study universe consisted of magnetic resonance images of 180 healthy pediatric subjects (age, 9.50 ± 5.20 years, sex, 90 girls and 90 boys). The cross-sectional area (CSA), vertical diameter (VD), and horizontal diameter (HD) of the ITA were measured and in addition, its location was noted. HD, VD, and CSA of the ITA were measured as 8.47 ± 1.64 mm, 7.59 ± 1.57 mm, and 52.06 ± 18.51 mm2, respectively. HD did not change from infancy until postpubescence, but then significantly decreased (P < 0.001). VD increased up to early childhood but then did not alter until the end of prepubescence. After that period, it decreased in postpubescence (P < 0.001). CSA tended to decrease in an irregular pattern according to pediatric age periods (P < 0.001). The ITA was located at the anterosuperior quadrant in 138 individuals (76.70%), at the anteroinferior quadrant in 7 individuals (3.90%), and the center of the lateral wall of the third ventricle in 35 individuals (19.40%). Linear functions were calculated as y= 9.490-0.107× age (years) for HD, y= 8.453-0.091× age (years) for VD, and y= 63.559-1.211× age (years) for CSA. ITA size irregularly decreases with advancing age from 1 to 18 years. Our calculated linear functions, showing the growth dynamics of the ITA by pediatric ages, may be helpful in estimating its dimension.

Reference data for left ventricular filling and atrial function in children using cardiovascular magnetic resonance

BackgroundDiastolic dysfunction is associated with morbidity and mortality in multiple pediatric disease processes. Cardiovascular magnetic resonance (CMR) provides a non-invasive method of studying left ventricular (LV) diastolic dysfunction through the assessment of LV filling curves and left atrial (LA) volume and function. However, there are no normative data for LV filling curves and the standard method is time-intensive. This study aims to compare an alternate, more rapid method of obtaining LV filling curves to standard methodology and report normative CMR diastolic function data for LV filling curves and LA volumes and function. MethodsNinety-six healthy pediatric subjects (14.3 ± 3.4 years) with normal CMR defined by normal biventricular size and systolic function without late gadolinium enhancement were included. LV filling curves were generated by removing basal slices without myocardium present throughout the cardiac cycle and apical slices with poor endocardial delineation (compressed method), then re-generated including every phase of myocardium from apex to base (standard method). Indices of diastolic function included peak filling rate and time to peak filling. Systolic metrics included peak ejection rate and time to peak ejection. Both peak ejection and peak filling rates were indexed to end-diastolic volume. LA maximum, minimum and pre-contraction volumes were calculated using a biplane method. Inter-and intra-observer variability were assessed with intraclass correlation coefficient. Multivariable linear regression was used to assess the effects of body surface area (BSA), gender and age on metrics of diastolic function. ResultsBSA had the largest effect on LV filling curves. Normal LV filling data are reported for both compressed and standard methods. The time to perform the compressed method was significantly shorter than the standard method (median 6.1 min vs. 12.5 min, p < 0.001). Both methods had strong to moderate correlation for all metrics. Intra-observer reproducibility was moderate to high for all LV filling and LA metrics except for time to peak ejection and peak filling. ConclusionsWe report reference values for LV filling metrics and LA volumes. The compressed method is more rapid and produces similar results to standard methodology, which may facilitate the use of LV filling in clinical CMR reporting.

Repeatability of retinal thickness measurements in children using spectral domain optical coherence tomography

AbstractPurpose: To evaluate the influence of age in the repeatability of retinal thickness measurements in a healthy paediatric population with spectral domain Optical Coherence Tomography (SD‐OCT). Knowledge of RNFL parameters and macular characteristics in a normal population and differences between ages and sexes is useful for evaluating normal development of the eyes. Also, an essential quality in determining the utility of a device for clinical use is its measurement variability. Repeatability is important for distinguishing normal subjects from patients with disease as well as for following ocular modifications over time for follow‐up after treatment, especially in young population.Methods: Seventy‐six eyes from 76 healthy paediatric subjects underwent three fast macula scans and 81 eyes from 81 healthy paediatric subjects were studied by three retinal nerve fiver layer (RNFL) measurements using a Spectralis OCT device. Mean thicknesses in the nine Early Treatment Diabetic Retinopathy Study (ETDRS) and in the seven optic nerve RNFL areas were measured. Mean values were evaluated by age and by sex. Children were divided in two groups, Group 1/ 6 years old or younger and group 2/ children older than 6 years. We calculated the repeatability comparing the two age groups, looking for intraclass correlation coefficient (ICC) and coefficient of variation (COV) values.Results: In the younger group central macular thickness value was 262.52 ± 18.28, and the central RNFL 104.03 ± 7.99. In the group of children older than 6, central macular thickness was 270.57 ± 18.49 and the central RNFL 100.27 ± 8.58. No statistically significant differences were found. Central retina thickness COVs were 7.00 in group 1% and 6.83% in Group 2. Optic disc RNFL thickness COVs were 7.72% in Group 1 and 8.69% in Group 2. All ICCs were higher than 0.8 showing excellent correlation among the three measurements performed by the same operator.Conclusions: Repeatability of Spectralis OCTs is high in healthy macula measurements, and significantly higher with Spectralis. Small differences were found between repeatability of macular thickness measurements obtained by both devices analysed by age.

Agreement of iCare IC200 tonometry with Perkins applanation tonometry in healthy children

PurposeTo assess interdevice agreement between the iCare IC200 rebound tonometer and Perkins applanation tonometry (gold standard) in a healthy pediatric population. MethodsA total of 42 eyes of 42 healthy children were assessed using both tonometers. Data was collected on subject’s age, sex, best-corrected visual acuity, and central corneal thickness (CCT). Intraclass correlation coefficient (ICC) and Bland-Altman analyses were used to determine agreement between IC200 and Perkins applanation tonometers. Linear regression analyzed the effects of intraocular pressure (IOP) on device difference. ResultsThe mean age and standard deviation of healthy pediatric subjects was 10.0 ± 3.3 years. The mean difference between IC200 and Perkins tonometers (IC200-Perkins) was 0.72 mm Hg, with a mean of 17.1 ± 3.0 mm Hg and 16.4 ± 2.5 mm Hg, respectively. The absolute agreement, or ICC, between tonometers was 0.63 (95% CI, 0.56-0.70). Bland-Altman analysis showed 95% limits of agreement ranging from −5.2 to +6.6 mm Hg. CCT was not correlated with IOP for either the IC200 (P = 0.35) or the Perkins tonometer (P = 0.052). ConclusionsCompared to applanation tonometry, IC200 overestimated IOP in healthy children, with a greater frequency of readings > +2 mm Hg than < −2 mm Hg compared to Perkins. There was moderate agreement between tonometers. CCT was not found to influence IOP measurement for either tonometer.

Soluble Isoform of Suppression of Tumorigenicity 2 (ST2) Biomarker in a Large Cohort of Healthy Pediatric Population: Determination of Reference Intervals.

Introduction: Only little data exists on ST2 reference intervals in healthy pediatric populations despite the high importance of this biomarker in adults with heart failure. The aim of the study was to assess the reference intervals of ST2 in a wide healthy pediatric cohort. Methods: We evaluated the serum concentrations of ST2 biomarker in 415 healthy pediatric subjects referred to our analysis laboratory. Subjects were categorized according to age (i.e., 0–6 (n = 79), 7–11 (n = 142) and 12–18 years (n = 191)) and sex. They were not suffering from any cardiac disorders, metabolic disorders, lung diseases, autoimmune disorders or malignancies. A written consent was obtained for each individual. No duplicate patients were included in the analysis and the presence of outliers was investigated. Reference intervals (Mean and central 95% confidence intervals) were determined. Results: Three outliers have been identified and removed from the analysis (60.0, 64.0 and 150.2 ng/mL). A total of 412 subjects were therefore included. The mean value for the whole population was 15.8 ng/mL (2.4–36.4 ng/mL). Males present a significantly higher mean concentration compared to females (17.2 versus 14.4 ng/mL, p = 0.001). A significant trend toward higher ST2 values with age was also observed, but for males only (r = 0.43, p < 0.0001). If considering age partitions, only males of 12–18 years (mean = 21.7 ng/mL) had significantly higher ST2 values compared to the other groups (ranging from 11.9 for males 0–6 years to 15.2 for females 12–18 years; p < 0.0001). Conclusions: We described age and sex-specific reference intervals for ST2 in a large healthy pediatric population. We found that ST2 values differ between sexes if considering all participants. A significant increase in ST2 with age was also observed, but only for males of 12–18 years.

Parathyroid Hormone-Related Peptide (PTHrP): Evaluation of Pediatric, Covariate-Stratified Reference Intervals.

Parathyroid hormone-related peptide (PTHrP) is expressed at a wide range of sites in the body and performs different functions including vasodilation, relaxation of smooth muscle cells, and regulation of bone development. PTHrP also mediates hypercalcemia related to neoplastic diseases. However, reference ranges specific method and age were not evaluated. We establish PTHrP reference ranges in apparently healthy, normocalcemic, normophosphatemic pediatric individuals. In this observational prospective, study we measured PTHrP in serum from 178 samples (55.06% male 44.94% female) from apparently healthy pediatric subjects [median age 10 years (range 1–18)] subunit ELISA method The statistical analysis performed provided for the calculation of the 95% reference interval, right-sided, with a non-parametric percentile method (CLSI C28-A3). Upper reference limits (URL) for PTHrP was 2.89 ng/mL (2.60 to 3.18; 90% CI). No significant differences were found between the median PTHrP concentrations in males vs females and in the age range categories selected. Comprehensive normal values for PTHrP are indispensable to the assessment of calcium phosphorus dysfunction in children. Severe hypercalcemia is a rare, but clinically significant condition, in infancy and childhood. PTHrP values higher than the reference value may help to distinguish the hypercalcemic product of a malignancy, paraneoplastic syndromes mediated by PTHrP, from other causes.

Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1

Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5–5.6 years old) and adult (n = 4; 47–63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.

Retinal and choroidal vascular changes in newly diagnosed celiac disease: An optical coherence tomography angiography study.

Purpose:To investigate the retinal and choroidal microcirculation changes in celiac disease (CD) patients via optical coherence tomography angiography (OCT-A).Methods:This cross-sectional study included 44 pediatric patients with newly diagnosed CD and 44 healthy pediatric subjects. The vascular densities (VD) of the superficial, deep, and choriocapillar plexuses (VDs, VDd, and VDcc, respectively) (%), the superficial and deep foveal avascular zones (FAZs and FAZd) (%), the central macular thickness (CMT) (mm), and the subfoveal choroidal thickness (SFCT) (mm) were measured with swept-source OCT-A in addition to a complete ophthalmological examination.Results:Mean ages of the CD patients and the healthy participants were 12.02 ± 2.9 and 13.6 ± 2.3 years, respectively. The central sectors of the VDs and VDd measurements were found to be significantly higher in the study group compared to the control group (p = 0.006; P = 0.001, respectively), and the temporal and nasal values of the VDcc measurements were significantly lower in the study group than in the control group (p < 0.05 for both values). CMT and FAZ metrics did not differ between the groups (p > 0.05). SFCT was significantly reduced (p = 0.001), and choroidal thinning was more considerable in female CD patients (p = 0.045).Conclusion:CD seems to affect macular and choroidal microcirculation. The reduced choriocapillaris plexus parameters and choroidal thickness may provide disease activity information.

Cine phase-contrast magnetic resonance imaging evaluation of cerebrospinal fluid flow dynamics in healthy pediatric subjects.

ObjectiveTo evaluate cerebrospinal fluid dynamics, using cine phase-contrast magnetic resonance imaging (cine-PC MRI), in healthy pediatric subjects, determining the normal flow values in this population, as well as identifying differences related to age, sex, and body surface area.Materials and MethodsThis was a descriptive cross-sectional study involving 32 healthy children and adolescents, in whom the flow of cerebrospinal fluid through the cerebral aqueduct was evaluated quantitatively with cine-PC MRI. We used specialized software to analyze the images obtained with cine-PC MRI, drawing a region of interest on the aqueduct. A flow-time curve was obtained, as were automated measurements of the various parameters.ResultsThe following normal (mean) values were obtained: net flow, 1.10 ± 0.99 mL/m; stroke volume, 12.2 ± 10.1 µL/cycle; mean velocity, 0.72 ± 1.00 cm/s; peak systolic velocity, 5.28 ± 2.30 cm/s; peak diastolic velocity, 4.51 ± 1.77 cm/s. These values were not affected by age or sex. In addition, body surface area was not found to correlate significantly with mean velocity or stroke volume.ConclusionIn children and adolescents, the basic cerebrospinal fluid flow parameters, as determined by cine-PC MRI, appear to be independent of age and sex.

Immune Regulatory Functions of IgG in the Ontogeny of Human Natural Regulatory T Cells

The heavy constant region of IgG (Fc) is highly immunogenic for human natural regulatory T cells (nTreg). Mature IgG+ B cells prime Fc-specific Treg via recycling of surface immunoglobulin with an antigen-processing pathway that is very efficient in presenting immunodominant Fc peptides to Treg. Some of these peptides are pan-HLA binders, explaining the presence of Fc-specific Treg in circulation in healthy pediatric and adult subjects. Following IgG+ B cell priming, further Treg expansion occurs with the presentation of Fc peptides following IgG uptake and processing by CD14+ myeloid dendritic cells type 2 (cDC2) and CD4+ immunoglobulin-like transcript 4 (ILT-4+) tolerogenic DC that secretes IL-10 when stimulated by the Fc that enters cells prevalently via Fcg receptor II. Fc-specific Treg are important in regulating naive T cell differentiation and account for a key mechanism of success for intravenous immunoglobulin therapy (IVIG) in several inflammatory conditions, including Kawasaki disease (KD) a pediatric acute vasculitis of the coronary arteries.

Epithelial component and intraepithelial lymphocytes of conjunctiva-associated lymphoid tissue in healthy children.

Conjunctiva-associated lymphoid tissue (CALT) plays a key role in protecting the eye surface by initiating and regulating immune responses. The aim of this study was to investigate in healthy children the proportion of intraepithelial lymphocytes (IELs), the degree of viability and/or apoptosis and cell proliferation in three different topographic areas of the conjunctiva. Superior tarsal, superior bulbar, and inferior tarsal-bulbarfornix conjunctival cells were collected by brush cytology (BC) from 24 healthy paediatric subjects (13 boys and 11 girls, mean age 6±2 years) who were to undergo strabismus correction surgery under general anaesthesia. Subsequently, these cells were analysed phenotypically and functionally by flow cytometry (FC). Flow cytometry analysis showed that not all the cells obtained by BC were of the epithelial lineage, but that there was a population of CD45+ cells (IELs) regularly present in the conjunctiva of healthy children. These IELs were mostly T-lymphocytes (CD3+) and B-lymphocytes (CD19+), with higher levels of T-lymphocytes (CD3+) in the upper areas than in the inferior tarsal-bulbar-fornix, where the highest levels of B-lymphocytes (CD19+) were found. In the apoptosis assay, two groups of cell populations were differentiated by cell size and complexity (cytoplasmic granularity), with more complex cells predominating in the upper areas of the conjunctiva and less complex cells being more abundant in the inferior tarsal-bulbar-fornix. Finally, the proliferative capacity of the conjunctival epithelium was significantly higher in the upper tarsal zone than in the rest of the zones analysed. These results suggest that the epithelial component and the IELs of CALT are also regularly present in the conjunctiva of the healthy child, varying in phenotype, viability and cell proliferation according to the different conjunctival regions analysed, which could lead us to believe that each conjunctival zone plays a different, specific role in the regulation of the immune response at the ocular level.

New reference intervals for endocrinological biomarkers in pediatric patients: what can we learn from the LIFE child study?

Abstract Objectives We established reference intervals for serum concentrations of hormones from healthy pediatric subjects and investigated their associations with gender, body mass index (BMI), puberty and oral contraceptives (oC). Methods We calculated reference intervals for the thyroid parameters thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and calcitonin (Ct); the bone markers osteocalcin, procolagen type 1 N-propeptide, and carboxy-terminal cross-linking telopeptide of type 1 collagen; the calciotropic hormones 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone and the steroids cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estradiol, dehydroepiandrosterone sulfate and aldosterone. Up to 10,002 blood serum samples from 3,229 healthy children and adolescents (age interval: 3 months to 20 years) were measured. To investigate the associations between the hormone levels with age, sex, weight status and the role of puberty-based changes, the measurement and BMI values were transformed into standard deviation scores. Results Most of the hormones depended on age- and gender. Puberty was linked to a, in part, temporary decrease in TSH, FT3 (for females), FT4, Ct, cortisol (for girls) and aldosterone (for boys) and peak in the bone marker and calciotropic hormones (excluding 25(OH)D) and nearly all remaining steroids. BMI had effects on the thyroid, bone, and calciotropic parameters, whereas oC led to increased cortisol, suppressed progesterone and estradiol values. Conclusions Age- and gender-specific reference intervals are essential for the interpretation of pediatric patients’ hormone measurements. Influencing factors as puberty, BMI, or oC should be taken into consideration for diagnosis and treatment monitoring.

Antibody responses against heterologous A/H5N1 strains for an MF59-adjuvanted cell culture–derived A/H5N1 (aH5N1c) influenza vaccine in healthy pediatric subjects

BackgroundVaccines are the main prophylactic measure against pandemic influenza. Adjuvanted, cell culture–derived vaccines, which are not subject to limitations of egg-based vaccine production, have the potential to elicit an antibody response against heterologous strains and may be beneficial in the event of an A/H5N1 pandemic. MethodsA prespecified exploratory analysis of data from a phase 2, randomized, controlled, observer-blind multicenter trial (NCT01776554) to evaluate the immunogenicity of a MF59-adjuvanted, cell culture–based A/H5N1 influenza vaccine (aH5N1c), containing 7.5 µg hemagglutinin antigen per dose, in subjects 6 months through 17 years of age was conducted. Geometric mean titers (GMT) were determined using hemagglutination inhibition (HI) and microneutralization (MN) assays, and proportions of patients achieving seroconversion, HI and MN titers ≥ 1:40, and a 4-fold increase in MN titers against 5 heterologous strains (influenza A/H5N1 Anhui/2005, Egypt/2010, Hubei/2010, Indonesia/2005, and Vietnam/1203/2004) three weeks after administration of the second dose were assessed. ResultsAfter the second dose, HI GMTs against heterologous strains increased between 8- and 40-fold, and MN GMTs increased 13- to 160-fold on Day 43 vs Day 1. On Day 43, 32–72% of subjects had HI titers ≥ 1:40 and achieved seroconversion against the heterologous strains. Using the MN assay, 84–100% of subjects had MN titers ≥ 1:40 and 83–100% achieved an at least 4-fold increase in MN titers against the heterologous strains. The highest responses were consistently against A/H5N1 Egypt/2010. ConclusionsWhen given to children aged 6 months through 17 years, aH5N1c resulted in increased immunogenicity from baseline against all 5 heterologous A/H5N1 strains tested, demonstrating the potential of an MF59-adjuvanted, cell-derived A/H5N1 vaccine to provide cross-protection against other A/H5N1 strains (NCT01776554).

Normal childhood brain growth and a universal sex and anthropomorphic relationship to cerebrospinal fluid.

OBJECTIVEThe study of brain size and growth has a long and contentious history, yet normal brain volume development has yet to be fully described. In particular, the normal brain growth and cerebrospinal fluid (CSF) accumulation relationship is critical to characterize because it is impacted in numerous conditions of early childhood in which brain growth and fluid accumulation are affected, such as infection, hemorrhage, hydrocephalus, and a broad range of congenital disorders. The authors of this study aim to describe normal brain volume growth, particularly in the setting of CSF accumulation.METHODSThe authors analyzed 1067 magnetic resonance imaging scans from 505 healthy pediatric subjects from birth to age 18 years to quantify component and regional brain volumes. The volume trajectories were compared between the sexes and hemispheres using smoothing spline ANOVA. Population growth curves were developed using generalized additive models for location, scale, and shape.RESULTSBrain volume peaked at 10–12 years of age. Males exhibited larger age-adjusted total brain volumes than females, and body size normalization procedures did not eliminate this difference. The ratio of brain to CSF volume, however, revealed a universal age-dependent relationship independent of sex or body size.CONCLUSIONSThese findings enable the application of normative growth curves in managing a broad range of childhood diseases in which cognitive development, brain growth, and fluid accumulation are interrelated.