Electrical impedance spectroscopy detects skin barrier dysfunction in childhood atopic dermatitis.

BACKGROUND: Skin barrier dysfunction is associated with the development of atopic dermatitis (AD), however methods to assess skin barrier function are limited. We investigated the use of electrical impedance spectroscopy (EIS) to detect skin barrier dysfunction in children with AD of the CARE (Childhood AlleRgy, nutrition, and Environment) cohort. METHODS: EIS measurements taken at multiple time points from 4 months to 3-year-old children, who developed AD (n = 66) and those who did not (n = 49) were investigated. Using only the EIS measurement and the AD status, we developed a machine learning algorithm that produces a score (EIS/AD score) which reflects the probability that a given measurement is from a child with active AD. We investigated the diagnostic ability of this score and its association with clinical characteristics and age. RESULTS: Based on the EIS/AD score, the EIS algorithm was able to clearly discriminate between healthy skin and clinically unaffected skin of children with active AD (area under the curve 0.92, 95% CI 0.85-0.99). It was also able to detect a difference between healthy skin and AD skin when the child did not have active AD. There was no clear association between the EIS/AD score and the severity of AD or sensitisation to the tested allergens. The performance of the algorithm was not affected by age. CONCLUSIONS: This study shows that EIS can detect skin barrier dysfunction and differentiate skin of children with AD from healthy skin and suggests that EIS may have the ability to predict future AD development.

Systematic review of the association between short-chain fatty acids and allergic diseases.

We performed a systematic review to investigate the current evidence on the association between allergic diseases and short chain fatty acids (SCFAs), which are microbially produced and suggested as one mechanism on how gut microbiome affects the risk of allergic diseases. Medline, Embase and Web of Science were searched from data inception until September 2022. We identified 37 papers, of which 17 investigated prenatal or early childhood SCFAs and the development of allergic diseases in childhood, and 20 assessed SCFAs in patients with pre-existing allergic diseases. Study design, study populations, outcome definition, analysis method and reporting of the results varied between papers. Overall, there was some evidence showing that the three main SCFAs (acetate, propionate and butyrate) in the first few years of life had a protective effect against allergic diseases, especially for atopic dermatitis, wheeze or asthma and IgE-mediated food allergy in childhood. The association between each SCFA and allergic disease appeared to be different by disease and the age of assessment. Further research that can determine the potentially timing specific effect of each SCFA will be useful to investigate how SCFAs can be used in treatment or in prevention against allergic diseases.

Environmental influences on childhood allergies and asthma - The Farm effect.

Asthma and allergies are major health problems and exert an enormous socioeconomic burden. Besides genetic predisposition, environmental factors play a crucial role in the development of these diseases in childhood. Multiple worldwide epidemiological studies have shown that children growing up on farms are immune to allergic diseases and asthma. Farm-related exposures shape children's immune homeostasis, via mediators such as N-glycolylneuraminic acid or arabinogalactan, or by diverse environmental microbes. Moreover, nutritional factors, such as breastfeeding or farm milk and food diversity, inducing short-chain fatty acids-producing bacteria in the intestine, contribute to farm-related effects. All farm-related exposures induce an anti-inflammatory response of the innate immunity and increase the differentiation of regulatory T cells and T helper cell type 1. A better understanding of the components of the farm environment, that are protective to the development of allergy and asthma, and their underlying mechanisms, will help to develop new strategies for the prevention of allergy and asthma.

Interrelations of Intraoperative Changes in Cerebral Tissue Oxygen Saturation with Brain Volumes and Neurodevelopment Outcome After the Comprehensive Stage II Procedure in Infants With Hypoplastic Left Heart Syndrome: A Retrospective Cohort Study.

OBJECTIVES: The monitoring of cerebral tissue oxygen saturation by near-infrared spectroscopy (ScerebO2) is used widely in pediatric cardiac anesthesia. However, little information is available on the effects of changes in perioperative ScerebO2 on brain morphology and neurologic outcome. The primary hypothesis tested in this study was that intraoperative ScerebO2 during the comprehensive stage II procedure correlated with brain volumes assessed by magnetic resonance imaging and neurodevelopmental scores. DESIGN: Retrospective observational cohort study. SETTING: University Hospital, Pediatric Heart Centre. PATIENTS AND MEASUREMENTS: In 19 infants, the intraoperative course of ScerebO2 during the comprehensive stage II procedure was examined. Minimal ScerebO2 and integrated ScerebO2 below 45% (AUC) during surgery, as well as cerebral magnetic resonance imaging (MRI) examinations and Bayley III test at the ages of two-to-three years, were analyzed. MAIN RESULTS: A positive correlation between minimal ScerebO2 and intracranial volume (p = 0.0243), total brain volume (p = 0.0243), and white matter volume (p = 0.0276) was observed, as was a negative correlation between AUC and intracranial volume (p = 0.0454) and white matter volume (p = 0.0381), respectively. No association was found between ScerebO2 and Bayley-III Score. CONCLUSION: The correlation between ScerebO2 and brain volumes measured by MRI pointed out a possible importance of neuroprotective strategies aimed at optimizing ScerebO2 during complex congenital heart surgery. That no correlation between ScerebO2 and Bayley III Score was found suggested multifactorial causes for neurologic outcome in children with congenital heart defects.

Growth and Intellectual Abilities of Six-Year-Old Children with Congenital Heart Disease.

OBJECTIVE: To determine growth and its relationship to IQ in children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery within the first year of life. STUDY DESIGN: Prospective single-center cohort study on 143 children (91 males) with different types of CHD (29 univentricular). Children with recognized genetic disorders were excluded. Growth (weight, height, and head circumference [HC]) was assessed at birth, before surgery, and at 1, 4, and 6 years and compared with Swiss growth charts. IQ was assessed at 6 years using standardized tests. Univariate and multivariable linear regressions were performed to determine predictors of HC and IQ at 6 years. RESULTS: HC at birth was in the low average range (33rd percentile, P = .03), and weight (49th percentile, P = .23) and length (47th percentile, P = .06) were normal. All growth measures declined until the first surgery, with a catch-up growth until 6 years for height (44th percentile, P = .07) but not for weight (39th percentile, P = .003) or for HC (23rd percentile, P < .001). Children undergoing univentricular palliation showed poorer height growth than other types of CHD (P = .01). Median IQ at 6 years was 95 (range 50-135). Lower IQ at 6 years was independently predicted by lower HC at birth, lower socioeconomic status, older age at first bypass surgery, and longer length of intensive care unit stay. CONCLUSIONS: Smaller HC at birth and postnatal factors are predictive of impaired intellectual abilities at school age. Early identification should alert clinicians to provide early childhood interventions to optimize developmental potential.

Health-related quality of life in pre-school age children with single-ventricle CHD.

BACKGROUND: Little is known about health-related quality of life in young children undergoing staged palliation for single-ventricle CHD. The aim of this study was to assess the impact of CHD on daily life in pre-schoolers with single-ventricle CHD and to identify determinants of health-related quality of life. METHOD: Prospective two-centre cohort study assessing health-related quality of life using the Preschool Paediatric Cardiac Quality of Life Inventory in 46 children at a mean age of 38 months and 3 weeks. Children with genetic anomalies were excluded. Scores were compared with reference data of children with biventricular CHD. Multiple linear regression analysis was used to identify determinants of health-related quality of life. RESULTS: Health-related quality of life in pre-schoolers with single-ventricle CHD was comparable to children with biventricular CHD. Preterm birth and perioperative variables were significant predictors of low health-related quality of life. Notably, pre-Fontan brain MRI findings and neurodevelopmental status were not associated with health-related quality of life. Overall, perioperative variables explained 24% of the variability of the total health-related quality of life score.InterpretationDespite substantial health-related burden, pre-schoolers with single-ventricle CHD showed good health-related quality of life. Less-modifiable treatment-related risk factors and preterm birth had the highest impact on health-related quality of life. Long-term follow-up assessment of self-reported health-related quality of life is needed to identify patients with poorer health-related quality of life and to initiate supportive care.

Reduction of brain volumes after neonatal cardiopulmonary bypass surgery in single-ventricle congenital heart disease before Fontan completion.

BackgroundLittle is known about the relationship between brain volumes and neurodevelopmental outcome at 2 years of age in children with single-ventricle congenital heart disease (CHD). We hypothesized that reduced brain volumes may be associated with adverse neurodevelopmental outcome.MethodsVolumetric segmentation of cerebral magnetic resonance imaging (MRI) scans was carried out in 44 patients without genetic comorbidities and in 8 controls. Neurodevelopmental outcome was assessed with the Bayley-III scales.ResultsGray matter (GM), deep GM, white matter (WM), and cerebrospinal fluid (CSF) volumes were 611±59, 43±4.5, 277±30, and 16.4 ml, respectively (interquartile range (IQR) 13.1, 23.3 ml). Children undergoing neonatal cardiopulmonary bypass surgery showed smaller deep GM (P=0.005) and WM (P=0.021) volumes. Brain volumes were smaller in patients compared with controls (GM: P=0.017, deep GM: P=0.012, and WM: P=0.015), whereas CSF volumes were greater (P=0.014). Of all intracranial volumes, only CSF volume was associated with neurodevelopmental outcome, accounting for 21% (P=0.011) of variability in the cognitive composite score when combined with common risk factors in a multivariable analysis.ConclusionIncreased CSF volume represents a significant risk factor for neurodevelopmental impairment in children with single-ventricle CHD. Later assessments are warranted to determine the prognostic role of intracranial volumes for long-term outcome.

Modified Beer-Lambert algorithm to measure pulsatile blood flow, critical closing pressure, and intracranial hypertension.

We introduce a frequency-domain modified Beer-Lambert algorithm for diffuse correlation spectroscopy to non-invasively measure flow pulsatility and thus critical closing pressure (CrCP). Using the same optical measurements, CrCP was obtained with the new algorithm and with traditional nonlinear diffusion fitting. Results were compared to invasive determination of intracranial pressure (ICP) in piglets (n = 18). The new algorithm better predicted ICP elevations; the area under curve (AUC) from logistic regression analysis was 0.85 for ICP ≥ 20 mmHg. The corresponding AUC for traditional analysis was 0.60. Improved diagnostic performance likely results from better filtering of extra-cerebral tissue contamination and measurement noise.

Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Long-term neurodevelopmental outcome and serial cerebral magnetic resonance imaging assessment in Fontan patients at school age.

OBJECTIVES: Children with univentricular congenital heart disease undergoing staged surgical palliation are at risk for impaired neurodevelopmental (ND) outcome. Little is known about the long-term effects on brain growth until school age. METHODS: In a prospective two-centre study, consecutive patients undergoing stage I (Hybrid or Norwood) to stage III (Fontan procedure) were evaluated by 2 serial cerebral magnetic resonance imaging examinations, somatic growth and ND testing before Fontan procedure at 2 years of age (Bayley-III) and after Fontan at 6-8 years of age (Wechsler Intelligence Scale for Children-third edition). Magnetic resonance imaging findings were compared with 8 healthy controls. Medical and sociodemographic characteristics were documented and related to cerebral and ND findings. RESULTS: We examined 33 children (16 female) at a mean age of 2.3 (0.35) and 6.8 (± 0.7) years. The mean Bayley-III cognitive scales were 99.1 (9.9), language scales 98.4 (11.9) and motor scales 98.5 (13.8) at the first examination. Follow-up at school age showed a mean total IQ of 86.7 (13.6). The rate of structural brain lesions increased from 39% at 2 years to 58% at school age. Bayley-III language scale (P = 0.021) and mean Wechsler Intelligence Scale for Children-third edition (P = 0.019) were lower in children with pathological MR findings. Total brain volume (P < 0.001), total grey matter volume (P = 0.002), deep grey matter volume (P = 0.001) and white matter volume (P < 0.001) were smaller in patients compared to age- and gender-matched healthy controls. CONCLUSIONS: Smaller brain volumes and structural brain lesions in complex congenital heart defect patients at school age are associated with impaired ND outcome. For the evaluation of predictive surgical or clinical factors, larger multicentre studies are needed.

Impaired Maternal-Fetal Environment and Risk for Preoperative Focal White Matter Injury in Neonates With Complex Congenital Heart Disease.

Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single-center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal-fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%-22.1%) and mean volumes (119.7-160.4 mm3) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29-6.30]), male sex (OR, 2.27 [95% CI, 1.03-5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03-1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43-0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE-related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.

Neurodevelopmental outcome in hypoplastic left heart syndrome after hybrid procedure.

BACKGROUND: Little is known about the mid-term outcome and brain development in patients following the hybrid approach for hypoplastic left heart syndrome (HLHS). This study investigates neurodevelopmental outcome, quality of life (QoL) and brain MRI findings in HLHS preschoolers treated with the hybrid approach. METHODS: Twenty HLHS patients (60% males) have been examined after neonatal hybrid Stage I and comprehensive stage II operation at the Pediatric Heart Center Giessen, Germany, between 2012 and 2016. Patients were evaluated with the Bayley Scales of Infant and Toddler Development III (Bayley-III), neurological examination, the Preschool Children Quality of Life Questionnaire (TAPQOL) at age 26.5±3.6 months, and again at 39.7±3.9 months with the Pediatric Cardiac Quality of Life Inventory (PCQLI). Furthermore, brain volumetric measurements and conventional brain MRI findings (27.3±4.5 months) were analyzed and compared with six healthy controls (29.2±11.1 months, P=0.53). Children with verified genetic comorbidities were excluded. RESULTS: Mean cognitive, language, and motor composite scores on the Bayley-III were not different from healthy norms (100±15), and were 101±9.3 (P=0.48), 100±13 (P=0.93), and 98±11.7 (P=0.45), respectively. Status post stroke was the most common brain MRI abnormality, and was found in 3/19 (16%) patients, most common affecting the middle cerebral artery territory. In comparison to controls, total white matter volumes were reduced (P=0.014), and cerebrospinal fluid (CSF) volumes were increased (P=0.042) in patients. Overall health-related QoL in 2 to 3 years aged children HLHS was good, but inferior scores in the motor subscale were noted compared to healthy norms (P=0.007). However, at 3 to 4 years, parents reported comparable QoL for their children in the PCQLI to children with biventricular heart lesion. CONCLUSIONS: HLHS patients followed by hybrid approach without major complications show a favorable neurodevelopment at 2-3 years of age. Despite extensive health-related burden, the vast majority of Fontan preschoolers with HLHS showed a good health-related QoL. Nevertheless, comprehensive care and establishing routine follow-up examinations are important to recognize long-term challenges and further improve neurodevelopmental outcome of this high-risk patient population.

Smaller brain volumes at two years of age in patients with hypoplastic left heart syndrome - Impact of surgical approach.

BACKGROUND: Brain growth in hypoplastic left heart syndrome (HLHS) is reduced before and after birth. Little is known about further brain growth until two years of age before Fontan procedure and the potential impact of type of surgery. METHODS: In a prospective, two-center study 29 patients with HLHS and variants were treated by Norwood (n = 5) or Hybrid procedure (n = 24). At two years of age a cerebral MRI was performed and brain volumes (total gray, deep gray, white matter) and cerebrospinal fluid volume were calculated using FreeSurfer image analysis suite and compared to a healthy control group (n = 8). RESULTS: The total brain volumes in patients with HLHS were smaller compared to controls (HLHS: 893 ±â€¯76 ml vs. controls: 1015 ±â€¯148 ml, p = 0.005). This difference was found in all three brain compartments after Norwood procedure, whereas patients after Hybrid procedure had total and deep gray volumes comparable to controls. When comparing Norwood to Hybrid patients, deep gray matter volume reduction was more pronounced (Norwood: 38.4 ±â€¯4.1 ml vs. Hybrid: 44.4 ±â€¯3.9 ml, p = 0.005) than white matter reduction (Norwood: 255 ±â€¯19 ml vs. Hybrid: 285 ±â€¯31 ml, p = 0.032). CONCLUSIONS: Smaller total and regional brain volumes were found two years after Norwood or Hybrid procedure in children with HLHS. The brain volume reduction was more distinct after Norwood than after Hybrid procedure. Longitudinal studies are needed to identify impact of early staged-surgeries on brain development and may become part of the decision-making process in individual patients.

Interrelationship Between Hemodynamics, Brain Volumes, and Outcome in Hypoplastic Left Heart Syndrome.

BACKGROUND: The long-term impact of altered hemodynamics after stage II in children with hypoplastic left heart syndrome (HLHS) and hypoplastic left heart complex (HLHC) on cerebral growth and neurodevelopmental outcome is unknown. We aimed to investigate whether elevated central venous and atrial filling pressures before the Fontan procedure may be associated with smaller brain volumes and poorer neurodevelopmental outcome after the initial hybrid procedure. METHODS: In a two-center cohort study semiautomated segmentation of cerebral magnetic resonance imaging scans was conducted in 25 children with HLHS/HLHC (25 hybrid) before the Fontan procedure (27.6 ± 4.3 months) and in 8 healthy control subjects (29.7 ± 9.5 months). Study patients were evaluated with the Bayley Scales of Infant and Toddler Development III (Bayley-III) and a neurologic examination. Hemodynamic measures after stage II were assessed with cardiac catheterization at 2 years of age before Fontan completion. Children with known genetic comorbidities were excluded. RESULTS: In HLHS/HLHC patients higher atrial filling pressures (6 ± 3 mm Hg; range, 2-14) were correlated with reduced brain volumes and lower language composite score, whereas higher Glenn pressures (10 ± 3 mm Hg; range, 6-16) were related to higher cerebrospinal fluid, reduced brain volumes, and lower cognitive, language, and motoric composite scores in the Bayley-III. Compared with control subjects white matter volumes were reduced and cerebrospinal fluid volumes increased in study patients. CONCLUSIONS: These data suggest that altered cardiovascular hemodynamics after stage II influence brain growth and neurodevelopmental outcome in infants with HLHS/HLHC.

Neurodevelopmental Outcome and Health-related Quality of Life in Children With Single-ventricle Heart Disease Before Fontan Procedure.

Neurodevelopmental impairment and impaired quality of life constitute a major source of morbidity among children with complex congenital heart disease, in particular for single-ventricle (SV) morphologies. Risk factors and quality of life determining clinical and neurodevelopmental outcome at 2 years of age are examined. In a 2-center cohort study, 48 patients with SV morphology (26 hypoplastic left heart syndrome and 22 other types of univentricular heart defect) have been examined before Fontan procedure between 2010 and 2015. Patients were assessed with the Bayley Scales of Infant and Toddler Development, Third Version (Bayley-III), and the Preschool Children Quality of Life (TAPQOL) questionnaire. A total of 44 patients underwent hybrid procedure (n = 25), Norwood procedure (n = 7), or shunt or banding procedure (n = 12) as first surgery before subsequent bidirectional cavopulmonary anastomosis (n = 48). Median cognitive, language, and motor composite scores on the Bayley-III were 100 (range 65-120), 97 (68-124), and 97 (55-124), respectively. The language composite score was significantly below the norm (P = 0.025). Risk factors for poorer neurodevelopmental outcome were prolonged mechanical ventilation, longer days of hospital stay, and more reinterventions (all P < 0.05). Parents reported a good quality of life for their children. Children undergoing Fontan procedure show a favorable development and good quality of life. More complicated postoperative course and reinterventions constitute risk factors for impaired neurodevelopment. Improving postoperative management and implementing routine follow-up assessments aremeasures to further improve the neurodevelopmental outcome of this high-risk patient population.