Skin TARC/CCL17 increase precedes the development of childhood atopic dermatitis.

BACKGROUND: It is unknown whether skin biomarkers collected in infancy can predict the onset of atopic dermatitis (AD) and be used in future prevention trials to identify children at risk. OBJECTIVES: This study sought to examine whether skin biomarkers can predict AD during the first 2 years of life. METHODS: This study enrolled 300 term and 150 preterm children at birth and followed for AD until the age of 2 years. Skin tape strips were collected at 0 to 3 days and 2 months of age and analyzed for selected immune and barrier biomarkers. Hazard ratio (HR) with 95% confidence interval (CI) using Cox regression was calculated for the risk of AD. RESULTS: The 2-year prevalence of AD was 34.6% (99 of 286) and 21.2% (25 of 118) among term and preterm children, respectively. Skin biomarkers collected at birth did not predict AD. Elevated thymus- and activation-regulated chemokine/C-C motif chemokine ligand 17 -levels collected at 2 months of age increased the overall risk of AD (HR: 2.11; 95% CI: 1.36-3.26; P = .0008) and moderate-to-severe AD (HR: 4.97; 95% CI: 2.09-11.80; P = .0003). IL-8 and IL-18 predicted moderate-to-severe AD. Low filaggrin degradation product levels increased the risk of AD (HR: 2.04; 95% CI: 1.32-3.15; P = .001). Elevated biomarker levels at 2 months predicted AD at other skin sites and many months after collection. CONCLUSIONS: This study showed that noninvasively collected skin biomarkers of barrier and immune pathways can precede the onset of AD.

Skin biomarkers predict development of atopic dermatitis in infancy.

BACKGROUND: There is currently no insight into biomarkers that can predict the onset of pediatric atopic dermatitis (AD). METHODS: Nested in a prospective birth cohort study that examined the occurrence of physician-diagnosed AD in 300 children, 44 random children with onset of AD in the first year of life were matched on sex and season of birth with 44 children who did not develop AD. Natural moisturizing factor (NMF), corneocyte surface protrusions, cytokines, free sphingoid bases (SBs) of different chain lengths and their ceramides were analyzed from tape strips collected at 2 months of age before onset of AD using liquid chromatography, atomic force microscopy, multiplex immunoassay, and liquid chromatography mass spectrometry, respectively. RESULTS: Significant alterations were observed for four lipid markers, with phytosphingosine ([P]) levels being significantly lower in children who developed AD compared with children who did not (median 240 pmol/mg vs. 540 pmol/mg, p < 0.001). The two groups of children differed in the relative amounts of SB of different chain lengths (C17, C18 and C20). Thymus- and activation-regulated chemokine (TARC/CCL17) was slightly higher in children who developed AD, whereas NMF and corneocyte surface texture were similar. AD severity assessed by the eczema area and severity index (EASI) at disease onset was 4.2 (2.0;7.2). [P] had the highest prediction accuracy among the biomarkers (75.6%), whereas the combination of 5 lipid ratios gave an accuracy of 89.4%. CONCLUSION: This study showed that levels and SB chain length were altered in infants who later developed AD, and that TARC/CCL17 levels were higher.

The association between Staphylococcus aureus colonization on cheek skin at 2†months and subsequent atopic dermatitis in a prospective birth cohort.

BACKGROUND: Staphylococcus aureus may worsen already established atopic dermatitis (AD), but its primary role in the aetiopathogenesis and severity of AD is unclear. OBJECTIVES: To compare the prevalence of S. aureus colonization in early infancy in children who developed AD during the first 2 years of life with children who did not. METHODS: In this prospective birth cohort study, which included 450 infants, we analysed bacterial swabs collected from cheek skin at 0 and 2 months of age. The development of AD, and its severity, was diagnosed by a physician and monitored prospectively for 2 years. Information on parental atopy, filaggrin gene mutation status and use of antibiotics and emollients was included in the analyses. RESULTS: At birth, the occurrence of S. aureus colonization was similar in infants who developed subsequent AD and those who did not. At 2 months of age, S. aureus colonization was more common in children who later developed AD (adjusted hazard ratio 1.97, 95% confidence interval 1.21-3.19; P = 0.006). No association was found between S. aureus colonization and AD severity or age at onset. CONCLUSIONS: It remains unknown whether colonization with S. aureus may directly increase the risk of AD, or whether it should be considered as secondary to skin barrier impairment or a skewed immune activity, but according to our findings, S. aureus colonization is more commonly increased at 2 months of age in children who later developed AD.

Preterm birth in the Nordic countries-Capacity, management and outcome in neonatal care.

AIM: Organisation of care, perinatal and neonatal management of very preterm infants in the Nordic regions were hypothesised to vary significantly. The aim of this observational study was to test this hypothesis. METHODS: Information on preterm infants in the 21 greater healthcare regions of Denmark, Finland, Iceland, Norway and Sweden was gathered from national registers in 2021. Preterm birth rates, case-mix, perinatal interventions, neonatal morbidity and survival to hospital discharge in very (<32 weeks) and extremely preterm infants (<28 weeks of gestational age) were compared. RESULTS: Out of 287 642 infants born alive, 16 567 (5.8%) were preterm, 2389 (0.83%) very preterm and 800 (0.28%) were extremely preterm. In very preterm infants, exposure to antenatal corticosteroids varied from 85% to 98%, live births occurring at regional centres from 48% to 100%, surfactant treatment from 28% to 69% and use of mechanical ventilation varied from 13% to 77% (p < 0.05 for all comparisons). Significant regional variations within and between countries were also seen in capacity in neonatal care, case-mix and number of admissions, whereas there were no statistically significant differences in survival or major neonatal morbidities. CONCLUSION: Management of very preterm infants exhibited significant regional variations in the Nordic countries.

Differences in Occurrence, Risk Factors and Severity of Early-onset Atopic Dermatitis among Preterm and Term Children.

This prospective birth cohort followed 150 preterm and 300 term newborns during the first year of life to assess possible differences in risk factors, age at onset, anatomical location, and severity of atopic dermatitis. Atopic dermatitis was diagnosed clinically, and severity was assessed using Eczema Area Severity Index (EASI). DNA was analysed for filaggrin gene mutations. Parents were asked about environmental exposures and emollient use. Atopic dermatitis during the first year of life was observed in 21.2% of children and was more common in term children compared with preterm children (26.7% vs 11.7%, p < 0.001), with lower age of onset (4 vs 6 months, p < 0.05) and more severe disease at onset (EASI: 4.8 vs 0.4, p < 0.0005). Environmental risk factors for atopic dermatitis were essentially similar for preterm and term born children, apart from winter and autumn births. Filaggrin gene mutations were less common in preterm than term children (4.1% vs 9.2%, p = 0.06).

Point-of-care ultrasound in neonatal intensive care.

This review investigates how point-of-care ultrasound (POCUS) allows individualised treatment based on the patient's clinical and physiological state. Serial examinations enable timely adjustments of interventions, potentially fewer side effects, and less need for x-ray examinations. One of the main barriers to POCUS is the lack of systematic training and quality control. The next step toward more widespread use of neonatal POCUS is systematic theoretical and practical training and implementing standardized examination protocols.

Switch from intravenous-to-oral antibiotics in neonatal probable and proven early-onset infection: a prospective population-based real-life multicentre cohort study.

OBJECTIVE: To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI). DESIGN, SETTING AND PATIENTS: A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020. INTERVENTION: Intravenous-to-oral switch antibiotic therapy in clinically stable neonates. MAIN OUTCOME MEASURES: The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period. RESULTS: During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5-3.5) and 7.4 days (IQR 7.0-7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019-2020), compared with 1.2% before (2017-2018). CONCLUSION: In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics.

Reduced Skin Microbiome Diversity in Infancy Is Associated with Increased Risk of Atopic Dermatitis in High-Risk Children.

It is currently unknown whether alterations in the skin microbiome exist before development of atopic dermatitis (AD). In this prospective Danish birth cohort of 300 children, we examined whether skin microbiome alterations during the first 2 months of life were associated with an increased risk of AD in the first 2 years and its severity after adjustment for environmental factors and selected skin chemokine and natural moisturizing factor levels. We found no overall association between the skin microbiome at birth and age 2 months and AD during the first 2 years of life. However, when restricting the analysis to children with at least one parent with atopy, a lower alpha diversity at age 2 months was associated with an increased risk of AD (adjusted hazard ratio = 1.7, 95% confidence interval = 1.1-2.6). We observed a stronger association in children where both parents had atopy (adjusted hazard ratio = 4.4, 95% confidence interval = 1.1-18.2). The putative pathogenic role of changes in the skin microbiome on AD risk remains uncertain but may play a role in those with an atopic predisposition.

Downregulation of aquaporin-1 in alveolar microvessels in lungs adapted to chronic heart failure.

The threshold pressure for lung edema formation is increased in severe chronic heart failure (CHF) due to reduced microvascular permeability. The water channel aquaporin-1 (AQP1) is present in the pulmonary microvascular endothelium, and a number of studies suggest the importance of AQP1 as a molecular determinant of pulmonary microvascular water transport. The present study examined the abundance and localization of AQP1 in lungs from rats with CHF. We used two different models of CHF: ligation of the left anterior descending coronary artery (LAD ligation) and aorta-banding (AB). Sham-operated rats served as controls. Echocardiographic verification of left ventricular dysfunction, enhanced left ventricular end-diastolic pressure, and right ventricular hypertrophy confirmed the presence of CHF. Western blotting of whole-lung homogenates revealed significant downregulation of AQP1 in LAD-ligated rats (24 h: 58 ± 5% of sham; 3 weeks: 8 ± 3% of sham; 9 weeks: 16 ± 6% of sham) and after AB (30 weeks: 37 ± 5% of sham), whereas the protein levels of the specific endothelial cell marker PECAM-1 was increased 3 weeks after LAD ligation (229 ± 20% of sham), but unchanged after 9 weeks and in the AB rats compared to controls. Immunohistochemical examination 3 weeks after LAD ligation showed intact labeling of PECAM-1 but an almost complete absence of AQP1 in the pulmonary alveolar microvessels in the CHF rats. These results suggest that downregulation of AQP1 in the alveolar microvessels may act as a compensatory mechanism to protect against formation of excessive pulmonary edema in CHF.

[Neonatal survival and health in Denmark].

This review gives a summary of Danish preterm care, which has been defined by national adaptation of antenatal corticosteroids in the 1970ies and continuous positive airway pressure in the 1980ies. Today, preterm survival in Denmark is high, by international standards, but lower than in the neighbouring countries Sweden and Norway. The lack of a national neonatal quality database may offer an explanation to this. Starting in 2019, the Danish Newborn Quality Database reports complete population-based measures of newborn survival and health and may help improve standards of care in the future.

'Barrier dysfunction in Atopic newBorns studY' (BABY): protocol of a Danish prospective birth cohort study.

INTRODUCTION: Skin barrier development and dysfunction in premature and mature newborns is important for the risk of atopic dermatitis (AD). METHODS AND ANALYSIS: The Barrier dysfunction in Atopic newBorns studY (BABY) Cohort is a prospective birth cohort study of 150 preterm children (gestational age (GA) below 37+0) and 300 term children (GA 37+0 to 41+6). Skin barrier is assessed through transepidermal water loss, tape stripping, Raman-spectroscopy and microbiome sampling. Clinical examinations are done and DNA from buccal swabs is collected for genetic analyses. Thymus size is assessed by ultrasound examination. Information on pregnancy, delivery, parental exposures and diseases are collected, and structured telephone interviews are conducted at 18 and 24 months to assess exogenous exposures in the child and onset of AD. Hanifin and Rajka criteria as well as The UK Working Party's Diagnostic Criteria for Atopic Dermatitis are used to diagnose AD. Severity of AD is assessed using the Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM). ETHICS AND DISSEMINATION: The study is approved by the scientific Ethical Committee of the Capital Region (H-16042289 and H-16042294).Outcomes will be presented at national and international conferences and in peer-reviewed publications.

Lactate acidosis and cardiac output during initial therapeutic cooling in asphyxiated newborn infants.

AIM: We hypothesized that compromised cardiac output in asphyxiated infants may influence on the rate of disappearance of lactate due to insufficient perfusion. METHODS: The study was a prospective, observational study, where infants with perinatal asphyxia who met the criteria for therapeutic hypothermia were included. Cardiac output, stroke volume and heart rate were measured by electrical velocimetry in 15 newborn infants with perinatal asphyxia during the first six hours of active therapeutic hypothermia. Results from routine blood samples were collected retrospectively. Cardiac parameters were also measured in 10 healthy, term infants after caesarian section. Cardiac parameters were compared between the asphyxiated group and the control group prior to and during hypothermia. Rate of disappearance of lactate was correlated to cardiac output in the asphyxiated infants. RESULTS: Cardiac output was stable in the healthy infants from 0.5 to 6 hours postnatally. The infants with perinatal asphyxia had lower cardiac output prior to and during therapeutic hypothermia compared to the control group. Rate of disappearance of lactate was not related to cardiac output. CONCLUSION: An association between disappearance of lactate acidosis and low cardiac output was not confirmed. A low rate of disappearance of lactate may rather be an indicator of organ injury due to asphyxia.

Spontaneous Septostomy in a Twin Pregnancy Causing Fatal Amniotic Band Syndrome.

Complications due to spontaneous septostomy of the dividing membrane in monochorionic diamniotic pregnancies are rarely described. Herein, we report the case of a preterm female neonate from a monochorionic diamniotic twin pregnancy delivered by caesarean section at 32 weeks of gestation. She was born with a broad band of a transparent membrane-like material firmly attached to her lower abdomen. Postnatally, she developed respiratory distress syndrome and persistent pulmonary hypertension, complicated by bilateral pneumothorax. She died due to respiratory failure when she was 1 day old. Her twin sister survived with no malformations. At postmortem examination, the neonate had severe lung hypoplasia, and the attached material was diagnosed as the dividing septum. We hypothesize that the lung hypoplasia was secondary to local oligohydramnios, which developed as a consequence of the twin being firmly stuck in the defect of the dividing membrane. To our best knowledge, spontaneous septostomy causing an ultimately fatal amniotic band syndrome has not previously been described.

Mechanical and vasomotor properties of piglet isolated middle cerebral artery.

Piglets are often used as experimental models for studying cerebrovascular responses in newborn infants. However, the mechanical characteristics of piglets' middle cerebral arteries (MCA) are not well characterized. Additionally, the vessels' response to dopamine, the most commonly used vasopressor in newborns, is not characterized in piglets' MCA. Finally, the influence of preterm birth on the dopamine response is not known. The aim of this current was to compare by wire myography the active and passive mechanical characteristics and dopamine concentration-response relations of MCAs isolated from preterm and term newborn piglets. Second-order branches of the MCA with a diameter <400 µm were chosen for study. The active and passive mechanical properties were comparable between vessels from six preterm (90% gestation, nsegments = 11) and nine term (nsegments = 22) newborn piglets. The response to increasing concentrations of dopamine was biphasic, starting with vasodilation in the 1 nmol/L-0.3 µmol/L concentration range followed by vasoconstriction at higher concentrations. The response was very similar between the two groups. In conclusion, the mechanical properties of the MCA as well as the response to dopamine were comparable between term and 90% gestation preterm piglets.

Noradrenaline-induced increases in calcium and tension in skeletal muscle conductance and resistance arteries from rats with post-infarction heart failure.

We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham-operated rats, skeletal muscle conductance and resistance arteries (mean lumen diameters: 514 and 186 microm) were isolated and mounted on wire myographs, and wall tension was recorded in response to cumulative application of acetylcholine and noradrenaline to the vessel segments. In a subset of experiments, wall tension and cytosolic free calcium ion concentration [Ca(2+)](i) were recorded simultaneously during noradrenaline application, using wire myography and the FURA-2 technique. No significant differences were found in the arterial baseline levels of [Ca(2+)](i) or tension between CHF and sham rats. In the resistance arteries of CHF rats, the noradrenaline-induced increases in [Ca(2+)](i) were significantly enhanced (P=0.003). Despite the augmented [Ca(2+)](i) levels, the tension responses to noradrenaline were unaltered in these arteries. In the conductance arteries, there were no significant differences in noradrenaline-induced [Ca(2+)](i) or tension responses between CHF and control rats. CHF did not alter vascular morphology or change vascular relaxations to acetylcholine in either type of artery. In conclusion, these results do not support the contention that arterial reactivity to noradrenaline is augmented in the skeletal muscle vascular bed in CHF. On the contrary, the unchanged contractile responsiveness in the resistance arteries despite the enhanced levels of [Ca(2+)](i) during noradrenaline application suggests that the contractile function of these vessels is compromised in CHF. Neither vascular remodeling, endothelial dysfunction nor changes in baseline vascular tone could be demonstrated in the skeletal muscle vascular bed of this animal model of heart failure.

Ca(2+) sensitisation of force production by noradrenaline in femoral conductance and resistance arteries from rats with postinfarction congestive heart failure.

In this study we tested the hypothesis that arterial myofilament Ca(2+) sensitivity and/or the Ca(2+) sensitising effect of noradrenaline (NA) is enhanced in post-infarction congestive heart failure (CHF), which could contribute to the high peripheral vascular resistance in this condition. Femoral skeletal muscle resistance and conductance arteries (mean lumen diameters of 159 and 519 microm) from rats with CHF and sham-operated control rats were used. Isometric tension development and intracellular free calcium concentration ([Ca(2+)](i)) were measured simultaneously in isolated vessel segments using wire myography and the FURA-2 fluorescence technique. In conductance and resistance arteries, the resting levels of [Ca(2+)](i) and tension in physiological saline solution (PSS) and active tension in response to single doses of 125 mM K(+) (KPSS) were unaffected by CHF. During cumulative application of extracellular Ca(2+) to arteries depolarised with 125 mM K(+) or activated with 30 microM NA, [Ca(2+)](i) and vessel wall tension were similar in CHF and control rats. However, the conductance arteries showed significantly higher calcium sensitivity than resistance arteries in these experiments. We conclude that an abnormality in the sensitivity of the contractile apparatus to Ca(2+), or in NA-induced Ca(2+) sensitisation in arterial vascular smooth muscle cells is unlikely to contribute to the ubiquitously elevated vascular resistance associated with CHF. However, our data demonstrate significant differences in vascular Ca(2+) handling, myofilament Ca(2+) sensitivity and tension development between resistance and conductance arteries, regardless of CHF.

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment.

Here we report a patient with a new pathogenic mutation in ACAD9. Shortly after birth she presented with respiratory insufficiency and a high lactate level. At age 7 weeks, she was diagnosed with severe hypertrophic cardiomyopathy and she suffered from muscle weakness and hypotonia. Her condition deteriorated during intercurrent illnesses and she died at 6 months of age in cardiogenic shock. Analysis of respiratory chain activities in muscle and fibroblasts revealed an isolated complex I deficiency. A genome-wide screen for homozygosity revealed several homozygous regions. Four candidate genes were found and sequencing revealed a homozygous missense mutation in ACAD9. The mutation results in an Ala220Val amino acid substitution located near the catalytic core of ACAD9. SDS and BN-PAGE analysis showed severely decreased ACAD9 and complex I protein levels, and lentiviral complementation of patient fibroblasts partially rescued the complex I deficiency. Riboflavin supplementation did not ameliorate the complex I deficiency in patient fibroblasts. More than a dozen ACAD9 patients with complex I deficiency have been identified in the last 3 years, indicating that ACAD9 is important for complex I assembly, and that ACAD9 mutations are a relatively frequent cause of complex I deficiency.

[Neuromyelitis optica with atypical cerebral lesions demonstrated by magnetic resonance imaging in a 9-year old girl]. / Neuromyelitis optica med udtalte cerebrale magnetisk resonans-skannings-forandringer hos en niårig pige.

Neuromyelitis optica (NMO) is a rare inflammatory disorder characterised by optic neuritis and transverse myelitis. We report a severe pediatric case presenting with impaired vision, tetraparesis, bladder retention and lower extremity pain. Magnetic resonance imaging demonstrated longitudinally extensive lesions of the spinal chord and atypical lesions in both cerebral hemispheres. Cerebrospinal fluid was pleocytotic. Symptoms responded well to intravenous immunoglobulin G and high-dose methyl prednisolone therapy.