Summary
Background
Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin ...degradation products natural moisturizing factors (NMFs), activities of filaggrin‐processing enzymes bleomycin hydrolase (BH) and calpain‐1 (C‐1) and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown.
Objectives
We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life.
Methods
We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined.
Results
NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin.
Conclusions
Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.
What's already known about this topic?
Atopic dermatitis (AD) frequently starts in early infancy, and the first eczematous lesions emerge on the cheeks.
Filaggrin is a major structural protein in the stratum corneum (SC).
Filaggrin deficiency is associated with the development of AD and, in the context of AD, food allergies and asthma.
Filaggrin is metabolized into natural moisturizing factors (NMFs), which can be measured in the SC.
What does this study add?
Regional differences in NMF levels, corneocyte envelope immaturity and protease activities may help explain why infantile AD most often initially affects the cheeks.
Filaggrin processing, corneocyte maturity, and protease activities show regional and temporal differences in infant skin.
These findings may explain disease patterns in early‐life AD.
What is the translational message?
Cheek skin may be highly relevant for allergen priming.
Emollient therapy at the vulnerable cheek site might help to prevent AD and/or food sensitization.
Linked Editorial: Thyssen. Br J Dermatol 2018; 179:235–236.
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Summary
Background
MicroRNAs (miRNAs), important regulators of gene expression, have been implicated in a variety of disorders. The expression pattern of miRNAs in paediatric atopic dermatitis (AD) ...has not been well studied.
Objectives
We sought to investigate miRNA expression profiles in different blood compartments of infants with AD.
Methods
Small RNA and analysis with the HTG EdgeSeq system were performed to identify differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) and plasma of infants with AD vs. age‐matched healthy controls, with reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR) used for validation and measurement of miRNA targets. Logistic regression models with area under the receiving operating characteristic estimation was used to evaluate the diagnostic potential of chosen miRNAs for AD.
Results
RNA sequencing was performed to access miRNA expression profiles in paediatric AD. We identified 10 differentially expressed miRNAs in PBMCs and eight dysregulated miRNAs in plasma of infants with AD compared with controls. Upregulated miRNAs in PBMCs included miRNAs known to be involved in inflammation: miR‐223‐3p, miR‐126‐5p and miR‐143‐3p. Differential expression of only one miRNA, miR‐451a, was observed in both PBMCs and plasma of children with AD. Dysregulation of three miRNAs (miR‐451a, miR‐143‐3p and miR‐223‐3p) was validated in larger numbers of samples and miR‐451a was identified as a predictive biomarker for the early diagnosis of the disease. Experimentally verified targets of miR‐451a, interleukin 6 receptor (IL6R) and proteasome subunit beta type‐8 (PSMB8), were increased in patients with AD, negatively correlated with miR‐451a levels and upregulated following inhibition of miR‐451a in PBMCs.
Conclusions
In infants with AD, a distinct peripheral blood miRNA signature is seen, highlighting the systemic effects of the disease. miR‐451a is uniquely expressed in different blood compartments of patients with AD and may serve as a promising novel biomarker for the early diagnosis of AD.
What is already known about this topic?
Atopic dermatitis (AD) is a common childhood disease with a complex pathogenesis.
miRNA expression studies to date have been performed mainly on samples from adults or older children.
What does this study add?
miRNAs are differentially expressed in both plasma and peripheral blood cells of infants with AD.
miR‐451a may serve as a potential noninvasive biomarker for paediatric AD.
What is the translational message?
miR‐451a, uniquely expressed in different blood compartments of paediatric patients with AD, has potential for use as a noninvasive biomarker to diagnose the disease.
Better understanding of miR‐451a activity may provide better insights into AD pathogenesis.
Linked Comment: Polak. Br J Dermatol 2021; 184:391–392.
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The development of lightweight and flexible solar modules is highly desirable for high specific power applications, building integrated photovoltaics, unmanned aerial vehicles and space. Flexible ...metallic and polyimide foils are frequently used, but in this work an alternative substrate with attractive properties, ultra-thin glass (UTG) has been employed. CdTe solar cells with average efficiency reaching 14.7% AM1.5G efficiency have been produced on UTG of 100 μm thickness. Little has been reported on the effects on PV performance when flexed, so we investigated the effects on J-V parameters when the measurements were performed in 40 mm and 32 mm bend radius, and in a planar state before and after the bend curvature was applied. The flat J-V measurements after 32 mm bending test showed some improvement in efficiency, Voc and FF, with values higher than the first measurement in a planar state. In addition, two CdTe solar cells with identical initial performance were subjected to 32 mm static bending test for 168 hours, the results showed excellent uniformity and stability and no significant variation on J-V parameters was observed. External quantum efficiency and capacitance voltage measurements were performed and showed no significant change in spectral response or carrier concentration. Residual stress analysis showed that no additional strain was induced within the film after the bending test and that the overall strain was low. This has demonstrated the feasibility of using CdTe solar cells on UTG in new applications, when a curved module is required without compromising performance.
•CdTe solar cell on flexible ultra-thin glass was successfully produced with average efficiency reaching 14.7%.•Effect of photovoltaic characteristics under 40 mm and 32 mm bend radius are revealed.•Performances were compared to the measurements in a planar state before and after bending test.•The impact of bending test on EQE, C-V and residual stress measurements were analysed.
Summary
Background
Carriage rates of Staphylococcus aureus on affected skin in atopic dermatitis (AD) are approximately 70%. Increasing disease severity during flares and overall disease severity ...correlate with increased burden of S. aureus. Treatment in AD therefore often targets S. aureus with topical and systemic antimicrobials.
Objectives
To determine whether antimicrobial sensitivities and genetic determinants of resistance differed in S. aureus isolates from the skin of children with AD and healthy child nasal carriers.
Methods
In this case–control study, we compared S. aureus isolates from children with AD (n = 50) attending a hospital dermatology department against nasal carriage isolates from children without skin disease (n = 49) attending a hospital emergency department for noninfective conditions. Using whole genome sequencing we generated a phylogenetic framework for the isolates based on variation in the core genome, then compared antimicrobial resistance phenotypes and genotypes between disease groups.
Results
Staphylococcus aureus from cases and controls had on average similar numbers of phenotypic resistances per isolate. Case isolates differed in their resistance patterns, with fusidic acid resistance (FusR) being significantly more frequent in AD (P = 0·009). The genetic basis of FusR also differentiated the populations, with chromosomal mutations in fusA predominating in AD (P = 0·049). Analysis revealed that FusR evolved multiple times and via multiple mechanism in the population. Carriage of plasmid‐derived qac genes, which have been associated with reduced susceptibility to antiseptics, was eight times more frequent in AD (P = 0·016).
Conclusions
The results suggest that strong selective pressure drives the emergence and maintenance of specific resistances in AD.
What's already known about this topic?
Staphylococcus aureus frequently colonizes individuals with atopic dermatitis (AD), with increasing disease severity correlating with greater bacterial load of the organism.
Antimicrobial therapies are routinely used in AD for management and prevention of disease flares.
What does this study add?
Staphylococcus aureus isolates from children with AD differ in their antimicrobial resistance profiles from those in healthy, nonatopic nasally colonized children.
Fusidic acid resistance is significantly more prevalent in cases of AD, and arises through distinct genetic mechanisms when compared with healthy controls.
Carriage of plasmid‐derived genetic determinants associated with antiseptic resistance also clearly differentiated S. aureus from cases of AD and controls.
Linked Editorial: Leung. Br J Dermatol 2018; 179:807–808.
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Summary
Background
Comparative, real‐life and long‐term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate‐to‐severe atopic eczema (AE) is limited. Such data ...must come from well‐designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling.
Objectives
To reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE.
Methods
Proposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face‐to‐face consensus meetings, one teleconference and via e‐mail. The frequency of follow‐up visits was determined by an expert survey.
Results
A total of 16 experts from seven countries participated in the ‘how to measure’ consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow‐up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined.
Conclusions
This core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long‐term effectiveness and safety of phototherapy and systemic therapy used in patients with AE.
What's already known about this topic?
Comparable, real‐life and long‐term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed.
There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling.
What does this study add?
Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries.
This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data.
What are the clinical implications of this work?
The data collected through this core dataset will help to gain better insights into the long‐term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice.
Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment‐related adverse events that require large patient numbers).
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Summary
Background Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG ...mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD.
Objectives To investigate further the spectrum of FLG‐null mutations in Chinese patients and to compare it with that in other populations.
Methods We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate‐to‐severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls.
Results In total, 22 FLG‐null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD Fisher’s exact test; P = 5·3 × 10−9; odds ratio (OR) 3·3, palmar hyperlinearity (Fisher’s exact test; P = 9·0 × 10−15; OR 5·8), keratosis pilaris (Fisher’s exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063).
Conclusions This study emphasizes the wider genetic landscape of FLG‐null mutations in Asia that is slowly emerging.
Summary
Background
Epidemiological studies indicate that gene–environment interactions play a role in atopic dermatitis (AD).
Objectives
To review the evidence for gene–environment interactions in AD ...aetiology, focusing on filaggrin (FLG) loss‐of‐function mutations.
Methods
A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS‐I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta‐analysis.
Results
Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG–environment interactions in six of the studies (P‐value for interaction ≤ 0·05), including early‐life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss‐of‐function mutations and exposure to specific environmental factors, and variation in exposure definitions.
Conclusions
Evidence on FLG–environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment.
Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.
What's already known about this topic?
Gene–environment interactions are considered important in the aetiology of atopic dermatitis.
Loss‐of-function mutations in the gene coding filaggrin (FLG) are the most consistently reported genetic variants for atopic dermatitis.
Studies have reported evidence for gene–environment interaction involving FLG and a range of different environmental exposures.
What does this study add?
There is some evidence for FLG–environment interactions in the aetiology of atopic dermatitis; however, the evidence is limited.
Studies lack large enough sample sizes to achieve adequate power in order to assess these interactions fully.
Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.
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Summary
Background
Evidence of immunomodulatory therapies to guide clinical management of atopic eczema (AE) is scarce, despite frequent and often off‐label use. Patient registries provide valuable ...evidence for the effects of treatments under real‐world conditions that can inform treatment guidelines, give the opportunity for health economic evaluation and the evaluation of quality of care, as well as pharmacogenetic and dynamic research, which cannot be adequately addressed in clinical trials.
Objectives
The TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek international consensus on a core set of domains and items (‘what to measure’) for AE research registries, using a Delphi approach.
Methods
Participants from six stakeholder groups were included: doctors, nurses, nonclinical researchers, patients, industry and regulatory body representatives. The eDelphi comprised three sequential online rounds, requesting participants to rate the importance of each proposed domain item. Participants could add domain items to the proposed list in round 1. A final consensus meeting was held to ratify the core set.
Results
Participants (n = 479) from 36 countries accessed the eDelphi platform, of whom 86%, 79% and 74% completed rounds 1, 2 and 3, respectively. At the face‐to‐face consensus meeting attended by 42 participants the final core set was established containing 19 domains with 69 domain items (49 baseline and 20 follow‐up items).
Conclusions
This core set of domains and items to be captured by national AE systemic therapy registries will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries. Ultimately, it will provide greater insight into the effectiveness, safety and cost‐effectiveness of photo‐ and systemic immunomodulatory therapies.
What's already known about this topic?
Evidence of photo‐ and systemic immunomodulatory therapies to guide clinical management for atopic eczema (AE) is scarce, despite frequent and often off‐label use.
There is a need to gather long‐term, comparative and real‐life data on the effectiveness, safety and cost‐effectiveness of these therapies beyond the confines of short‐term randomized controlled trials, especially when new biological and small‐molecule therapies are entering clinical practice.
Patient registries can provide valuable data to address these issues.
What does this study add?
By performing an international Delphi exercise, consensus was reached on a core set of domains and items to be captured by national AE patient registries.
This core set will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries.
What are the clinical implications of this work?
Ultimately, this core set will provide greater insight into the effectiveness, safety and cost‐effectiveness of photo‐ and systemic immunomodulatory therapies.
This may fill the current gaps of evidence and lead to new guidelines for daily clinical practice, and thereby may contribute to the improvement of the care of children and adults with AE.
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Summary
Background
Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This ...condition usually occurs in children and is often self‐limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies.
Objectives
To identify a possible genetic basis of loose anagen hair using next‐generation DNA sequencing and functional analysis of variants identified.
Methods
In this case study, whole‐exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed.
Results
The patient was found to be compound heterozygous for two single‐nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D‐glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity.
Conclusions
TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.
What is already known about the topic?
Loose anagen hair syndrome is a rare condition with an estimated incidence of two cases per million per year, mainly observed in female children aged between 2 years and 6 years.
Loose anagen hairs are loosely anchored and can be easily plucked from the scalp.
To date, no gene pathology has been associated with loose anagen syndrome.
What does this study add?
By undertaking whole‐exome sequencing in an individual with loose anagen hairs, and in other unaffected family members, we identified compound heterozygosity for missense mutations in TKFC.
Functional analysis of both amino acid variants showed defective catalytic activity implicating TKFC in hair cycling and structural maintenance.
The identification of TKFC mutations expands the molecular basis of hypotrichosis and provides a new biochemical target for potential therapeutic intervention.
What is the translational message?
DNA variants in many different genes, including TKFC, contribute to hypotrichosis.
Defining individual gene pathology provides more precise mechanistic insights into the diverse aetiology of inherited forms of hypotrichosis and a basis to develop personalized medicine to improve hair growth.
Linked Comment: Brown. Br J Dermatol 2021; 184:800–801.
This article outlines analytical solutions to quantify the length scale associated with “upstream dispersion,” the artificial movement of solutes in the opposite direction to groundwater flow, in ...solute transport models. Upstream dispersion is an unwanted artifact in common applications of the advection‐dispersion equation (ADE) in problems involving groundwater flow in the direction of increasing solute concentrations. Simple formulae for estimating the one‐dimensional distance of upstream dispersion are provided. These show that under idealized conditions (i.e., steady‐state flow and transport, and a homogeneous aquifer), upstream dispersion may be a function of only longitudinal dispersivity. The scale of upstream dispersion in a selection of previously presented situations is approximated to highlight the utility of the presented formulae and the relevance of this ADE anomaly in common transport problems. Additionally, the analytical solution is applied in a hypothetical scenario to guide the modification of dispersion parameters to minimize upstream dispersion.
Article impact statement: We derive 1D analytical solutions to quantify, and provide a simple approach to reduce, upstream dispersion in solute transport models.
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