Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes. METHODS: We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting. RESULTS: MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease. CONCLUSION: We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.

Getting it right the first time: an Irish paediatric dermatology perspective from a national care centre.

The Dermatology: 'Getting It Right the First Time' (GIRFT) Programme National Specialty Report recommended improving access to, and the quality of, paediatric dermatology services. Understanding referral patterns makes it easier to identify areas that can be improved. This study analysed 292 new referrals to a national care centre that provides secondary care to 50% of all Irish children. Results showed that 51% of new referrals could have been managed in primary care and 41% of new referrals were inappropriate, including 5.5% having no abnormal skin findings. These results indicate that up to 876 referrals could have been avoided over a 13-month period, freeing up resources and reducing wait times for cases more appropriate for a secondary and tertiary care centre. This would improve access for children, allowing them to be diagnosed at the right place and time, in alignment with GIRFT values.

Novel mixed-method, inclusive protocol involving global key stakeholders, including carers as experts, to co-develop relevant Caregiver-Reported Outcome Domains (CRODs) in skin disease.

INTRODUCTION: Ichthyoses comprise a heterogenous group of rare genetic skin disorders that involves the entire skin surface, often with additional syndromic features, and pose many clinical challenges. Without curative intervention, the mainstay of life-long symptom management is supportive in nature and can remain the responsibility of the caregiver. Although impact on the wider family is considered an important outcome of policies and services, there is a lack of caregiver consensus on what outcome domains to measure to fully assess the impact of ichthyosis on the patient and the caregiver. This project aims to identify a set of core outcome domains towards a core outcome set for ichthyosis that can measure all relevant concepts of ichthyosis in clinical practice, service delivery and research. METHODS AND ANALYSIS: Following the COMET (Core Outcome Measures in Effectiveness Trials) initiative, this project will employ a mixed-method study design which was developed using public and patient involvement and an international multidisciplinary expert group (clinical experts, patients and their representatives, policymakers, researchers and service providers). Experts by experience, or caregivers, will be recruited through online ichthyosis support groups. Phase one will focus on item generation and involve: (1) a systematic literature review, (2) a multimethods international qualitative study with ichthyosis caregivers and (3) co-development of items for an e-survey. Phase two, item refinement, will employ a novel four-pronged consensus approach: (1) an e-Delphi survey, (2) statistical analysis of e-Delphi survey results, (3) online qualitative feedback and (4) an online consensus discussion. All methodological considerations will be clearly linked with each Core Outcome Set-STAndards for Developing recommendation. ETHICS AND DISSEMINATION: Research Ethics Committee approval obtained from the School of Psychology, Ulster University (UK)(Ref:REC/20/0004). Results will be presented in published international peer-reviewed journals, at scientific meetings and support groups. REGISTRATION: COMET database (January 2019).

Dermatitis in an irritable infant.

This is the case of an infant with a persistent dermatitis affecting the perioral, acral and napkin areas, in whom a simple oral therapy provided a rapid treatment response.

Data mining and machine learning approaches for prediction modelling of schistosomiasis disease vectors: Epidemic disease prediction modelling.

This research presents viable solutions for prediction modelling of schistosomiasis disease based on vector density. Novel training models proposed in this work aim to address various aspects of interest in the artificial intelligence applications domain. Topics discussed include data imputation, semi-supervised labelling and synthetic instance simulation when using sparse training data. Innovative semi-supervised ensemble learning paradigms are proposed focusing on labelling threshold selection and stringency of classification confidence levels. A regression-correlation combination (RCC) data imputation method is also introduced for handling of partially complete training data. Results presented in this work show data imputation precision improvement over benchmark value replacement using proposed RCC on 70% of test cases. Proposed novel incremental transductive models such as ITSVM have provided interesting findings based on threshold constraints outperforming standard SVM application on 21% of test cases and can be applied with alternative environment-based epidemic disease domains. The proposed incremental transductive ensemble approach model enables the combination of complimentary algorithms to provide labelling for unlabelled vector density instances. Liberal (LTA) and strict training approaches provided varied results with LTA outperforming Stacking ensemble on 29.1% of test cases. Proposed novel synthetic minority over-sampling technique (SMOTE) equilibrium approach has yielded subtle classification performance increases which can be further interrogated to assess classification performance and efficiency relationships with synthetic instance generation.

Connecting patients, practitioners, and regulators in supporting positive experiences and processes of shared decision making: A progress report.

This paper describes a novel approach to explore how regulators, working with patients and practitioners, may contribute to supporting person-centred care and processes of shared decision making in implementing professional standards and reducing harms. Osteopathic patients report high levels of patient care. However, areas of consultations less likely to be rated as high included "fully understanding your concerns," "helping you to take control," and "making a plan of action with you," suggestive of a paternalistic approach to care and a barrier to the effective implementation of standards. This programme explored how to support patients and practitioners to make more explicit what is important to support consultations with better communication in accordance with standards. A series of workshops took place involving approximately 80 participants, which explored and identified practitioner and patient values; these were themed to develop a common framework and tested using case studies. Aspects of what enables or presents a barrier to a positive consultation were further explored with real patient narratives, and a range of resources were subsequently developed, which may support patients and practitioners to make explicit what is important to them in a consultation. A series of approaches and tools were then developed for piloting including patient curriculum vitae; patient goal planner; patient animation to support preparation for an appointment; infographic: a patient poster or leaflet; practitioner reflective tool; and an audio recording to increase awareness and understanding of values-based practice. In conclusion, a range of approaches may help to support patients and practitioners to make explicit what is important to them in a consultation. The next phase of our programme will use a range of methods including cluster sampling, pre-testing and post-testing with the Consultation and Relational Empathy (CARE) measure tool, and interviews and focus groups with users and practitioners to demonstrate impact.

Phy-PMRFI: Phylogeny-Aware Prediction of Metagenomic Functions Using Random Forest Feature Importance.

High-throughput sequencing techniques have accelerated functional metagenomics studies through the generation of large volumes of omics data. The integration of these data using computational approaches is potentially useful for predicting metagenomic functions. Machine learning (ML) models can be trained using microbial features which are then used to classify microbial data into different functional classes. For example, ML analyses over the human microbiome data has been linked to the prediction of important biological states. For analysing omics data, integrating abundance count of taxonomical features with their biological relationships is important. These relationships can potentially be uncovered from the phylogenetic tree of microbial taxa. In this paper, we propose a novel integrative framework Phy-PMRFI. This framework is driven by the phylogeny-based modeling of omics data to predict metagenomic functions using important features selected by a random forest importance (RFI) strategy. The proposed framework integrates the underlying phylogenetic tree information with abundance measures of microbial species (features) by creating a novel phylogeny and abundance aware matrix structure (PAAM). Phy-PMRFI progresses by ranking the microbial features using an RFI measure. This is then used as input for microbiome classification. The resultant feature set enhances the performance of the state-of-art methods such as support vector machines. Our proposed integrative framework also outperforms the state-of-the-art pipeline of phylogenetic isometric log-ratio transform (PhILR) and MetaPhyl. Prediction accuracy of 90 % is obtained with Phy-PMRFI over human throat microbiome in comparison to other approaches of PhILR with 53% and MetaPhyl with 71% accuracy.

Review of applications of high-throughput sequencing in personalized medicine: barriers and facilitators of future progress in research and clinical application.

There has been an exponential growth in the performance and output of sequencing technologies (omics data) with full genome sequencing now producing gigabases of reads on a daily basis. These data may hold the promise of personalized medicine, leading to routinely available sequencing tests that can guide patient treatment decisions. In the era of high-throughput sequencing (HTS), computational considerations, data governance and clinical translation are the greatest rate-limiting steps. To ensure that the analysis, management and interpretation of such extensive omics data is exploited to its full potential, key factors, including sample sourcing, technology selection and computational expertise and resources, need to be considered, leading to an integrated set of high-performance tools and systems. This article provides an up-to-date overview of the evolution of HTS and the accompanying tools, infrastructure and data management approaches that are emerging in this space, which, if used within in a multidisciplinary context, may ultimately facilitate the development of personalized medicine.

A Comprehensive Study on Predicting Functional Role of Metagenomes Using Machine Learning Methods.

"Metagenomics" is the study of genomic sequences obtained directly from environmental microbial communities with the aim to linking their structures with functional roles. The field has been aided in the unprecedented advancement through high-throughput omics data sequencing. The outcome of sequencing are biologically rich data sets. Metagenomic data consisting of microbial spe-cies which outnumber microbial samples, lead to the "curse of dimensionality". Hence the focus in metagenomics studies has moved towards developing efficient computational models using Machine Learning (ML), reducing the computational cost. In this paper, we comprehensively assessed various ML approaches to classifying high-dimensional human microbiota effectively into their functional phenotypes. We propose the application of embedded feature selection methods, namely, Extreme Gradient Boost-ing and Penalized Logistic Regression to determine important species. The resultant feature set enhanced the performance of one of the most popular state-of-the-art methods, Random Forest (RF) over metagenomic studies. Experimental results indicate that the proposed method achieved best results in terms of accuracy, area under Receiver Operating Characteristic curve (ROC-AUC) and major improvement in processing time. It outperformed other feature selection methods of filters or wrappers over RF and classifiers such as Support Vector Machine (SVM), Extreme Learning Machine (ELM), and -Nearest Neighbors (-NN).

Catalogue of inherited disorders found among the Irish Traveller population.

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Integrated metagenomic analysis of the rumen microbiome of cattle reveals key biological mechanisms associated with methane traits.

Methane is one of the major contributors to global warming. The rumen microbiota is directly involved in methane production in cattle. The link between variation in rumen microbial communities and host genetics has important applications and implications in bioscience. Having the potential to reveal the full extent of microbial gene diversity and complex microbial interactions, integrated metagenomics and network analysis holds great promise in this endeavour. This study investigates the rumen microbial community in cattle through the integration of metagenomic and network-based approaches. Based on the relative abundance of 1570 microbial genes identified in a metagenomics analysis, the co-abundance network was constructed and functional modules of microbial genes were identified. One of the main contributions is to develop a random matrix theory-based approach to automatically determining the correlation threshold used to construct the co-abundance network. The resulting network, consisting of 549 microbial genes and 3349 connections, exhibits a clear modular structure with certain trait-specific genes highly over-represented in modules. More specifically, all the 20 genes previously identified to be associated with methane emissions are found in a module (hypergeometric test, p<10-11). One third of genes are involved in methane metabolism pathways. The further examination of abundance profiles across 8 samples of genes highlights that the revealed pattern of metagenomics abundance has a strong association with methane emissions. Furthermore, the module is significantly enriched with microbial genes encoding enzymes that are directly involved in methanogenesis (hypergeometric test, p<10-9).

Hemosiderotic Juvenile Xanthogranuloma.

Juvenile xanthogranuloma is a non-Langerhans cell lesion mostly limited to the skin but occasionally presenting in extracutaneous locations or associated with systemic conditions. Lesions need to be distinguished mainly from dermatofibroma, xanthoma, Langerhans cell histiocytosis, or reticulohistiocytoma. Herein, we present a hemosiderotic variant of juvenile xanthogranuloma in a 12-year-old girl, which we have not found described in literature. The lesion presented at the back of the scalp as a slowly growing yellowish polypoid lesion showing occasional bleeding. The histopathological examination demonstrated a cellular infiltrate expanding the dermis, with a Grenz zone and with no remarkable changes in the overlying epidermis. The papule was made of mononucleated macrophages, many of which were xanthomatous. There were some Touton giant cells. The lesion was intermingled with a mild inflammatory infiltrate comprising lymphocytes, plasma cells, neutrophils, and some eosinophils. Many of the macrophages contained abundant cytoplasmic deposits of iron. The macrophages expressed CD68 and CD163, whereas they failed to express S100 protein, CD1a, and Langerin.

The role of fortified foods and nutritional supplements in increasing vitamin D intake in Irish preschool children.

PURPOSE: There are limited data on the contribution of fortified foods and nutritional supplements to intakes of vitamin D in young children. Our objective was to examine the intake, adequacy, risk of excessive intake and sources of dietary vitamin D. METHODS: The nationally representative cross-sectional dietary survey of young children (aged 1-4 years) (n 500) was used to evaluate vitamin D intake and quantify the contribution of the base diet, fortified foods and nutritional supplements to total intake. RESULTS: Median (IQR) intakes of vitamin D were generally low in this young population, ranging from 2.0 (1.9) to 2.5 (4.9) µg/day. Ninety-three and 78 % of children had intakes below 10 and 5 µg/day, respectively. While vitamin D supplement users (17 %) had the highest intakes [6.7 (6.4) µg/day] (P < 0.001), 74 % had intakes below 10 µg/day. Vitamin D-fortified foods, consumed by 77 % of children [2.2 (2.0) µg/day], made nutritionally significant contributions to intake [0.8 (1.6) µg/day], particularly in younger children [1.5 (4.6) µg/day]. Children who did not use nutritional supplements or fortified foods had significantly (P < 0.001) lower intakes of vitamin D than the other groups [1.0 (0.8) µg/day]. Our analyses show the importance of milk and yoghurt, meat and fortified ready-to-eat cereals as sources of vitamin D in this age group. The use of nutritional supplements or fortified foods at current levels does not represent a risk of intakes exceeding the European Food Safety Authority (EFSA) tolerable upper intake level (UL) (50 µg/day), as intakes did not exceed or even approach the UL (P95: 22 % of UL). CONCLUSION: Intakes of vitamin D in preschool children in Ireland are generally low. Nutritional supplements and fortified foods make significant contributions to intakes of vitamin D, without risk of unacceptably high intakes. Though supplements are effective in raising intakes of vitamin D in users, uptake is low (17 %). Food fortification may represent a suitable public health approach to increasing vitamin D intakes. The national food consumption data of Irish preschool children provide the ideal starting point for modelling of fortification scenarios to identify which foods and levels of addition will ensure effective and safe increases in vitamin D intake.

Predicting complications with pretreatment testing in infantile haemangioma treated with oral propranolol.

BACKGROUND: Since 2008, orally administered propranolol has rapidly gained acceptance as the preferred therapy for haemangiomas, and is usually initiated by ophthalmologists, dermatologists or plastic surgeons who do not routinely use propranolol for any other indication. During the initial years when experience was limited, most healthcare professionals justifiably adopted a cautious approach when initiating and monitoring treatment. A consensus recommendation from the American Society of Dermatologists suggests routine observation, monitoring and cardiology assessments prior to propranolol initiation. AIM: This study aims to analyse treatment initiation in a large tertiary children's hospital and investigate the value of pretreatment testing in predicting commonly seen adverse reactions of propranolol. METHOD: 104 eligible patients treated between January 2009 and July 2012 were included. All patients underwent pretesting either with protocol A (administration of test dose with routine observations) or protocol B (cardiology clinic assessment, including two-dimensional echocardiography without test dose). RESULTS: 38.5% (40/104) of patients developed adverse reactions during treatment; however, there were no severe or life-threatening reactions. Protocol A has a sensitivity of 0 (95% CI 0 to 0.17) and specificity of 0.95 (95% CI 0.83 to 0.99). Protocol B has a sensitivity of 0.07 (95% CI 0 to 0.34) and specificity of 0.86 (95% CI 0.63 to 0.96). CONCLUSIONS: The predictive values of both protocols for the commonly observed adverse reactions are low. In this series, there is no evidence to suggest that routine pretreatment testing before propranolol initiation is of any value in otherwise healthy children.