Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Funding Information: Financial support. This work was supported by the European Union’s Horizon 2020 Program under grants (848196 DIAMONDS, 668303 PERFORM, 279185 EUCLIDS, Prof Levin), by the Imperial Biomedical Research Centre (BRC) of the National Institute for Health Research (NIHR), grants (206508/Z/17/Z and MRF-160-0008-ELP-KAFO-C0801 to Dr Kaforou) from the Wellcome Trust and the Medical Research Foundation, a grant (215214/Z/19/Z to Dr Jackson) from the Wellcome Trust, a grant (R61HD105590-01 PreVAIL kIds to Dr. Burns) from the National Institutes of Health, and grants (WDPI_G28062 and WDPI_P89720 to Drs Herberg and Georgiou) from the Community Jameel Imperial College COVID-19 Excellence Fund and the Rosetrees Trust. This work has been supported by the Imperial Confidence in Concept Scheme, funded by MRC Confidence in Concept, Wellcome Trust Institutional Strategic Support Fund, NIHR Imperial BRC, and Rosetrees Trust (to Rodriguez-Manzano and Kaforou). Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.Peer reviewe

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM) : a multi-cohort machine learning study

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.Peer reviewe

Doyne lecture 2016:intraocular health and the many faces of inflammation

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses

Impact of European vaccination policies on seasonal influenza vaccination coverage rates : An update seven years later

Publisher Copyright: © 2018, © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC.Seasonal influenza can have serious morbid consequences and can even result in death, particularly in at-risk populations, including healthcare professionals (HCPs), elderly and those living with a medical risk condition. Although in Europe recommendations exist for annual influenza vaccination in these populations in most countries, the vaccination coverage rate (VCR) is often well below the World Health Organization target of 75% coverage. In our previous survey in 2009 we showed that some elements of national vaccination policies, e.g. reminder systems, strong official recommendation, and easy access, seemed to contribute to achieving higher influenza VCRs among elderly. We repeated the survey in 2016, using the same methodology to assess changes in influenza VCRs among the elderly and in the impact of policy elements on these VCRs. In addition, we collected information about VCRs among HCPs, and those living with a medical risk condition. The median VCR in the 21 countries that had recommendations for influenza vaccination in the elderly was 35.3%, ranging from 1.1% in Estonia to 74.5% in Scotland. The average VCRs for HCPs and those living with medical risk conditions, available in 17 and 10 countries, respectively, were 28.3% (range 7% in Czech Republic to 59.1% in Portugal) and 32.2% (range from 20.0% in the Czech Republic and Hungary to 59.6% in Portugal), respectively. Fewer countries were able to provide data from HCP and those living with medical risk conditions. Since the initial survey during the 2007–2008 influenza season, VCRs have decreased in the elderly in the majority of countries, thus, achieving high VCRs in the elderly and the other target groups is still a major public health challenge in Europe. This could be addressed by the identification, assessment and sharing of best practice for influenza vaccination policies.publishersversionPeer reviewe

Challenges in the management of a patient with Cowden syndrome: case report and literature review

We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken

Prevalence of systemic inflammatory response syndrome (SIRS) in hospitalized children: a point prevalence study

<p>Abstract</p> <p>Background</p> <p>In accordance with the 1st International pediatric sepsis consensus conference, where sepsis was defined as SIRS associated with suspected or proven infection, we have identified the need to assess the prevalence of SIRS and sepsis in children with abnormal temperatures hospitalized in The Children's Clinical University Hospital in Latvia.</p> <p>Methods</p> <p>A descriptive prospective point prevalence study (using two time periods, each 24 h, randomly chosen) was conducted on all children (n = 943) treated in the hospital. All children with abnormal temperatures – fever or hypothermia (n = 92) – were included in the study. Questionnaires evaluating age-specific SIRS criteria were completed. The prevalence of SIRS was detected with 95% CI.</p> <p>Results</p> <p>Out of a total of 943 patients treated in the hospital, 10% (n = 92) had abnormal temperatures. In all these cases the abnormal temperature was a fever; hypothermia was not established in any patient. Of the children with fever, 72% (n = 66) had SIRS. Of the SIRS patients, 8% (n = 5) developed sepsis, 5% (n = 3) severe sepsis and 2% (n = 1) septic shock. Seventy-six percent (n = 50) of the SIRS patients had fever in combination with respiratory rate >2 SD above normal for age; 50% (n = 33) had fever with abnormal leukocyte count; 15% (n = 10) had fever with tachycardia >2 SD above normal for age. Most of the SIRS patients (39%, n = 25) were aged 2–5 years. Twenty-one percent (n = 14) of the children with SIRS and 50% (n = 2) of those with severe sepsis and septic shock had an underlying disease. In no case was SIRS and sepsis recognized by doctors and the diagnoses were not recorded on the patients' cards.</p> <p>Conclusion</p> <p>Our results would indicate a high risk for sepsis development in children with SIRS. Early SIRS diagnosis and awareness of risk of developing sepsis could change the medical approach to the patient in everyday clinical practice, eventually leading to early, goal-directed therapy for sepsis.</p

Investigation of the level of knowledge in different countries about edible insects : cluster segmentation

This study aimed to investigate the level of knowledge about edible insects (EIs) in a sample of people from thirteen countries (Croatia, Greece, Latvia, Lebanon, Lithuania, Mexico, Poland, Portugal, Romania, Serbia, Slovenia, Spain, and Turkey). Data collection was based on a questionnaire survey applied through online tools between July and November 2021. For data analysis, techniques such as factor analysis, cluster analysis, and chi-square tests were used, with a significance level of 5%. A total of 27 items were used to measure knowledge on a five-point Likert scale. Applying factor analysis with principal components and Varimax rotation, a solution that explains about 55% of variance was obtained. This accounts for four factors that retained 22 of the 27 initial items: F1 = Sustainability (8 items), F2 = Nutrition (8 items), F3 = Production Factors (2 items), and F4 = Health Concerns (4 items). Internal consistency was evaluated through Cronbach’s alpha. The cluster analysis consisted of the application of hierarchical methods followed by k-means and produced three clusters (1—‘fearful’, 2—‘farming,’ and 3—‘ecological’ individuals). The characterisation of the clusters revealed that age did not influence cluster membership, while sex, education, country, living environment, professional area, and income all influenced the composition of the clusters. While participants from Mexico and Spain were fewer in the ‘fearful’ cluster, in those from Greece, Latvia, Lebanon, and Turkey, the situation was opposed. Participants from rural areas were mostly in cluster 2, which also included a higher percentage of participants with lower income. Participants from professional areas linked with biology, food, and nutrition were mostly in cluster 3. In this way, we concluded that the level of knowledge about EIs is highly variable according to the individual characteristics, namely that the social and cultural influences of the different countries lead to distinct levels of knowledge and interpretation of information, thus producing divergent approaches to the consumption of insects—some more reluctant and measuring possible risks. In contrast, others consider EIs a good and sustainable protein-food alternative.info:eu-repo/semantics/publishedVersio

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

HLA B27 allele types in homogeneous groups of juvenile idiopathic arthritis patients in Latvia

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and therapeutic strategies vary in different JIA types. The routinely accepted practice to start with Sulphasalazine (SS) as the first line treatment in patients with HLA B27 positive JIA proves to be ineffective in a large proportion of children