Tisham De

Background During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. Methods and findings Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and inciden...

BackgroundTo investigate the impact of the COVID-19 pandemic and infection prevention measures on children visiting emergency departments across Europe.MethodsRoutine health data were extracted retrospectively from electronic patient records of children aged <16 years, presenting to 38 emergency departments (ED) in 16 European countries for the period January 2018 – May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRR) were used to compare age groups, diagnoses and outcomes.FindingsReductions in pediatric ED attendances, hospital admissions and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (incidence rate ratio (IRR) 2·62, 95% CI 2·19 to 3·13) and in children aged >12 months (12-<24 months IRR 0·89, 95% CI 0·86 to 0·92; 2-...

Objective Understanding how paediatric emergency departments (PEDs) across Europe adapted their healthcare pathways in response to COVID-19 will help guide responses to ongoing waves of COVID-19 and potential future pandemics. This study aimed to evaluate service reconfiguration across European PEDs during the initial COVID-19 wave. Design This cross-sectional survey included 39 PEDs in 17 countries. The online questionnaire captured (1) study site characteristics, (2) departmental changes and (3) pathways for children with acute illness pre and during the first wave of COVID-19 pandemic (January–May 2020). Number of changes to health services, as a percentage of total possible changes encompassed by the survey, was compared with peak national SARS-CoV-2 incidence rates, and for both mixed and standalone paediatric centres. Results Overall, 97% (n=38) of centres remained open as usual during the pandemic. The capacity of 18 out of 28 (68%) short-stay units decreased; in contrast, 2 ...

Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI.Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classifi...

Copy number variants (CNVs) play an important role in the disease pathogenesis, including epilepsy, diabetes and many others. CNVs, are also known to affect cellular phenotypes through several phenomenon such as gene dosage. Next generation technologies for sequencing (DNA and RNA) and metabolite profiling (metabolomics) has led to the systematic discovery and evaluation of various genomic variants and their relationship to multiple phenotypes. Such approaches often involve application of several statistical and machine learning methods for unravelling new relationships between genomic variants and phenotypes i.e. disease outcomes or quantitative traits characterized at the molecular level. This thesis explores and develops several statistical methods for CNV detection and association with complex human phenotypes, in particular for epilepsy drug-response, epilepsy susceptibility, metabolomics and gene expression. In more detail, chapter 3, describes a genome wide CNV association an...

COSMIC (http://cancer.sanger.ac.uk) is an expert-curated database of somatic mutations in human cancer. Broad and comprehensive in scope, recent releases in 2016 describe over 4 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on over 400 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non-coding mutations, 1 million copy-number aberrations, 9 million gene-expression variants, and almost 8 million differentially methylated CpGs. This information combines a consistent interpretation of the data from the major cancer genome consortia and cancer genome literature with exhaustive hand curation of over 22,000 gene-specific literature publications. This unit describes the graphical Web site in detail; alternative protocols overview other ways the entire database can be accessed, analyzed, and downloaded. ...

COSMIC (http://cancer.sanger.ac.uk) is an expert-curated database of somatic mutations causing human cancer. Broad and comprehensive in scope, its 75th release (Nov 2015) describes over 3.7 million coding mutations across all human cancer disease types. Mutations are annotated across the entire genome, but expert curation is focused on almost 200 key cancer genes. Now encompassing the majority of molecular mutation mechanisms in oncogenetics, COSMIC additionally describes 10 million non-coding mutations, 1 million copy number aberrations, 9 million gene expression variants and almost 8 million differentially methylated CpG’s. This information combines a consistent interpretation of the data from the major cancer genome consortia and cancer genome literature, with hand-curation of over 22,000 gene-specific literature publications. With such a large volume of data, it is increasingly important to indicate which information is most significant. All mutations in COSMIC are now given a f...

COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world's largest and most comprehensive online resource for exploring the impact of somatic mutations in human cancer. Live since 2004, the 71st release (Nov 2014) describes over 2 million mutations in more than 1 million tumour samples across most human genes. To emphasise depth of knowledge on known cancer genes, mutation information is curated manually from the scientific literature, allowing very precise definitions of disease types and clinically relevant patient details. Combination of over 20,000 published studies gives substantial resolution of how mutations and phenotypes relate in human cancer, providing insights into the stratification of populations and new diseases behind known biomarkers. Conversely, our curation of over 15,000 cancer genome studies emphasises knowledge breadth, driving discovery of new unrecognised cancer-driving hotspots and molecular targets. Our high-resolut...

Here, I demonstrate that sex determination and sexual dimorphism across tree of life are deeply related to polyamine biochemistry in cells, especially to the synteny of genes: [SAT1-NR0B1], [SAT2-SHBG] and DMRT1. This synteny was found to be most distinct in mammals. Further, the common protein domain of SAT1 and SAT2 - PF00583 was shown to be present in the genome of the last universal common ancestor (LUCA). Protein domain-domain interaction analysis of LUCA’s genes suggests the possibility that LUCA had developed an immune defence against viruses. This domain-domain interaction analysis is the first scientific evidence indicating that viruses existed at least 3.5 billions years ago and probably co-existed with LUCA on early Hadean Earth.

COSMIC, the Catalogue of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk) is a high-resolution resource for exploring targets and trends in the genetics of human cancer. Currently the broadest database of mutations in cancer, the information in COSMIC is curated by expert scientists, primarily by scrutinizing large numbers of scientific publications. Over 4 million coding mutations are described in v78 (September 2016), combining genome-wide sequencing results from 28 366 tumours with complete manual curation of 23 489 individual publications focused on 186 key genes and 286 key fusion pairs across all cancers. Molecular profiling of large tumour numbers has also allowed the annotation of more than 13 million non-coding mutations, 18 029 gene fusions, 187 429 genome rearrangements, 1 271 436 abnormal copy number segments, 9 175 462 abnormal expression variants and 7 879 142 differentially methylated CpG dinucleotides. COSMIC now details the genetics of drug resistance, novel...

Here, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, CNV association with complex human traits such as 1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 as a new locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D), obesity and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define new metabolomic signatures for several new genomic loci, which can act as a catalyst for new diagnostics and therapeutic approaches.

The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5%]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5%), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments.

COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world's largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer. Our latest release (v70; Aug 2014) describes 2 002 811 coding point mutations in over one million tumor samples and across most human genes. To emphasize depth of knowledge on known cancer genes, mutation information is curated manually from the scientific literature, allowing very precise definitions of disease types and patient details. Combination of almost 20,000 published studies gives substantial resolution of how mutations and phenotypes relate in human cancer, providing insights into the stratification of mutations and biomarkers across cancer patient populations. Conversely, our curation of cancer genomes (over 12,000) emphasizes knowledge breadth, driving discovery of unrecognized cancer-driving hotspots and molecular targets. Our high-resolution curation approach is globa...