Surveillance of congenital Zika syndrome in England and Wales: methods and results of laboratory, obstetric and paediatric surveillance.

The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK - the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring - enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.

Continuing rise of Type 2 diabetes incidence in children and young people in the UK.

AIMS: To estimate the incidence of Type 2 diabetes in children aged <17 years, compare this with similar data 10 years ago, and characterize clinical features at diagnosis in the UK and Republic of Ireland. METHODS: Using the British Paediatric Surveillance Unit reporting framework, cases of Type 2 diabetes diagnosed in children aged <17 years between 1 April 2015 and 30 April 2016 were reported each month. RESULTS: A total of 106 cases were reported, giving a UK incidence of 0.72/100 000 (95% CI 0.58-0.88). Children from ethnic minorities had significantly higher incidence compared with white children (0.44/100 000) with rates of 2.92/100 000 and 1.67/100 000, in Asian and BACBB (black/African/Caribbean/black British) children respectively. Sixty-seven percent were girls and 81% had a family history of Type 2 diabetes. The mean BMI sd score at diagnosis was 2.89 (2.88, girls; 2.92, boys); 81% were obese. Children of Asian ethnicity had a significantly lower BMI sd score compared with white children (P<0.001). There was a trend in increased incidence from 2005 to 2015, with a rate ratio of 1.35 (95% CI 0.99-1.84), although this was not statistically significant (P=0.062). There was statistical evidence of increased incidence among girls (P=0.03) and children of South-Asian ethnicity (P=0.01) when comparing the 2005 and 2015 surveys. CONCLUSIONS: Type 2 diabetes remains far less common than Type 1 diabetes in childhood in the UK, but the number of cases continues to rise, with significantly increased incidence among girls and South-Asian children over a decade. Female gender, family history, non-white ethnicity and obesity were found to be strongly associated with the condition.

Ascertainment of early onset eating disorders: a pilot for developing a national child psychiatric surveillance system.

BACKGROUND: A Child & Adolescent Psychiatric Surveillance System was established as part of a British Paediatric Surveillance Unit study of early onset eating disorders (EOED). METHOD: A study of EOED presenting to paediatricians was undertaken through the BPSU over 15 months in 2005-06. RESULTS: Monthly report cards compliance was 83%, identifying 208 EOED cases. On evaluation, 99% of psychiatrists responding supported the need for surveillance and 95% would continue to contribute. CONCLUSIONS: The findings of this pilot study suggest that a monthly surveillance of rare conditions in child and adolescent psychiatry is feasible and enhances ascertainment.

The use of electronic reporting to aid surveillance of ADRs in children: a proof of concept study.

OBJECTIVE: To investigate: (1) the feasibility of establishing active paediatric surveillance for adverse drug reactions (ADRs), (2) whether electronic reporting is effective and (3) whether such a system could complement the Medicines and Healthcare products Regulatory Agency (MHRA) yellow card system. DESIGN: Between January 2006 and February 2007 ADRs in children under 16 were reported each month by consultant paediatricians and paediatric pharmacists in Scotland. For 8 months respondents received a postal card, after which half were selected to report electronically via an email card for a further 6 months and half continued with the postal card. Reports of paediatric ADRs severe enough to warrant hospital admission or to delay discharge of hospitalised patients or resulting from an outpatient prescription were followed up. A postal questionnaire evaluated the system at the end of the study. RESULTS: Following a 2-month lead-in period, 83% of the cards were returned over the year, 84% by paediatricians and 82% by pharmacists. With electronic reporting the response rate was 80%. Eighty-seven confirmed reports of a drug being associated with one or more adverse reactions were reported in 67 children. Only eight children were also identified through the MHRA yellow card system. Respondents indicated continuing willingness to contribute to an active (preferably electronic) reporting system. CONCLUSIONS: Active paediatric ADR surveillance is feasible; electronic reporting is effective and data collected are different to, but could complement, those collected by the MHRA yellow card.

Peptide sequencing and site-directed mutagenesis identify tyrosine-727 as the active site tyrosine of Saccharomyces cerevisiae DNA topoisomerase I.

Extensive digestion of the covalent intermediate between DNA and Saccharomyces cerevisiae DNA topoisomerase I with trypsin yields a 7-amino acid peptide covalently linked to DNA. Direct sequencing of the DNA-linked peptide identifies Tyr-727 as the active site tyrosine that forms an O4-phosphotyrosine bond with DNA when the enzyme cleaves a DNA phosphodiester bond. Site-directed mutagenesis of the cloned yeast TOP1 gene encoding the enzyme confirms the essentiality of Tyr-727 for the relaxation of supercoiled DNA by the enzyme. From amino acid sequence homology, Tyr-771 and -773 are readily identified as the active site tyrosines of Schizosaccharomyces pombe and human DNA topoisomerase I, respectively. Sequence comparison and site-directed mutagenesis also implicate Tyr-274 of vaccinia virus DNA topoisomerase as the active site residue. There appears to be a 70-amino acid domain near the carboxyl terminus of eukaryotic DNA topoisomerase I and vaccinia topoisomerase, within which the active site tyrosine resides.

Peptide sequencing and site-directed mutagenesis identify tyrosine-319 as the active site tyrosine of Escherichia coli DNA topoisomerase I.

Tyrosine 319 of E. coli topoisomerase I is shown to be the active site tyrosine that becomes covalently attached to a DNA 5' phosphoryl group during the transient breakage of a DNA internucleotide bond by the enzyme. The tyrosine was mapped by trapping the covalent complex between the DNA and DNA topoisomerase I, digesting the complex exhaustively with trypsin, and sequencing the DNA-linked tryptic peptide. Site-directed mutagenesis converting Tyr-319 to a serine or phenylalanine completely inactivates the enzyme. The structure of the enzyme and its catalysis of DNA strand breakage, passage, and rejoining are discussed in terms of the available information.

Folding of ribonuclease A from a partially disordered conformation. Kinetic study under transition conditions.

Bovine pancreative ribonuclease A (RNase A), denatured by 3.5 M LiClO4 (pH 3.0), has some ordered conformation as indicated by a high retention of alpha-helix and compact structure. This effect of LiClO4 was confirmed by the observation that the alpha-helix of isolated S-peptide is stabilized in the presence of 3.5 M LiClO4 (pH 3.0), as measured by circular dichroism and nuclear magnetic resonance. The effect of the retained alpha-helices and compact structure on the folding kinetics of RNase A was studied by comparison with the kinetic folding from urea-denatured RNase A, which has no ordered structure. In contrast to our previous study under folding conditions [Denton, J.B., Konishi, Y., & Scheraga, H. A. (1982) Biochemistry 21, 5155], the kinetic folding/unfolding experiments were carried out here in the transition regions between native and LiClO4-denatured RNase A and between native and urea-denatured RNase A. The measured relaxation times were extrapolated to the triple point, where native RNase A, LiClO4-denatured RNase A, and urea-denatured RNase A have the same thermodynamic stability and are at the same concentration, in order to compare the rates of these two processes under the same solvent conditions. Under these conditions, both folding and unfolding pathways are studied simultaneously without any accumulated intermediates. No significant acceleration of folding was observed from LiClO4-denatured RNase A as compared to that from urea-denatured RNase A. This indicates that all ordered structures in RNase A are not equivalent in their influence on the folding pathway; some may play an essential role and some may not.(ABSTRACT TRUNCATED AT 250 WORDS)