The external auditor’s role in regulation – An insight into the advisory activity of the National Audit Office of the United Kingdom

There has been considerable growth in recent years of government regulations over a whole range of activities and businesses. Regulation is a product of the way in which society perceives and responds to risk. In devising regulations, there must be a proper consideration of where the risks lie and how to balance the need for protection against the need to foster a society where people accept and share responsibility for managing life's risks. Good, effective regulation requires proper risk analysis, a thorough assessment of cost versus benefits and an independent approach – all skills that can be well deployed by the external auditor. In the UK, the National Audit Office has been working with the Better Regulation Commission to reduce regulatory burdens without endangering regulatory outcomes. The Better Regulation Commission (www.brc.gov.uk) is an independent body which is responsible for advising and challenging the Government on regulatory reform, and scrutinising the Government's plans for regulatory simplification. Its focus on reducing burdens has the benefit of releasing resources for higher value activities, increasing voluntary compliance and improving legitimacy. This paper concludes that regulatory reform is an important issue for Supreme Audit Institutions

Global citizens: Who are they?

A growing desire to instigate global citizenship programmes in Higher Education (HE) has led to the development of optional structured opportunities for students to engage in prosocial activities. One of the challenges facing such programmes is to demonstrate and plan for the personal growth of those students. This paper reports the dispositional, prosocial and attitudinal characteristics; knowledge and skills; and perceptions of social justice that students who undertake these activities bring to their initial participation. The findings indicate, that in comparison to a control group, the students differ significantly in a number of important ways (e.g. conscientiousness, extraversion, openness; Machiavellianism, prosocial behaviour; self-esteem; skills relating to social action and tolerance and understanding and their concern regarding social problems). However, consideration should be given to the ways in which those students can be developed within a framework for social justice. Further, recruitment procedures for citizenship programmes in general should encourage the participation of a more diverse group of students than currently appears to be the case

Effects of Pre-Natal Vitamin D Supplementation with Partial Correction of Vitamin D Deficiency on Early Life Healthcare Utilisation: A Randomised Controlled Trial

Funded by Asthma UK grant number 09/ 36

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Cost analysis of options for management of African Animal Trypanosomiasis using interventions targeted at cattle in Tororo District; south-eastern Uganda

BACKGROUND: Tsetse-transmitted African trypanosomes cause both nagana (African animal Trypanosomiasis-AAT) and sleeping sickness (human African Trypanosomiasis - HAT) across Sub-Saharan Africa. Vector control and chemotherapy are the contemporary methods of tsetse and trypanosomiasis control in this region. In most African countries, including Uganda, veterinary services have been decentralised and privatised. As a result, livestock keepers meet the costs of most of these services. To be sustainable, AAT control programs need to tailor tsetse control to the inelastic budgets of resource-poor small scale farmers. To guide the process of tsetse and AAT control toolkit selection, that now, more than ever before, needs to optimise resources, the costs of different tsetse and trypanosomiasis control options need to be determined. METHODS: A detailed costing of the restricted application protocol (RAP) for African trypanosomiasis control in Tororo District was undertaken between June 2012 and December 2013. A full cost calculation approach was used; including all overheads, delivery costs, depreciation and netting out transfer payments to calculate the economic (societal) cost of the intervention. Calculations were undertaken in Microsoft Excel™ without incorporating probabilistic elements. RESULTS: The cost of delivering RAP to the project was US$6.89 per animal per year while that of 4 doses of a curative trypanocide per animal per year was US$ 5.69. However, effective tsetse control does not require the application of RAP to all animals. Protecting cattle from trypanosome infections by spraying 25 %, 50 % or 75 % of all cattle in a village costs US$1.72, 3.45 and 5.17 per animal per year respectively. Alternatively, a year of a single dose of curative or prophylactic trypanocide treatment plus 50$ 4.87 and US$ 5.23 per animal per year. Pyrethroid insecticides and trypanocides cost 22.4 and 39.1 % of the cost of RAP and chemotherapy respectively. CONCLUSIONS: Cost analyses of low cost tsetse control options should include full delivery costs since they constitute 77.6 % of all project costs. The relatively low cost of RAP for AAT control and its collateral impact on tick control make it an attractive option for livestock management by smallholder livestock keepers

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities