Fifteen-minute consultation: The efficient investigation of infantile and childhood epileptic encephalopathies in the era of modern genomics

The investigation of children presenting with infantile and childhood epileptic encephalopathies (ICEE) is challenging due to diverse aetiologies, overlapping phenotypes and the relatively low diagnostic yield of MRI, electroencephalography (EEG) and biochemical investigations. Careful history and thorough examination remain essential as these may identify an acquired cause or indicate more targeted investigation for a genetic disorder. Whole exome sequencing (WES) with analysis of a panel of candidate epilepsy genes has increased the diagnostic yield. Whole genome sequencing (WGS), particularly as a trio with both parents' DNA, is likely to supersede WES. Modern genomic investigation impacts on the timing and necessity of other testing. We propose a structured approach for children presenting with ICEE where there is diagnostic uncertainty, emphasising the importance of WGS or, if unavailable, WES early in the investigative process. We note the importance of expert review of all investigations, including radiology, neurophysiology and biochemistry, to confirm the technique used was appropriate as well as the results. It is essential to counsel families on the risks associated with the procedures, the yield of the procedures, findings that are difficult to interpret and implication of 'negative' results. Where children remain without a diagnosis despite comprehensive investigation, we note the importance of ongoing multidisciplinary care

Top Quark Decays into Heavy Quark Mesons

For top quark decays into heavy quark mesons $\Upsilon$ and $\bar{B}_c^*$ , a complete calculation to the leading order both in QCD coupling constant $\alpha_s$ and in $v$, the typical velocity of the heavy quarks inside the mesons, is performed. Relatons between the top quark mass and the decay branching ratios are studied. Comparion with the results which are obtained by using the quark frangmentation functions is also discussed. The branching ratios are consistent (within a factor of $2\sim 3$) with that obtained using fragmentation functions at $m_t\sim 150$ GeV.Comment: 15 pages in LaTex form, 4 figures include

Training of Vancouver 2010 volunteers: a legacy opportunity?

The successful delivery of a mega-sport event depends upon a volunteer workforce. It is often asserted that the training of event volunteers contributes to the creation of a social legacy via the transfer of learning to other volunteer contexts; thereby creating an enhanced volunteer pool after the event that will support the tourism and events industries in the host communities. This article reflects upon the reality of that assertion and argues that in order to achieve legacy both training and development strategies are required. As such an analysis of data collected at the Vancouver 2010 Olympic and Paralympic Winter Games around training and legacy is discussed. A Legacy Training and Development Model is offered and subsequently, applied to the case study. The article concludes by suggesting that training at Vancouver 2010 was a missed opportunity in achieving legac

Motivations and experiences of museum visitors: The case of the Imperial War Museum, United Kingdom

This study explores motivations of visitors to the Imperial War Museum (North and South), United Kingdom, with a view to understanding why people visit museums associated with conflicts. Though museums are part of the education and leisure industry, the distinction between education and leisure is often blurred. There are a number of reasons why people visit museums. Motives of museum visitors can be grouped into intrinsic and extrinsic factors. This study analysed the extent to which museum visitors are motivated by extrinsic and intrinsic factors. Semi-structured interviews with visitors were conducted w at the Imperial Museum of War (North and South), United Kingdom. The findings do establish that extrinsic motivations are more dominant than the intrinsic ones for visiting the Imperial War Museum. The importance of extrinsic factors in motivating museum visitors would suggest that providing an opportunity for a good day out has more appeal to the visitors than the collections in the museum for the average visitors. The experiencing of museum in its totality is more important than the individual collections or the theme of the museum to the mainstream visitor. This work has made a contribution to understanding visitor motivations, which are multi-facetted, complex and not necessarily fully understood by the visitors themselves

'From mosh pit to posh pit': Festival imagery in the context of the boutique festival

This paper addresses market-based cultural production in the context of the UK festival field, with a focus on the framing of the festival experience through anticipation. In particular, boutique festivals are discussed as examples of a contemporary cultural ?product category? which has emerged and proliferated in the last decade. Through discourse analysis of media representations of boutique festivals, we situate the boutique festival in a broader sociocultural discourse of agency and choice, which makes it meaningful and desirable, and outline the type of consumer it is meant to attract. For the contemporary consumer, the boutique festival is presented as an anticipated experience based on countercultural festival imagery, while simultaneously framing cultural participation through consumption. The paper contributes to a wider debate on the construction of the consumer in the cultural economy

Phenomenological psychology & descriptive experience sampling: a new approach to exploring music festival experience

This paper provides in-depth discussion of a methodological approach to researching music festival experience. Grounded in existential phenomenology (Heidegger, 1927/1962. Being and time (J. Macquarrie and E. Robinson, Trans.). Oxford: Blackwell) it argues for the adoption of an interpretative phenomenological perspective (Merleau–Ponty, 1945/1962. Phenomenology of perception (C. Smith, Trans.). New York, NY: Humanities Press) to more fully understand the live music festival experience. Phenomenological psychology (Smith, Harre and Van angenhove, 1995. Ideography and the case–study. In J. A. Smith, R. Harre, & L.Van Langenhove (Eds.), Rethinking psychology (pp. 59–69). London: SAGE Publications) contextualises the music festival experience within the attendee’s Lifeworld. Interpretative Phenomenological Analysis (IPA) (Smith, 2015. Qualitative psychology: A practical guide to research methods (3rd ed.). Los Angeles, CA: Sage Publications Ltd) provides a robust process for analysing the music festival experience ideographically. Participants used Descriptive Experience Sampling (DES)(Hurlburt & Heavey, 2001. Telling what we know: Describing inner experience. Trends in Cognitive Sciences, 5(9), 400–403) to record their Green Man music festival experiences, this data was then explored during phenomenological interviews. DES and IPA provide a contrasting conceptualisation of experience, with findings that contribute to Ashworth’s (2003b. The phenomenology of the lifeworld and social psychology. Social Psychology Review, 5(1), 18–34) theories of Lifeworld and Krueger’s (2014b. Varieties of extended emotions. Phenomenology and the Cognitive Sciences, 13(4), 533–555) Hypothesis of Individual Extended Emotions and his Hypothesis of Collective Extended Emotions. Lastly, building upon the application and adaptability to the music festival context allows a consideration of future studies

Benefits for children with suspected cancer from routine whole-genome sequencing

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.</p

Stakeholder views on secondary findings in whole-genome and whole-exome sequencing:a systematic review of quantitative and qualitative studies

Purpose: As whole-exome and whole-genome sequencing (WES/WGS) move into routine clinical practice, it is timely to review data that might inform the debate around secondary findings (SF) and the development of policies that maximize participant benefit. Methods: We systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes. Results: 44 articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning ‘actionable’ findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients’ views were largely influenced by a sense of rights, while views of genomics professionals were informed by a sense of professional responsibility. Experience of genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings. Conclusion: This review suggests that bidirectional interaction during consent might best facilitate informed decision-making about SF, and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.</p

Assisted reproduction treatment and epigenetic inheritance

Background: The subject of epigenetic risk of assisted reproduction treatment (ART), initiated by reports on an increase of children with the Beckwith–Wiedemann imprinting disorder, is very topical. Hence, there is a growing literature, including mouse studies. Methods: In order to gain information on transgenerational epigenetic inheritance and epigenetic effects induced by ART, literature databases were searched for papers on this topic using relevant keywords. Results: At the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are convincingly observed in mice, especially for placenta, and seem more frequent than in humans. Data generally provide a warning as to the use of ovulation induction and in vitro culture. In human sperm from compromised spermatogenesis, sequence-specific DNA hypomethylation is observed repeatedly. Transmittance of sperm and oocyte DNA methylation defects is possible but, as deduced from the limited data available, largely prevented by selection of gametes for ART and/or non-viability of the resulting embryos. Some evidence indicates that subfertility itself is a risk factor for imprinting diseases. As in mouse, physiological effects from ART are observed in humans. In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found. In the mouse, a broader range of CpG sequences has not yet been studied. Also, a multigeneration study of systematic ART on epigenetic parameters is lacking. Conclusions: The field of epigenetic inheritance within the lifespan of an individual and between generations (via mitosis and meiosis, respectively) is growing, driven by the expansion of chromatin research. ART can induce epigenetic variation that might be transmitted to the next generation

Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2andndash;3andnbsp;weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2andndash;3andnbsp;week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children.</p