Context, ethics and pharmacogenetics

Most of the literature on pharmacogenetics assumes that the main problems in implementing the technology will be institutional ones (due to funding or regulation) and that although it involves genetic testing, the ethical issues involved in pharmacogenetics are different from, even less than, 'traditional' genetic testing. Very little attention has been paid to how clinicians will accept this technology, their attitudes towards it and how it will affect clinical practice. This paper presents results from interviews with clinicians who are beginning to use pharmacogenetics and explores how they view the ethics of pharmacogenetic testing, its use to exclude some patients from treatment, and how this kind of testing fits into broader debates around genetics. In particular this paper examines the attitudes of breast cancer and Alzheimer's disease specialists. The results of these interviews will be compared with the picture of pharmacogenetics painted in the published literature, as a way of rooting this somewhat speculative writing in clinical practice

New ophthalmosaurid ichthyosaurs from the European lower cretaceous demonstrate extensive ichthyosaur survival across the Jurassic–Cretaceous boundary

Background Ichthyosauria is a diverse clade of marine amniotes that spanned most of the Mesozoic. Until recently, most authors interpreted the fossil record as showing that three major extinction events affected this group during its history: one during the latest Triassic, one at the Jurassic–Cretaceous boundary (JCB), and one (resulting in total extinction) at the Cenomanian-Turonian boundary. The JCB was believed to eradicate most of the peculiar morphotypes found in the Late Jurassic, in favor of apparently less specialized forms in the Cretaceous. However, the record of ichthyosaurs from the Berriasian–Barremian interval is extremely limited, and the effects of the end-Jurassic extinction event on ichthyosaurs remains poorly understood. Methodology/Principal Findings Based on new material from the Hauterivian of England and Germany and on abundant material from the Cambridge Greensand Formation, we name a new ophthalmosaurid, Acamptonectes densus gen. et sp. nov. This taxon shares numerous features with Ophthalmosaurus, a genus now restricted to the Callovian–Berriasian interval. Our phylogenetic analysis indicates that Ophthalmosauridae diverged early in its history into two markedly distinct clades, Ophthalmosaurinae and Platypterygiinae, both of which cross the JCB and persist to the late Albian at least. To evaluate the effect of the JCB extinction event on ichthyosaurs, we calculated cladogenesis, extinction, and survival rates for each stage of the Oxfordian–Barremian interval, under different scenarios. The extinction rate during the JCB never surpasses the background extinction rate for the Oxfordian–Barremian interval and the JCB records one of the highest survival rates of the interval. Conclusions/Significance There is currently no evidence that ichthyosaurs were affected by the JCB extinction event, in contrast to many other marine groups. Ophthalmosaurid ichthyosaurs remained diverse from their rapid radiation in the Middle Jurassic to their total extinction at the beginning of the Late Cretaceous

Biobanking and consenting to research: a qualitative thematic analysis of young people’s perspectives in the North East of England

Background: Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people’s (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. Methods: We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person’s Advisory Group North England (YPAGne) and participating CYP’s secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. Results: One hundred two CYP completed the survey. Most were between 16–18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: ‘altruism’, ‘potential benefits outweigh individual risk’, 'frugality', and ‘(in)convenience’. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: ‘altruism’, ‘body integrity’ and ‘sample frugality’. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80). Conclusion: Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible

More insight into the fate of biomedical meeting abstracts: a systematic review

BACKGROUND: It has been estimated that about 45% of abstracts that are accepted for presentation at biomedical meetings will subsequently be published in full. The acceptance of abstracts at meetings and their fate after initial rejection are less well understood. We set out to estimate the proportion of abstracts submitted to meetings that are eventually published as full reports, and to explore factors that are associated with meeting acceptance and successful publication. METHODS: Studies analysing acceptance of abstracts at biomedical meetings or their subsequent full publication were searched in MEDLINE, OLDMEDLINE, EMBASE, Cochrane Library, CINAHL, BIOSIS, Science Citation Index Expanded, and by hand searching of bibliographies and proceedings. We estimated rates of abstract acceptance and of subsequent full publication, and identified abstract and meeting characteristics associated with acceptance and publication, using logistic regression analysis, survival-type analysis, and meta-analysis. RESULTS: Analysed meetings were held between 1957 and 1999. Of 14945 abstracts that were submitted to 43 meetings, 46% were accepted. The rate of full publication was studied with 19123 abstracts that were presented at 234 meetings. Using survival-type analysis, we estimated that 27% were published after two, 41% after four, and 44% after six years. Of 2412 abstracts that were rejected at 24 meetings, 27% were published despite rejection. Factors associated with both abstract acceptance and subsequent publication were basic science and positive study outcome. Large meetings and those held outside the US were more likely to accept abstracts. Abstracts were more likely to be published subsequently if presented either orally, at small meetings, or at a US meeting. Abstract acceptance itself was strongly associated with full publication. CONCLUSIONS: About one third of abstracts submitted to biomedical meetings were published as full reports. Acceptance at meetings and publication were associated with specific characteristics of abstracts and meetings

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

The influence of muscular action on bone strength via exercise

Mechanical stimuli influence bone strength, with internal muscular forces thought to be the greatest stressors of bone. Consequently, the effects of exercise in improving and maintaining bone strength have been explored in a number of interventional studies. These studies demonstrate a positive effect of high-impact activities (i.e. where large muscle forces are produced) on bone strength, with benefits being most pronounced in interventions in early pubertal children. However, current studies have not investigated the forces acting on bones and subsequent deformation, preventing the development of optimised and targeted exercise interventions. Similarly, the effects of number and frequency of exercise repetitions and training sessions on bone accrual are unexplored. There are conflicting results as to gender effects on bone response to exercise, and the effects of age and starting age on the osteogenic effects of exercise are not well known. It also appears that exercise interventions are most effective in physically inactive people or counteracting conditions of disuse such as bed rest. Bone strength is only one component of fracture risk, and it may be that exercise resulting in improvements in, e.g., muscle force/power and/or balance is more effective than those whose effects are solely osteogenic. In summary, exercise is likely to be an effective tool in maintaining bone strength but current interventions are far from optimal. © Springer Science+Business Media 2013

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Vancomycin Overdose in a 6-Month-Old Girl

INTRODUCTIONVancomycin is a commonly used antibiotic for the treatment of serious gram-positive infections. The use of this agent has increased over the past decade, as organisms have become increasingly resistant to penicillinase-resistant penicillins.1,2 Formal pharmacokinetics-based dosing strategies for infants were first reported in 1980.1 Since then, various dosing regimens for vancomycin have been studied in neonates and infants to take into account their differing kidney maturation status. Vancomycin dosing strategies typically target a “therapeutic range” (peaks of 20 to 40 mg/L, troughs of 5 to 10 mg/L) in an effort to enhance efficacy and minimize the potential toxic effects of the drug. The primary toxicities of concern to clinicians are ototoxicity and nephrotoxicity. However, definitive data that support concentration-efficacy or concentration-toxicity relationships for vancomycin are lacking.3 The following case illustrates the clinical course of an infant who was inadvertently given a 10-fold overdose of vancomycin