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

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

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

ABSTRACTBackground: The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified.Objective: To review dosing and monitoring of methadone therapy in pregnancy.Methods: A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were “methadone”, “pregnancy”, “pharmacokinetic”, “clearance”, “metabolism”, “therapeutic drug monitoring”, and “methadone dosing”. Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded.Results: The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence.Conclusions: Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric dosage adjustments throughout pregnancy are still recommended.RÉSUMÉContexte : Le comportement pharmacocinétique de la méthadone est modifié durant la grossesse; la posologie la plus adéquate et le suivi nécessaire n’ont pas encore été déterminés. Objectif : Évaluer la posologie et le suivi thérapeutique de la méthadone durant la grossesse.Méthodes : Une recherche bibliographique a été effectuée dans plusieurs bases de données (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts et Cochrane Database of Systematic Reviews) depuis leurs débuts jusqu’au mois de mai 2012. Les termes utilisés pour la recherche étaient : « méthadone », « grossesse », « pharmacocinétique », « clairance », « métabolisme », « suivi thérapeutique pharmacologique » et « posologie de la méthadone ». D’autres articles ont été trouvés par suite de recherches dans les bibliographies des articles primaires et des articles de synthèse. Tous les articles primaires de langue anglaise ayant trait au comportement pharmacocinétique de la méthadone durant la grossesse ont été inclus dans l’analyse et les articles non liés à l’issue de la grossesse ont été rejetés.Résultats : La recherche bibliographique a permis de trouver dix études et une observation clinique sur l’emploi de la méthadone par les femmes enceintes. Le comportement pharmacocinétique de la méthadone durant la grossesse a été examiné dans trois études de pharmacocinétique et l’administration de doses de méthadone fractionnées chez la femme enceinte a été décrite dans une observation clinique et trois études sur la posologie. Seulement quatre études ont évalué la surveillance des concentrations sériques de méthadone durant la grossesse. Les études retenues pour la présente analyse confirment que le comportement pharmacocinétique de la méthadone est modifié durant la grossesse et est potentiellement corrélé à une augmentation des symptômes de sevrage de la mère. Les données sont insuffisantes pour recommander la surveillance systématique des concentrations sériques de méthadone chez les femmes ayant une dépendance aux opioïdes.Conclusions : Il existe peu d’études portant sur le comportement pharmacocinétique et le suivi thérapeutique pharmacologique de la méthadone chez la femme enceinte ayant une dépendance aux opioïdes. Bien qu’on sache que le comportement pharmacocinétique de la méthadone est modifié durant la grossesse, les données sont insuffisantes pour guider les ajustements posologiques et la surveillance des concentrations sériques de la méthadone. Jusqu’à ce que d’autres études aient été menées, la surveillance périodique des symptômes de sevrage de la mère et les ajustements posologiques empiriques sont recommandés tout au long de la grossesse

Stability of Epinephrine at Standard Concentrations

ABSTRACTBackground: To minimize medication errors, standard concentrations are recommended for medications intended for continuous infusion in pediatric patients. Premixing of epinephrine (commonly used to manage septic shock in children) would improve timeliness, safety, and costeffectiveness. However, information about the stability of epinephrine at standard concentrations is limited.Objectives: To evaluate the stability of epinephrine in 5% dextrose in water at standard concentrations and to extend its expiration date after storage in infusion bags at 4°C and 25°C for up to 30 days.Methods: A total of 6 infusion bags were prepared with 200 mL of epinephrine solution, 2 bags for each of 3 standard concentrations (25, 50, and 100 μg/mL). Three bags (one for each concentration) were stored under refrigeration (4°C), and the remaining 3 bags were stored at room temperature (25°C). Physical characteristics (including pH, colour, and presence of precipitate) were evaluated daily for the first 14 days and every 1 to 5 days thereafter until day 30. Three 1.5-mL samples were collected from each bag immediately after preparation (time 0), every 24 h (at 24 h, 48 h, 72 h, 96 h, etc.) for the first 14 days, and every 1 to 5 days thereafter until day 30. Each sample was analyzed by stability-indicating high-performance liquid chromatography. A solution was considered stable if it maintained at least 90% of its initial concentration.Results: No notable changes in pH, colour, or precipitation were observed in any of the solutions after storage at 4°C or 25°C for up to 30 days. All formulations maintained more than 95% of the initial epinephrine concentration on day 30. In addition, the calculated lower limit of the 95% confidence interval indicated that 93% or more of the initial concentration remained on day 30.Conclusions: Preparations of epinephrine were stable for up to 30 days, with or without refrigeration. Because stability alone does not guarantee bioavailability or efficacy of a drug, future clinical studies are recommended to evaluate the pharmacokinetics and pharmacodynamics of these formulations.RÉSUMÉContexte : Afin de réduire au maximum les erreurs de médication, il est recommandé d’utiliser des concentrations standards pour les médicaments administrés par perfusion continue aux enfants. La préparation préalable des solutions d’épinéphrine (couramment utilisée pour traiter le choc septique chez l’enfant) permettrait d’améliorer la rapidité d’action, la sécurité et le rapport coût-efficacité. Il existe malheureusement peu de données portant sur la stabilité de solutions d’épinéphrine de concentrations standards.Objectifs : Évaluer la stabilité de l’épinéphrine de concentrations standards dans du dextrose à 5 % dans l’eau et augmenter la durée de conservation des solutions entreposées dans des sacs pour perfusion à 4 °C et à 25 °C jusqu’à 30 jours.Méthodes : Six sacs pour perfusion contenant 200 mL d’une solution d’épinéphrine ont été préparés, soit une paire de chacune des trois concentrations standards (25, 50 et 100 μg/mL). Trois sacs ont été conservés au réfrigérateur (4 °C) et les trois autres ont été entreposés à la température ambiante (25 °C). Les propriétés physiques (notamment le pH, la couleur et la présence de précipité) ont été évaluées quotidiennement les 14 premiers jours, puis à des intervalles de 1 à 5 jours jusqu’au jour 30. Trois échantillons de 1,5 mL ont été recueillis de chaque sac immédiatement après la préparation de la solution (temps 0), puis toutes les 24 heures (24 h, 48 h, 72 h, 96 h, etc.) pendant les 14 premiers jours et ensuite à des intervalles de 1 à 5 jours jusqu’à la fin de la période de 30 jours. Chaque échantillon a été analysé à l’aide d’une épreuve mesurant la stabilité par chromatographie liquide haute performance. Une solution était considérée comme stable si elle conservait au moins 90 % de sa concentration initiale.Résultats : Aucun précipité et aucun changement notable du pH ou de la couleur n’ont été observés dans l’ensemble des solutions après un entreposage à 4 °C ou à 25 °C d’une période de 30 jours. Toutes les préparations avaient conservé plus de 95 % des concentrations initiales d’épinéphrine au jour 30. De plus, la limite inférieure de l’intervalle de confiance à 95 % indiquait que les préparations avaient conservé 93 % ou plus de leurs concentrations initiales au jour 30.Conclusions : Les préparations d’épinéphrine sont demeurées stables pendant les 30 jours, qu’elles aient été réfrigérées ou non. Comme la stabilité seule ne garantit pas la biodisponibilité ou l’efficacité d’un médicament, d’autres études cliniques sont recommandées afin d’évaluer le comportement pharmacocinétique et pharmacodynamique de ces préparations