Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

Paired measurement of urinary creatinine in neonates based on a Jaffe and an enzymatic IDMS-traceable assay

BACKGROUND: Urinary creatinine can be quantified by Jaffe or enzymatic assays and is commonly used as denominator of urinary excretion of electrolytes or protein. Paired analysis in pediatric and adult samples documented inter-assay differences (up to 80%). We verified the interchangeability of two IDMS-traceable assays (Jaffe and enzymatic) for neonatal urine and report on neonatal urinary creatinine values using these IDMS-traceable methods. METHODS: Creatinine was measured in 84 neonatal urine samples from 46 neonates by an IDMS traceable Jaffe and enzymatic assay (Roche Diagnostics, Cobas c702 module). Creatinine values, differences in urinary creatinine and clinical characteristics were described and covariates of between assay difference were explored (Wilcoxon, Bland-Altman, correlation, multiple regression). RESULTS: Median Jaffe and enzymatic urinary creatinine concentrations were 9.25 (range 3.7-42.2) and 9.15 (range 3.8-42.9) mg/dL respectively, resulting in a median difference of 0.08 (SD 0.6, range −2.4 to 0.96) mg/dL. In a multiple regression model, urinary enzymatic creatinine concentration (r = 0.45) and postnatal age (r = −0.59) remained independent variables of the difference between both assays (r(2) adj = 0.45). CONCLUSIONS: The tested IDMS-traceable assays showed interchangeable in heterogeneous neonatal urine samples. Using these assays, neonatal urinary creatinine showed 5–20 fold lower values than those observed in children or adults with a significant negative correlation with postnatal age

Towards an agroecological viticulture: advances and challenges

To improve its sustainability, viticulture should increase the provision of ecosystem services to decrease its use of inputs and the resulting environmental impact while maintaining high socio-economic performance. Soil functions in relation with their physical, chemical and biological properties can be regulated by proper soil surface management. Cover crops deliver ecosystem services such as protection of soils, better water infiltration and nitrogen fixation. Yet to avoid trade-off between provision of services and production of grapes, the management of cover crops should adapt to climate variations and to the yield objective. Pest and diseases can be regulated by various technical levers, including the control of the grape vegetative development. The assessment of damages due to pests and disease and of their consequences on yield losses is a key component of the design of alternative strategies of crop protection. This knowledge provides clues for designing management strategies with low pesticide use and high agro-ecological performance. A French national network of experiments has quantified the reduction of pesticide use with decision support systems, biocontrol or resistant varieties. To go further the challenge is now to design agroecological vineyards that combine innovations in management, and also in spatial organization at field, farm and landscape scales

Un nouvel indicateur intégré d’évaluation des dégâts occasionnés aux grappes par des bioagresseurs majeurs au vignoble

Communication faite au cours du colloque DinABio2013, 13 et 14 novembre 2013; Tours, FranceAn original and integrative evaluation indicator has been developed to quantify the cumulated damage from major pests and diseases affecting grape bunches: downy mildew, powdery mildew, gray mould and tortricid moths. It made it possible to estimate the associated crop losses and to relate them to the plant protection strategy in different modes of production (organic farming, in-transition, conventional). Thus, overall plant losses were higher in 2012 than in 2011. The in-transition growers’ strategy, with reduced copper doses but increased numbers of sprays, led to a 20% increase in average severity on bunches (essentially due to Downy mildew). The more pragmatic approach of experienced organic growers and conventional ones (higher doses and fewer sprays) reduced the yield losses. The proposed indicator is used for two purposes, i) evaluating the quantitative losses due to pest attacksand ii) differentiating them from other non-pest ones. A more detailed analysis including the impact on performance will be achieved and published soon.Un indicateur d’évaluation, l’IEDG (Indicateur d’Evaluation des Dégâts sur Grappes), a été mis au point pour quantifier les dégâts cumulés dus aux principaux bioagresseurs affectant les grappes de raisin : mildiou, oïdium, pourriture grise et tordeuses. Il permet d’estimer la perte de récolte imputable au cortège parasitaire et de faire le lien avec la stratégie phytosanitaire adoptée (caractérisée ici par l’IFT) et le mode de production (AB, conversion, conventionnel). Ainsi, les pertes sanitaires ont été supérieures en 2012 par rapport à 2011. La stratégie phytosanitaire des viticulteurs en conversion, basée sur des réductions de dose de cuivre de près de 80% et des passages plus nombreux dans les parcelles, n’a pas été efficiente en 2012 avec des sévérités proches de 20% sur grappe, essentiellement dues au mildiou. L’utilisation de doses d’applications supérieures et moins de passages dans les parcelles limite les dommages chez les autres viticulteurs. L’indicateur proposé permet d’évaluer les pertes quantitatives générées par les attaques de bioagresseurs et de les différencier des autres pertes non parasitaires. Une analyse plus fine incluant l’effet région et l’impact sur le rendement devra être réalisée

Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells

Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4(+) T cells. DC-asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC-ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3-grabbing nonintegrin favors the generation of antigen-specific suppressive CD4(+) T cells that produce interleukin 10 (IL-10). These findings apply to both self-and foreign antigens, as well as memory and naive CD4(+) T cells. The generation of such IL-10-producing CD4(+) T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti-DC-ASGPR monoclonal antibody generates antigen-specific CD4(+) T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10-producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR

Safe use of human milk for preterms in the context of maternal polypharmacy:a framework to improve practices

Maternal pharmacotherapy during lactation is an ongoing research field, which relies on scientific evidence, pharmacological reasoning and extrapolation to support risk-to-benefit assessment. Typically, drugs are studied individually for potential effects on a nursing infant, with limited information on the preterm infant. Polypharmacy during lactation is still poorly studied, leaving healthcare professionals without any scientific guidance when consulting on human milk safety in this scenario. When focusing on a dyad of a postpartum mother on polypharmacy and a preterm infant, the benefits of mother's own milk (MOM) should be weighed against the unknown potential risks of polypharmacy during lactation. Within this setting of limited evidence, a framework to improve clinical and research practices is provided. Possible measures to minimize the risk of maternal (poly)pharmacy to the newborn include: multi-disciplinary prenatal counseling; preferring medications with low passage rate into human milk; relative rating of medications according to safety profile; and 'mixed feeding' (alternating between MOM and other types of feed, preferably donor human milk). These measures can be used to support shared informed decisions on the risk-to-benefit assessment. As the topic of polypharmacy during lactation is still poorly explored, a research agenda is suggested.ImpactPolypharmacy during lactation is poorly studied, and practical, evidence-based guidelines for healthcare professionals are lacking.Various methods can be employed to reduce exposure to medications through human milk, even more so when applied concomitantly: preference of medications with low passage into human milk, relative rating of medications according to known safety profile, or 'mixed feeding' where mother's own milk is alternated with other types of feed, preferably donor human milk.A framework to improve clinical and research practices on provision of human milk in the setting of maternal polypharmacy and prematurity as an added challenge is provided

West Nile virus (WNv) human vaccine : from research to vaccination

This project will educate readers about the West Nile virus (WNv), and the vaccine research approaches currently underway. A narrative review used an instrument to synthesize WNv vaccine research studies, into an easy to understand format. Results indicated the instrument had a high magnitude of reliability (r = 0.90, p<0.0001). The size and frequency of future epidemics of the rare occurrence WNv is uncertain. Research for a WNv vaccine for humans is a responsible public health initiative. The rationale for preplanning a vaccination program is discussed as a future application of this research. The public expects preventative and therapeutic solutions to infectious diseases, and the project's conclusion indicates that for WNv this can be achieved

Advocating for drug development in newborn infants

Neonatal care needs more robust guidance on pharmacotherapy, (formulation, dosage regimen, safety and efficacy information). This requires structured advocacy. We therefore discuss advocacy related to improving information about medicines including current practices, clinical trials, the current setting, and trial preparedness. This steps can improve neonatal drug development by generating evidence, particularly if a programmatic approach (identify dosing, eligibility criteria, and outcomes) to evidence generation is followed. Trial design should be guided by the intended use of the medicine and the benefits/risks that the study participant is exposed to. Regulatory trials (explanatory, controlled environment, internal validity, endpoints reflect clinically important outcomes, strong causal evidence) are sometimes necessary. However, some research questions are best addressed with informative trials. In either case, trial design can be supported by real world data and evidence, extrapolation from other subpopulations, or physiologically-based pharmacokinetic modeling. Data management, safety reporting, and management of drugs should be specified and proportionate. Trial design and conduct also necessitate awareness of Good Clinical Practice specific to neonates. Relevant aspects include protocol and trial design, research skills and interactions with Ethics Committees or Institutional Research Boards, capacities and competences needed within the research team, and aspects related to consent and recruitment.</p