Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view.

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators

Global Ocean Tide Models: Assessment and Use within a Surface Model of Lowest Astronomical Tide

The UK Hydrographic Office (UKHO)-sponsored Vertical Offshore Reference Frames (VORF) project aims to develop tidal level transformation models that are referenced to the GRS80 ellipsoid and thus compatible with GNSS positioning; in particular, heighting. Benefits include increasing the efficiency of hydrographic surveying, providing a stable consistent reference frame and enabling integration with land data in the coastal zone. Seven contemporary global ocean tide models are used to derive Lowest Astronomical Tide (LAT) surfaces which are each assessed by comparison with LAT values from the 7,389-strong UKHO tide gauge database, with the results correlated with distance from land. The proportion of truly offshore and pelagic gauges is relatively limited; however, the transition zone whereby the global ocean tide models commence to deteriorate in accuracy is evident at approximately 30km from the coast. The DTU10 model was selected as the strongest candidate overall. Subsequently, a thin plate spline method is used with the tide gauge dataset to enhance the DTU10 LAT surface in the coastal zone, creating a high resolution global LAT surface with respect to mean sea level. It is seen by cross-validation that the method may be used to predict LAT in near-shore locations with a standard error of 0.23 m

Modelling phosphorus fluxes in Loweswater

1. This is the final report to the Loweswater Care Project (in support of the Catchment Restoration Fund for England) ECRC-ENSIS Project 298, 'Loweswater 12-13'. The study was concerned with the spatial and temporal concentrations of sediment phosphorus (P) in the lake and the use of P measurements from the water column and inflow and outflow samples to derive a simple mass balance model for P in the lake. 2. A review of published and unpublished literature on Loweswater highlighted trends in water chemistry since the mid-eighteenth century. Land use and farming practises have changed over the past 200 years which have led to increased nutrient loading to the lake with significant increases occurring in the mid part of the last century. Agricultural intensification is likely to be a significant cause of the problem as well as inadequate septic tank management. Local management efforts, led by the Loweswater Care Project, has sought to reduce the primary sources of nutrients reaching the lake, but total phosphorus (TP) concentrations in the lake remain higher than desired. 3. Temperature and dissolved oxygen (DO) profiling confirmed that the site stratified in summer with major changes in DO occurring below a depth of 8 m. The deeper waters were almost entirely anoxic. During stratification the maximum TP value was recorded at the lake bottom. This is a clear indication that P is being released from the lake bed during summer stratification. 4. Analysis of the stream water from the Dub Beck inflow (data for 2013), shows that P influx remains high enough to explain the elevated lake water P concentrations, despite considerable efforts to reduce catchment P sources. 5. Analysis of the water column P profiles shows that P release from the sediment is only a minor contribution to the P load. While the sediment core data reveals a substantial pool of P in the sediment very little of this should be released each year to the water column. In 2013 it is estimated that more than 90% of the P came from the catchment and only ~10% from the sediment. 6. As with all modelling exercises there are uncertainties inherent in the approach. In this case the model output is based on a single year of input data for the inflow P flux calculations and it would be preferable to have a longer data series to inform the modelling. Inflow fluxes are highly dependent on flow conditions and here, in the absence of flow data from Dub Beck, we used data from a nearby stream. Further, the monthly sampling has resulted in most samples being taken in low flow conditions, thus missing potential storm flow conditions. Finally, stream input information is restricted to Dub Beck, and contributions from the other stream is unknown. 7. Nevertheless, the results from the modelling are clear and on that basis we conclude that the priority is for P loading to the lake to be reduced by better catchment management and that lake manipulation is not warranted. Integrated catchment management supported by modelling together with local stakeholder engagement should provide the most effective means of improving the condition of the lake

Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.

Trough gentamicin therapeutic drug monitoring (TDM) is time-consuming, disruptive to neonatal clinical care and a patient safety issue. Bayesian models could allow TDM to be performed opportunistically at the time of routine blood tests. This study aimed to develop and prospectively evaluate a new gentamicin model and a novel Bayesian computer tool (neoGent) for TDM use in neonatal intensive care. We also evaluated model performance for predicting peak concentrations and AUC(0-t). A pharmacokinetic meta-analysis was performed on pooled data from three studies (1325 concentrations from 205 patients). A 3-compartment model was used with covariates being: allometric weight scaling, postmenstrual and postnatal age, and serum creatinine. Final parameter estimates (standard error) were: clearance: 6.2 (0.3) L/h/70kg; central volume (V) 26.5 (0.6) L/70kg; inter-compartmental disposition: Q=2.2 (0.3) L/h/70kg, V2=21.2 (1.5) L/70kg, Q2=0.3 (0.05) L/h/70kg, V3=148 (52.0) L/70kg. The model's ability to predict trough concentrations from an opportunistic sample was evaluated in a prospective observational cohort study that included data from 163 patients with 483 concentrations collected in five hospitals. Unbiased trough predictions were obtained: median (95% confidence interval (CI)) prediction error was 0.0004 (-1.07, 0.84) mg/L. Results also showed peaks and AUC(0-t) could be predicted (from one randomly selected sample) with little bias but relative imprecision with median (95% CI) prediction error being 0.16 (-4.76, 5.01) mg/L and 10.8 (-24.9, 62.2) mg h/L, respectively. NeoGent was implemented in R/NONMEM, and in the freely available TDMx software

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence

Background: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice.Method: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views.Results: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance.Conclusion: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children

Joint phenotypes, evolutionary conflict and the fundamental theorem of natural selection

Multiple organisms can sometimes affect a common phenotype. For example, the portion of a leaf eaten by an insect is a joint phenotype of the plant and insect and the amount of food obtained by an offspring can be a joint trait with its mother. Here, I describe the evolution of joint phenotypes in quantitative genetic terms. A joint phenotype for multiple species evolves as the sum of additive genetic variances in each species, weighted by the selection on each species. Selective conflict between the interactants occurs when selection takes opposite signs on the joint phenotype. The mean fitness of a population changes not just through its own genetic variance but also through the genetic variance for its fitness that resides in other species, an update of Fisher\u27s fundamental theorem of natural selection. Some similar results, using inclusive fitness, apply to within-species interactions. The models provide a framework for understanding evolutionary conflicts at all levels

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

'Choosing shoes': a preliminary study into the challenges facing clinicians in assessing footwear for rheumatoid patients

Background: Footwear has been accepted as a therapeutic intervention for the foot affected by rheumatoid arthritis (RA). Evidence relating to the objective assessment of footwear in patients with RA is limited. The aims of this study were to identify current footwear styles, footwear characteristics, and factors that influence footwear choice experienced by patients with RA. Methods: Eighty patients with RA were recruited from rheumatology clinics during the summer months. Clinical characteristics, global function, and foot impairment and disability measures were recorded. Current footwear, footwear characteristics and the factors associated with choice of footwear were identified. Suitability of footwear was recorded using pre-determined criteria for assessing footwear type, based on a previous study of foot pain. Results: The patients had longstanding RA with moderate-to severe disability and impairment. The foot and ankle assessment demonstrated a low-arch profile with both forefoot and rearfoot structural deformities. Over 50% of shoes worn by patients were opentype footwear. More than 70% of patients’ footwear was defined as being poor. Poor footwear characteristics such as heel rigidity and sole hardness were observed. Patients reported comfort (17%) and fit (14%) as important factors in choosing their own footwear. Only five percent (5%) of patients wore therapeutic footwear. Conclusions: The majority of patients with RA wear footwear that has been previously described as poor. Future work needs to aim to define and justify the specific features of footwear that may be of benefit to foot health for people with RA

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research