Increased potential of a cationic liposome-based delivery system:enhancing stability and sustained immunological activity in pre-clinical development

The combination of dimethyl dioctadecyl ammonium bromide (DDA) and the synthetic cord factor trehalose dibehenate (TDB) with Ag85B-ESAT-6 (H1 fusion protein) has been found to promote strong protective immune responses against Mycobacterium tuberculosis. The development of a vaccine formulation that is able to facilitate the requirements of sterility, stability and generation of a vaccine product with acceptable composition, shelf-life and safety profile may necessitate selected alterations in vaccine formulation. This study describes the implementation of a sterilisation protocol and the use of selected lyoprotective agents in order to fulfil these requirements. Concomitantly, close analysis of any alteration in physico-chemical characteristics and parameters of immunogenicity have been examined for this promising DDA liposome-based tuberculosis vaccine. The study addresses the extensive guidelines on parameters for non-clinical assessment, suitable for liposomal vaccines and other vaccine delivery systems issued by the World Health Organisation (WHO) and the European Medicines Agency (EMEA). Physical and chemical stability was observed following alteration in formulations to include novel cryoprotectants and radiation sterilisation. Immunogenicity was maintained following these alterations and even improved by modification with lysine as the cryoprotective agent for sterilised formulations. Taken together, these results outline the successful alteration to a liposomal vaccine, representing improved formulations by rational modification, whilst maintaining biological activity.

Proplyene glycol intake from medications used on paediatric intensive care

here is an increasing number of reports of propylene glycol (PG) toxicity in the literature, regardless of its inclusion on the Generally Recognized as Safe List (GRAS).1 PG is an excipient used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Method A snapshot of 50 PICU patients oral or intravenous medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists' opinions on PG intake was sought via e-survey. Results The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52%) were parenteral formulations. Median weight of the patients was 5.5 kg (range 2–50 kg), ages ranged from 1 day to 13 years of age. Eleven of the patients were classed as renally impaired (defined as 1.5 times the baseline creatinine). Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received at least one prescription containing PG and 29/38 of these patients were receiving formulations that contained excipients that may have competed with the metabolic pathways of PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day. Total intake was inconclusive for 2 patients due to a of lack of availability of information from the manufacturer; these formulations were licensed but used in for off-label indications. Five commonly used formulations contributed to higher intakes of PG, namely co-trimoxazole, dexamethasone, potassium chloride, dipyridamole and phenobarbitone. Lactate levels were difficult to interpret due to the underlying conditions of the patients. One of the sixteen intensivist was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions Certain formulations used on PICU can considerably increase PG exposure to patients. Due to a lack of awareness of PG content, these should be highlighted to the clinician to assist with making informed decisions regarding risks versus benefits in continuing that drug, route of administration or formulation.

Proplyene glycol intake from medications used on paediatric intensive care

There is an increasing number of reports of propylene glycol (PG) toxicity in the literature, regardless of its inclusion on the Generally Recognized as Safe List (GRAS).1 PG is an excipient used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Method A snapshot of 50 PICU patients oral or intravenous medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists' opinions on PG intake was sought via e-survey. Results The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52%) were parenteral formulations. Median weight of the patients was 5.5 kg (range 2–50 kg), ages ranged from 1 day to 13 years of age. Eleven of the patients were classed as renally impaired (defined as 1.5 times the baseline creatinine). Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received at least one prescription containing PG and 29/38 of these patients were receiving formulations that contained excipients that may have competed with the metabolic pathways of PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day. Total intake was inconclusive for 2 patients due to a of lack of availability of information from the manufacturer; these formulations were licensed but used in for off-label indications. Five commonly used formulations contributed to higher intakes of PG, namely co-trimoxazole, dexamethasone, potassium chloride, dipyridamole and phenobarbitone. Lactate levels were difficult to interpret due to the underlying conditions of the patients. One of the sixteen intensivist was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions Certain formulations used on PICU can considerably increase PG exposure to patients. Due to a lack of awareness of PG content, these should be highlighted to the clinician to assist with making informed decisions regarding risks versus benefits in continuing that drug, route of administration or formulation.

Propylene glycol intake from medications used on paediatric intensive care

Background: There are increasing reports of propylene glycol (PG) toxicity, which is used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Methods: A snapshot of 50 patients’ medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists opinions on PG intake was sought via e-survey. Results: The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52 %) were parenteral formulations. Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received drugs with PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day, with 29/38 receiving formulations with concomitant pathway competing excipients. The total amount could not be quantified in two cases due to lack of availability of information from the manufacturer. Four commonly used formulations contributed to higher intakes of PG. Only 1/16intensivists was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions: Certain formulations used on PICU can considerably increase PG exposure to patients. These should be highlighted to the clinician to make an informed decision regarding risks versus benefits in continuing that drug or formulation.

First year qualifying report: neural networks for extracting wind vectors from satellite scatterometer data

The ERS-1 Satellite was launched in July 1991 by the European Space Agency into a polar orbit at about km800, carrying a C-band scatterometer. A scatterometer measures the amount of radar back scatter generated by small ripples on the ocean surface induced by instantaneous local winds. Operational methods that extract wind vectors from satellite scatterometer data are based on the local inversion of a forward model, mapping scatterometer observations to wind vectors, by the minimisation of a cost function in the scatterometer measurement space.par This report uses mixture density networks, a principled method for modelling conditional probability density functions, to model the joint probability distribution of the wind vectors given the satellite scatterometer measurements in a single cell (the `inverse' problem). The complexity of the mapping and the structure of the conditional probability density function are investigated by varying the number of units in the hidden layer of the multi-layer perceptron and the number of kernels in the Gaussian mixture model of the mixture density network respectively. The optimal model for networks trained per trace has twenty hidden units and four kernels. Further investigation shows that models trained with incidence angle as an input have results comparable to those models trained by trace. A hybrid mixture density network that incorporates geophysical knowledge of the problem confirms other results that the conditional probability distribution is dominantly bimodal.par The wind retrieval results improve on previous work at Aston, but do not match other neural network techniques that use spatial information in the inputs, which is to be expected given the ambiguity of the inverse problem. Current work uses the local inverse model for autonomous ambiguity removal in a principled Bayesian framework. Future directions in which these models may be improved are given.

A pragmatic Bayesian approach to wind field retrieval

The ERS-1 Satellite was launched in July 1991 by the European Space Agency into a polar orbit at about 800 km, carrying a C-band scatterometer. A scatterometer measures the amount of backscatter microwave radiation reflected by small ripples on the ocean surface induced by sea-surface winds, and so provides instantaneous snap-shots of wind flow over large areas of the ocean surface, known as wind fields. Inherent in the physics of the observation process is an ambiguity in wind direction; the scatterometer cannot distinguish if the wind is blowing toward or away from the sensor device. This ambiguity implies that there is a one-to-many mapping between scatterometer data and wind direction. Current operational methods for wind field retrieval are based on the retrieval of wind vectors from satellite scatterometer data, followed by a disambiguation and filtering process that is reliant on numerical weather prediction models. The wind vectors are retrieved by the local inversion of a forward model, mapping scatterometer observations to wind vectors, and minimising a cost function in scatterometer measurement space. This thesis applies a pragmatic Bayesian solution to the problem. The likelihood is a combination of conditional probability distributions for the local wind vectors given the scatterometer data. The prior distribution is a vector Gaussian process that provides the geophysical consistency for the wind field. The wind vectors are retrieved directly from the scatterometer data by using mixture density networks, a principled method to model multi-modal conditional probability density functions. The complexity of the mapping and the structure of the conditional probability density function are investigated. A hybrid mixture density network, that incorporates the knowledge that the conditional probability distribution of the observation process is predominantly bi-modal, is developed. The optimal model, which generalises across a swathe of scatterometer readings, is better on key performance measures than the current operational model. Wind field retrieval is approached from three perspectives. The first is a non-autonomous method that confirms the validity of the model by retrieving the correct wind field 99% of the time from a test set of 575 wind fields. The second technique takes the maximum a posteriori probability wind field retrieved from the posterior distribution as the prediction. For the third technique, Markov Chain Monte Carlo (MCMC) techniques were employed to estimate the mass associated with significant modes of the posterior distribution, and make predictions based on the mode with the greatest mass associated with it. General methods for sampling from multi-modal distributions were benchmarked against a specific MCMC transition kernel designed for this problem. It was shown that the general methods were unsuitable for this application due to computational expense. On a test set of 100 wind fields the MAP estimate correctly retrieved 72 wind fields, whilst the sampling method correctly retrieved 73 wind fields.

Designing a safety management support system using open architecture databases: the requirements of information representation in the support of managers' risk-related decision-making

This research was conducted at the Space Research and Technology Centre o the European Space Agency at Noordvijk in the Netherlands. ESA is an international organisation that brings together a range of scientists, engineers and managers from 14 European member states. The motivation for the work was to enable decision-makers, in a culturally and technologically diverse organisation, to share information for the purpose of making decisions that are well informed about the risk-related aspects of the situations they seek to address. The research examined the use of decision support system DSS) technology to facilitate decision-making of this type. This involved identifying the technology available and its application to risk management. Decision-making is a complex activity that does not lend itself to exact measurement or precise understanding at a detailed level. In view of this, a prototype DSS was developed through which to understand the practical issues to be accommodated and to evaluate alternative approaches to supporting decision-making of this type. The problem of measuring the effect upon the quality of decisions has been approached through expert evaluation of the software developed. The practical orientation of this work was informed by a review of the relevant literature in decision-making, risk management, decision support and information technology. Communication and information technology unite the major the,es of this work. This allows correlation of the interests of the research with European public policy. The principles of communication were also considered in the topic of information visualisation - this emerging technology exploits flexible modes of human computer interaction (HCI) to improve the cognition of complex data. Risk management is itself an area characterised by complexity and risk visualisation is advocated for application in this field of endeavour. The thesis provides recommendations for future work in the fields of decision=making, DSS technology and risk management.

The derivation and application of risk tolerability criteria

This research involves a study of the questions, "what is considered safe", how are safety levels defined or decided, and according to whom. Tolerable or acceptable risk questions raise various issues: about values and assumptions inherent in such levels; about decision-making frameworks at the highest level of policy making as well as on the individual level; and about the suitability and competency of decision-makers to decide and to communicate their decisions. The wide-ranging topics covering philosophical and practical concerns examined in the literature review reveal the multi-disciplined scope of this research. To support this theoretical study empirical research was undertaken at the European Space Research and Technology Centre (ESTEC) of the European Space Agency (ESA). ESTEC is a large, multi-nationality, high technology organisation which presented an ideal case study for exploring how decisions are made with respect to safety from a personal as well as organisational aspect. A qualitative methodology was employed to gather, analyse and report the findings of this research. Significant findings reveal how experts perceive risks and the prevalence of informal decision-making processes partly due to the inadequacy of formal methods for deciding risk tolerability. In the field of occupational health and safety, this research has highlighted the importance and need for criteria to decide whether a risk is great enough to warrant attention in setting standards and priorities for risk control and resources. From a wider perspective and with the recognition that risk is an inherent part of life, the establishment of tolerability risk levels can be viewed as cornerstones indicating our progress, expectations and values, of life and work, in an increasingly litigious, knowledgeable and global society.

Safety criteria for the private spaceflight industry

The Federal Aviation Administration (FAA) Office of Commercial Space Transportation (AST) has set specific rules and generic guidelines to cover experimental and operational flights by industry forerunners such as Virgin Galactic and XCOR. One such guideline Advisory Circular (AC) 437.55-1[1] contains exemplar hazard analyses for spacecraft designers and operators to follow under an experimental permit. The FAA's rules and guidelines have also been ratified in a report to the United States Congress, Analysis of Human Space Flight Safety[2] which cites that the industry is too immature and has 'insufficient data' to be proscriptive and that 'defining a minimum set of criteria for human spaceflight service providers is potentially problematic' in order not to 'stifle the emerging industry'. The authors of this paper acknowledge the immaturity of the industry and discuss the problematic issues that Design Organisations and Operators now face.

Translation practices at the European Central Bank with reference to metaphors

The European Union institutions represent a complex setting and a specific case of institutional translation. The European Central Bank (ECB) is a particular context as the documents translated belong to the field of economics and, thus, contain many specialised terms and neologisms that pose challenges to translators. This study aims to investigate the translation practices at the ECB, and to analyse their effects on the translated texts. In order to illustrate the way texts are translated at the ECB, the thesis will focus on metaphorical expressions and the conceptual metaphors by which they are sanctioned. Metaphor is often associated with literature and less with specialised texts. However, according to Lakoff and Johnson’s (1980) conceptual metaphor theory, our conceptual system is fundamentally metaphorical in nature and metaphors are pervasive elements of thought and speech. The corpus compiled comprises economic documents translated at the ECB, mainly from English into Romanian. Using corpus analysis, the most salient metaphorical expressions were identified in the source and target texts and explained with reference to the main conceptual metaphors. Translation strategies are discussed on the basis of a comparison of the source and target texts. The text-based analysis is complemented by questionnaires distributed to translators, which give insights into the institution’s translation practices. As translation is an institutional process, translators have to follow certain guidelines and practices; these are discussed with reference to translators’ agency. A gap was identified in the field of institutional translation. The translation process in the EU institutions has been insufficiently explored, especially regarding the new languages of the European Union. By combining the analysis of the institutional practices, the texts produced in the institution and the translators’ work (by the questionnaires distributed to translators), this thesis intends to bring a contribution to institutional translation and metaphor translation, particularly regarding a new EU language, Romanian.

Excipients in medicines for children:scientific and regulatory paradigms

There is an ongoing debate over the use of pharmaceutical excipients in medicines for children, triggered by the increased number of formulations suitable for this target patient population. Pharmaceutical excipients can be regarded as essential / necessary enablers in formulation development. These are materials other than the 'active pharmaceutical ingredient' which are added to the formulation to achieve a specific function1. This may include aiding in the processing or manufacture of the drug delivery system such as lubricants or flow aids, controlling the release of the active ingredient to achieve modified release, enhance patient acceptability by improving taste of medicines or to develop easily swallowed dosage forms.

The PHAR-QA project: competency framework for pharmacy practice—first steps, the results of the European Network Delphi round 1

PHAR-QA, funded by the European Commission, is producing a framework of competences for pharmacy practice. The framework is in line with the EU directive on sectoral professions and takes into account the diversity of the pharmacy profession and the on-going changes in healthcare systems (with an increasingly important role for pharmacists), and in the pharmaceutical industry. PHAR-QA is asking academia, students and practicing pharmacists to rank competences required for practice. The results show that competences in the areas of drug interactions, need for drug treatment and provision of information and service were ranked highest whereas those in the areas of ability to design and conduct research and development and production of medicines were ranked lower. For the latter two categories, industrial pharmacists ranked them higher than did the other five groups

What is the current practice of medicines reconciliation in children nationally in the UK?

INTRODUCTION: The National Institute for Health and Clinical Excellence/National Patient Safety Agency (NICE/NPSA) guidelines for medicines reconciliation (MR) on admission to hospital in adult inpatients were introduced in 2007, but they excluded children less than 16 years of age. METHOD: We conducted a survey of 98 paediatric pharmacists (each from a different hospital) to find out what the current practice of MR in children is in the UK. KEY FINDINGS: Responses showed that 67% (43/64) of pharmacists surveyed carried out MR in all children at admission and only a third 34% (22/64) had policies for MR in children. Of the respondents who did not carry out MR in all children, 80% (4/5) responded that they did so in selected children. Pharmacists considered themselves the most appropriate profession for carrying out MR. When asked whether the NICE guidance should be expanded to include children, 98% (54/55) of the respondents answered 'yes'. CONCLUSION: In conclusion, the findings suggest that MR is being conducted inconsistently in children and most paediatric pharmacists would like national guidance to be expanded to include children.

The clinical significance of medicines reconciliation in children admitted to hospital

Aims and Objectives: The NICE/NPSA guidance on Medicines Reconciliation in adults upon hospital admission excludes children under the age of 16.1 Hence the primary aim and objective of this study was to use medicines reconciliation to primarily identify if discrepancies occur upon hospital admission. Secondary objectives were to clinically assess for harm discrepancies that were identified in paediatric patients on long term medications at four hospitals across the UK. Method: Medicines reconciliation is a procedure where the current medication history of a patient prior to hospital admission would be taken and verifying the medication orders made at hospital admission against this history, addressing any discrepancies identified. Medicines reconciliation was carried out prospectively for 244 paediatric patients on chronic medication across four UK hospitals (Birmingham, London, Leeds and North Staffordshire) between January – May 2011. Medicines reconciliation was conducted by a clinical pharmacist using the following sources of information: 1) the patient's Pre-Admission Medication (PAM) from the patient's general practitioner 2) examination of the Patient's Own Medications brought into hospital, 3) a semi-structured interview with the parent-carers and 4) identification of admission medication orders written on the drug chart prior to clinical pharmacy input (Drug Chart). Discrepancies between the PAM and Drug Chart were documented and classified as intentional or unintentional. Intentional discrepancies were defined as changes that were made knowingly by the prescriber and confirmed. Unintentional discrepancies were assessed for clinical significance by an expert panel and assigned a significance score based on the likelihood of causing potential discomfort or clinical deterioration: class 1 unlikely, class 2 moderate and class 3 severe.2 Results: 1004 medication regimens were included from the 244 patients across the four sites. 588 of the 1004 (59%) medicines, had discrepancies between the PAM and Drug Chart; of these 36% (n = 209) were unintentional and included for clinically assessment. 189 drug discrepancies 30% were classified as class 1, 47% were class 2 and 23% were class 3 discrepancies. The remaining 20 discrepancies were cases where deviating from the PAM would have been the right thing to do, which might suggest that an intentional but undocumented discrepancy by the prescriber writing up the admission order may have occurred. Conclusion: The results suggest that medication discrepancies in paediatric patients do occur upon hospital admission, which do have a potential to cause harm and that medicines reconciliation is a potential solution to preventing such discrepancies. References: 1. National Institute for Health and Clinical Excellence. National Patient Safety Agency. PSG001. Technical patient safety solutions for medicines reconciliation on admission of adults to hospital. London: NICE; 2007. 2. Cornish, P. L., Knowles, S. R., Marchesano, et al. Unintended Medication Discrepancies at the Time of Hospital Admission. Archives of Internal Medicine 2005; 165:424–429