Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project

Socially and biologically inspired computing for self-organizing communications networks

The design and development of future communications networks call for a careful examination of biological and social systems. New technological developments like self-driving cars, wireless sensor networks, drones swarm, Internet of Things, Big Data, and Blockchain are promoting an integration process that will bring together all those technologies in a large-scale heterogeneous network. Most of the challenges related to these new developments cannot be faced using traditional approaches, and require to explore novel paradigms for building computational mechanisms that allow us to deal with the emergent complexity of these new applications. In this article, we show that it is possible to use biologically and socially inspired computing for designing and implementing self-organizing communication systems. We argue that an abstract analysis of biological and social phenomena can be made to develop computational models that provide a suitable conceptual framework for building new networking technologies: biologically inspired computing for achieving efficient and scalable networking under uncertain environments; socially inspired computing for increasing the capacity of a system for solving problems through collective actions. We aim to enhance the state-of-the-art of these approaches and encourage other researchers to use these models in their future work

Cardiovascular risk assessment in haemophilia patients

Haemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy age-matched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18-83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-values 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69-6.57) and 3.60 mM (1.68-5.95), respectively, p 10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: Study protocol for a multicentre randomised controlled trial

__Introduction__ Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. __Methods and analysis__ The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. __Ethics__ Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community

Learning about the opponent in automated bilateral negotiation: a comprehensive survey of opponent modeling techniques

A negotiation between agents is typically an incomplete information game, where the agents initially do not know their opponent’s preferences or strategy. This poses a challenge, as efficient and effective negotiation requires the bidding agent to take the other’s wishes and future behavior into account when deciding on a proposal. Therefore, in order to reach better and earlier agreements, an agent can apply learning techniques to construct a model of the opponent. There is a mature body of research in negotiation that focuses on modeling the opponent, but there exists no recent survey of commonly used opponent modeling techniques. This work aims to advance and integrate knowledge of the field by providing a comprehensive survey of currently existing opponent models in a bilateral negotiation setting. We discuss all possible ways opponent modeling has been used to benefit agents so far, and we introduce a taxonomy of currently existing opponent models based on their underlying learning techniques. We also present techniques to measure the success of opponent models and provide guidelines for deciding on the appropriate performance measures for every opponent model type in our taxonomy

Computers that negotiate on our behalf: Major challenges for self-sufficient, self-directed, and interdependent negotiating agents

Computers that negotiate on our behalf hold great promise for the future and will even become indispensable in emerging application domains such as the smart grid, autonomous driving, and the Internet of Things. Much research has thus been expended to create agents that are able to negotiate in an abundance of circumstances. However, up until now, truly autonomous negotiators have rarely been deployed in real-world applications. This paper sizes up current negotiating agents and explores a number of technological, societal and ethical challenges that autonomous negotiation systems are bringing about. The questions we address are: in what sense are these systems autonomous, what has been holding back their further proliferation, and is their spread something we should encourage? We relate the automated negotiation research agenda to dimensions of autonomy and distill three major themes that we believe will propel autonomous negotiation forward: accurate representation, long-term perspective, and user trust. We argue these orthogonal research directions need to be aligned and advanced in unison to sustain tangible progress in the field