This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.

This guidance document is intended to assist the applicant in the preparation and the presentation of an application, as foreseen in Article 7.6 of Regulation (EC) No 1831/2003, for the authorisation of additives for use in animal nutrition. It specifically covers the assessment of the safety for the consumer. Acknowledgements: The Panel wishes to thank the members of the Working Group on guidance update including Paul Brantom for the preparatory work on this scientific output and Davide Arcella and Rita Sousa for the support provided to this scientific output.

Most health system strengthening interventions ignore interconnections between systems components. In particular, complex relationships between medicines and health financing, human resources, health information and service delivery are not given sufficient consideration. As a consequence, populations' access to medicines (ATM) is addressed mainly through fragmented, often vertical approaches usually focusing on supply, unrelated to the wider issue of access to health services and interventions. The objective of this article is to embed ATM in a health system perspective. For this purpose, we perform a structured literature review: we examine existing ATM frameworks, review determinants of ATM and define at which level of the health system they are likely to occur; we analyse to which extent existing ATM frameworks take into account access constraints at different levels of the health system. Our findings suggest that ATM barriers are complex and interconnected as they occur at multiple levels of the health system. Existing ATM frameworks only partially address the full range of ATM barriers. We propose three essential paradigm shifts that take into account complex and dynamic relationships between medicines and other components of the health system. A holistic view of demand-side constraints in tandem with consideration of multiple and dynamic relationships between medicines and other health system resources should be applied; it should be recognized that determinants of ATM are rooted in national, regional and international contexts. These are schematized in a new framework proposing a health system perspective on ATM.

BackgroundIn Morocco, there is little information on the circumstances surrounding maternal near misses. This study aimed to determine the incidence, characteristics, and determinants of maternal near misses in Morocco.MethodA prospective case-control study was conducted at 3 referral maternity hospitals in the Marrakech region of Morocco between February and July 2012. Near-miss cases included severe hemorrhage, hypertensive disorders, and prolonged obstructed labor. Three unmatched controls were selected for each near-miss case. Three categories of risk factors (sociodemographics, reproductive history, and delays), as well as perinatal outcomes, were assessed, and bivariate and multivariate analyses of the determinants were performed. A sample of 30 near misses and 30 non-near misses was interviewed.ResultsThe incidence of near misses was 12‰ of births. Hypertensive disorders during pregnancy (45%) and severe hemorrhage (39%) were the most frequent direct causes of near miss. The main risk factors were illiteracy [OR = 2.35; 95% CI: (1.07–5.15)], lack of antenatal care [OR = 3.97; 95% CI: (1.42–11.09)], complications during pregnancy [OR = 2.81; 95% CI:(1.26–6.29)], and having experienced a first phase delay [OR = 8.71; 95% CI: (3.97–19.12)] and a first phase of third delay [OR = 4.03; 95% CI: (1.75–9.25)]. The main reasons for the first delay were lack of a family authority figure who could make a decision, lack of sufficient financial resources, lack of a vehicle, and fear of health facilities. The majority of near misses demonstrated a third delay with many referrals. The women’s perceptions of the quality of their care highlighted the importance of information, good communication, and attitude.ConclusionWomen and newborns with serious obstetric complications have a greater chance of successful outcomes if they are immediately directed to a functioning referral hospital and if the providers are responsive.

The concept of likelihood ratio has been advocated for several years as one of the better means to evaluate diagnostic tests and as a practical and valuable tool in clinical decision making. In this paper we review the basic concepts underlying the evaluation of diagnostic tests and we explore the properties and usefulness of both positive and negative likelihood ratios compared with sensitivity and specificity. Particular attention is given to the use of likelihood ratios in the clinical setting. Likelihood ratios have three main advantages: they are intuitive, they simplify the predictive value calculation and the overall evaluation of sequential testing. Disadvantages are the non-linearity and the necessity to recalculate probabilities in odds. Although they summarize the information contained in sensitivity and specificity, these characteristics are still necessary for certain clinical decisions. Since likelihood ratios have been promoted among physicians and medical students, we discuss examples of inappropriate use and misunderstandings in the medical literature: the frequent omission of confidence intervals, the choice of cut-off points based on likelihood ratios for positive test results only and the confusion between likelihood ratios for ranges and those for cut-off points.