Optimizing the identification of risk-relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence-based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger-sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2-negative families to be subjected to the BROCA-Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss-of-heterozygosity and further molecular studies. We identified loss-of-function mutations in 6 out 20 high-risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk-relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre-organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk-relevant alleles impacting on the clinical management of their carriers

Beyond averages: new approaches to understand heterogeneity and risk of technology success or failure in smallholder farming

Open Access ArticleIn recent years, many studies have demonstrated the heterogeneity of the smallholder production environment. Yet agronomic research for development (R4D) that aims to identify and test options for increasing productivity has not consistently adapted its approaches to such heterogeneous conditions. This paper describes the challenges facing research, highlighting the importance of variation in evaluating the performance of soil management recommendations, integrating aspects of production risk management within the formulation of recommendations, and proposing alternative approaches to implement agronomic R4D. Approaches are illustrated using two multi-locational on-farm paired trials, each having one no-input control treatment and a treatment with fertilizer application for maize in Western Kenya and for beans in Eastern Rwanda. The diversity of treatment responses should be embraced rather than avoided to gain a better understanding of current context and its relation with past management

Integration of fire management in forest planning management in Portugal

Doutoramento em Engenharia Florestal e dos Recursos Naturais - Instituto Superior de AgronomiaThe importance of ecological and socio - economic forest fires shows the relevance of research techniques and approaches for integrating the planning processes of forest management and fire management . This PhD aimed to investigate these approaches and contributing to the effectiveness of strategies for preventing fires both at the stand level or landscape level. In this context, probabilistic models of fire occurrence and estimated mortality to the main Portuguese forest species (maritime pine and eucalyptus) in pure composition of regular and irregular structures were developed. These were later integrated into a management model that optimizes harvests scheduling for each stand in order to create more fire resistant landscapes. It’s being developed a technologic platform to test these models and their combination with an innovative approach to incorporate fire risk and protective objectives in forest management planning

Perspectives for integrating human and environmental risk assessment and synergies with socio-economic analysis

International audienceFor more than a decade, the integration of human and environmental risk assessment (RA) has become an attractive vision. At the same time, existing European regulations of chemical substances such as REACH (EC Regulation No. 1907/2006), the Plant Protection Products Regulation (EC regulation 1107/2009) and Biocide Regulation (EC Regulation 528/2012) continue to ask for sector-specific RAs, each of which have their individual information requirements regarding exposure and hazard data, and also use different methodologies for the ultimate risk quantification. In response to this difference between the vision for integration and the current scientific and regulatory practice, the present paper outlines five medium-term opportunities for integrating human and environmental RA, followed by detailed discussions of the associated major components and their state of the art. Current hazard assessment approaches are analyzed in terms of data availability and quality, and covering non-test tools, the integrated testing strategy (ITS) approach, the adverse outcome pathway (AOP) concept, methods for assessing uncertainty, and the issue of explicitly treating mixture toxicity. With respect to exposure, opportunities for integrating exposure assessment are discussed, taking into account the uncertainty, standardization and validation of exposure modeling as well as the availability of exposure data. A further focus is on ways to complement RA by a socio-economic assessment (SEA) in order to better inform about risk management options. In this way, the present analysis, developed as part of the EU FP7 project HEROIC, may contribute to paving the way for integrating, where useful and possible, human and environmental RA in a manner suitable for its coupling with SEA

A Practical Guide to Integrating Reproductive Health and HIV/AIDS into Grant Proposals to the Global Fund

Integrating RH and HIV can greatly contribute to mitigating the AIDS pandemic by reducing unintended pregnancy; preventing perinatal transmission; expanding to more target groups; reducing gender based violence; meeting the needs of people living with HIV and providing our youth with the knowledge and services they need. Whether to integrate, how to integrate and exactly what to integrate will depend on a country's epidemiological profile, policies and program structures.Experience with implementation of integration initiatives in countries around the world shows that scale up and sustainability requires attention to policy and program operations issues. This document, with links to a range of resources, will help CCMs, civil society organizations and others developing proposals for the Global Fund that contribute to preventing HIV and mitigating the effects of the AIDS pandemic through programs that link and integrate RH and HIV/AIDS

The Medicare Physician Group Practice Demonstration: Lessons Learned on Improving Quality and Efficiency in Health Care

Discusses the experiences of ten large practices earning performance payments for improving the quality and cost-efficiency of health care delivered to Medicare fee-for-service beneficiaries

Methodology for Designing Decision Support Systems for Visualising and Mitigating Supply Chain Cyber Risk from IoT Technologies

This paper proposes a methodology for designing decision support systems for visualising and mitigating the Internet of Things cyber risks. Digital technologies present new cyber risk in the supply chain which are often not visible to companies participating in the supply chains. This study investigates how the Internet of Things cyber risks can be visualised and mitigated in the process of designing business and supply chain strategies. The emerging DSS methodology present new findings on how digital technologies affect business and supply chain systems. Through epistemological analysis, the article derives with a decision support system for visualising supply chain cyber risk from Internet of Things digital technologies. Such methods do not exist at present and this represents the first attempt to devise a decision support system that would enable practitioners to develop a step by step process for visualising, assessing and mitigating the emerging cyber risk from IoT technologies on shared infrastructure in legacy supply chain systems

Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness.

In the fourth article of a five-part series providing a global perspective on integrating mental health, Sylvia Kaaya and colleagues discuss the importance of integrating mental health interventions into HIV prevention and treatment platforms. Please see later in the article for the Editors' Summary

Integrating IVHM and asset design

Integrated Vehicle Health Management (IVHM) describes a set of capabilities that enable effective and efficient maintenance and operation of the target vehicle. It accounts for the collecting of data, conducting analysis, and supporting the decision-making process for sustainment and operation. The design of IVHM systems endeavours to account for all causes of failure in a disciplined, systems engineering, manner. With industry striving to reduce through-life cost, IVHM is a powerful tool to give forewarning of impending failure and hence control over the outcome. Benefits have been realised from this approach across a number of different sectors but, hindering our ability to realise further benefit from this maturing technology, is the fact that IVHM is still treated as added on to the design of the asset, rather than being a sub-system in its own right, fully integrated with the asset design. The elevation and integration of IVHM in this way will enable architectures to be chosen that accommodate health ready sub-systems from the supply chain and design trade-offs to be made, to name but two major benefits. Barriers to IVHM being integrated with the asset design are examined in this paper. The paper presents progress in overcoming them, and suggests potential solutions for those that remain. It addresses the IVHM system design from a systems engineering perspective and the integration with the asset design will be described within an industrial design process