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BACKGROUND: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. RESULTS: We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16- monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers. CONCLUSIONS: Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability . We would like to thank K. Pearce and M. Kristiansen (UCL Genomics) for processing the Illumina Infinium HumanMethylation450 BeadChips; D. Balzereit, S. Dökel, A. Kovacsovics, and M. Linser (Max Planck Institute for Molecular Genetics) for help with generating the RNA-seq data; B. Phipson (Murdoch Childrens Research Institute), H.C. Bravo (University of Maryland), and P. Guilhamon (UCL Cancer Institute) for advice on statistical analyses; C. Bock (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) for useful discussions; A. Orozco (University of Costa Rica) for technical support; V. Naranbhai, B. Fairfax, and J. Knight (University of Oxford) for providing access to the neutrophil gene expression data set for replication; and L. Phipps for proofreading the manuscript. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers, and thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the NIHR Cambridge Biomedical Research Centre (BRC) for funding. BLUEPRINT Consortium: Cornelis A. Albers (Radboud University), Vyacheslav Amstislavskiy (Max Planck Institute for Molecular Genetics), Sofie Ashford (University of Cambridge), Lorenzo Bomba (Wellcome Trust Sanger Institute), David Bujold (McGill University), Frances Burden (University of Cambridge), Stephan Busche (McGill University), Maxime Caron (McGill University), Shu-Huang Chen (McGill University), Warren A. Cheung (McGill University), Laura Clarke (European Bioinformatics Institute), Irina Colgiu (Wellcome Trust Sanger Institute), Avik Datta (European Bioinformatics Institute), Oliver Delaneau (University of Geneva), Heather Elding (Wellcome Trust Sanger Institute), Samantha Farrow (University of Cambridge), Diego Garrido-Martín (Centre for Genomic Regulation), Bing Ge (McGill University), Roderic Guigo (Centre for Genomic Regulation), Valentina Iotchkova (European Bioinformatics Institute), Kousik Kundu (Wellcome Trust Sanger Institute), Tony Kwan (McGill University), John J. Lambourne (University of Cambridge), Ernesto Lowy (European Bioinformatics Institute), Daniel Mead (Wellcome Trust Sanger Institute), Farzin Pourfarzad (Sanquin Research and Landsteiner Laboratory), Adriana Redensek (McGill University), Karola Rehnstrom (University of Cambridge), Augusto Rendon (University of Cambridge), David Richardson (European Bioinformatics Institute), Thomas Risch (Max Planck Institute for Molecular Genetics), Sophia Rowlston (University of Cambridge), Xiaojian Shao (McGill University), Marie-Michelle Simon (McGill University), Marc Sultan (Max Planck Institute for Molecular Genetics), Klaudia Walter (Wellcome Trust Sanger Institute), Steven P. Wilder (European Bioinformatics Institute), Ying Yan (Wellcome Trust Sanger Institute), Stylianos E. Antonarakis (University of Geneva), Guillaume Bourque (McGill University), Emmanouil T. Dermitzakis (University of Geneva), Paul Flicek (European Bioinformatics Institute), Hans Lehrach (Max Planck Institute for Molecular Genetics), Joost H. A. Martens (Radboud University), Marie-Laure Yaspo (Max Planck Institute for Molecular Genetics), Willem H. Ouwehand (University of Cambridge). Sí

A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) resident in the steady-state thymus is whether early thymic progenitors (ETPs) could escape T cell fate constraints imposed normally by a Notch-inductive microenvironment and undergo DC development. By modeling DC generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated Notch signaling allows human ETPs to undertake a myeloid transcriptional program, resulting in GATA2-dependent generation of CD34 CD123 progenitors with restricted pDC, cDC, and monocyte potential, whereas Delta-like1 signaling down-regulates GATA2 and impairs myeloid development. Progressive commitment to the DC lineage also occurs intrathymically, as myeloid-primed CD123 monocyte/DC and common DC progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. The identification of a discrete JAG1 thymic medullary niche enriched for DC-lineage cells expressing Notch receptors further validates the human thymus as a DC-poietic organ, which provides selective microenvironments permissive for DC development., Ministerio de Ciencia e Innovación grants SAF2013-44857-R and SAF2016-75442-R (Agencia Estatal de Investigación/European Regional Development Fund, European Union), Instituto de Salud Carlos III (RTI CC RD06/0014/1012); and by an Institutional Grant from Fundación Ramón Areces.

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement no.305444—the RD-Connect project. Pedro Sernadela is funded by Fundac¸ao para a Ci ˜ encia e Tecnologia (FCT) under the ˆGrant Agreement SFRH/BD/52484/2014. Lorena Gonzalez- ´Castro is funded by the Xunta de Galicia, including funding from the operative program FSE Galicia 2007–2013, under the Grant Agreement IN809A 19/2015.

BACKGROUND: Monitoring of human exposure to mercury is important due to its adverse health effects. This study aimed to determine the extent of mercury exposure among mothers and their children in Ireland, and to identify factors associated with elevated levels. It formed part of the Demonstration of a study to Coordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES) pilot biomonitoring study. METHODS: Hair mercury concentrations were determined from a convenience sample of 120 mother/child pairs. Mothers also completed a questionnaire. Rigorous quality assurance within DEMOCOPHES guaranteed the accuracy and international comparability of results. RESULTS: Mercury was detected in 79.2% of the samples from mothers, and 62.5% of children's samples. Arithmetic mean levels in mothers (0.262 µg/g hair) and children (0.149 µg /g hair) did not exceed the US EPA guidance value. Levels were significantly higher for those with higher education, and those who consumed more fish. CONCLUSIONS: The study demonstrates the benefit of human biomonitoring for assessing and comparing internal exposure levels, both on a population and an individual basis. It enables the potential harmful impact of mercury to be minimised in those highly exposed, and can therefore significantly contribute to population health. We would like to acknowledge the funders of the DEMOCOPHES project (LIFE09 ENV/BE/000410) which was jointly financed by the European Commission Programme LIFE and each participating country (http://www.eu-hbm.info/democophes/project-partners). In addition, we would like to thank the COPHES project for providing the operational and scientific framework (European Community’s Seventh Framework Programme—DG Research Grant Agreement Number 244237). Sí

Leishmaniasis is one of the most important neglected zoonosis and remains endemic in at least 88 developing countries in the world. In addition, anthropogenic environmental changes in urban areas are leading to its emergency world wide. Zoonotic leishmaniasis control might only be achieved by an integrated approach targeting both the human host and the animal reservoirs, which in certain sylvatic cycles are yet to be identified. Recently, hares have been pointed out as competent reservoirs of Leishmania infantum in Spain, but the role of other lagomorphs has not been clarified. Here, 69 rabbits (Oryctolagus cuniculus) from a natural area in Madrid in which a high density was present were analyzed using indirect (immunofluorescence antibody test, IFAT) and direct (PCR, culture) techniques. Fifty-seven (82.6%) of the animals were positive to at least one technique, with IFAT yielding the highest proportion of positive samples. L. infantum was isolated in 13% animals demonstrating the occurrence of infection in this setting. Our results suggest that rabbits could play a role of competent reservoir of L. infantum and demonstrate that the prevalence of infection is high in the analyzed area. The authors thank Raúl López, Gabriela Luz Torre, Ines de Cárdenas, S. Crespo, and A. B. Martín for their help in the collection and processing of samples. J. Alvarez received a Sara Borrell postdoctoral contract (CD11/00261, Ministerio de Ciencia e Innovación). This work is a contribution to the EU FP7 ANTIGONE Project (278976) and was partially supported by the program I+D “Vigilancia Sanitaria” from the Autonomous Community of Madrid. Sí

Clinical interest on human mesenchymal progenitor cells (hMPC) relies on their potential applicability in cell-based therapies. An in vitro characterization is usually performed in order to define MPC potency. However, in vitro predictions not always correlate with in vivo results and thus there is no consensus in how to really assess cell potency. Our goal was to provide an in vivo testing method to define cell behavior before therapeutic usage, especially for bone tissue engineering applications. In this context, we wondered whether bone marrow stromal cells (hBMSC) would proceed in an osteogenic microenvironment. Based on previous approaches, we developed a fibrin/ceramic/BMP-2/hBMSCs compound. We implanted the compound during only 2 weeks in NOD-SCID mice, either orthotopically to assess its osteoinductive property or subcutaneously to analyze its adequacy as a cell potency testing method. Using fluorescent cell labeling and immunohistochemistry techniques, we could ascertain cell differentiation to bone, bone marrow, cartilage, adipocyte and fibrous tissue. We observed differences in cell potential among different batches of hBMSCs, which did not strictly correlate with in vitro analyses. Our data indicate that the method we have developed is reliable, rapid and reproducible to define cell potency, and may be useful for testing cells destined to bone tissue engineering purposes. Additionally, results obtained with hMPCs from other sources indicate that our method is suitable for testing any potentially implantable mesenchymal cell. Finally, we propose that this model could successfully be employed for bone marrow niche and bone tumor studies. This work was supported by Seventh Framework Programme of the European Commission (EuroNanomed ERA-NET initiative, REBONE project; PI10/02985FIS to J.G-C), Madrid regional government (CellCAM; P2010/BMD-2420 to J.G-C), Ministerio de Ciencia e Innovación (PI11/00377FIS to J.G-C, CSD2009-00088 to J.L.L-L.) and Mapfre foundation (SA/12/AYU/197 to Ar.A). We are grateful to Elena Andrés, David Castejón and María Encarnación Fernandez-Valle for their support in image techniques, to Daniel Baizan for his technical support in animal care, to Isabel Mirones for her technical support in immunohistochemistry and to Isabel Colmenero, pathologist, for her support in sample characterizations. Sí

INTRODUCTION: The growing movement of innovative approaches to chronic disease management in Europe has not been matched by a corresponding effort to evaluate them. This paper discusses challenges to evaluation of chronic disease management as reported by experts in six European countries. METHODS: We conducted 42 semi-structured interviews with key informants from Austria, Denmark, France, Germany, The Netherlands and Spain involved in decision-making and implementation of chronic disease management approaches. Interviews were complemented by a survey on approaches to chronic disease management in each country. Finally two project teams (France and the Netherlands) conducted in-depth case studies on various aspects of chronic care evaluation. RESULTS: We identified three common challenges to evaluation of chronic disease management approaches: (1) a lack of evaluation culture and related shortage of capacity; (2) reluctance of payers or providers to engage in evaluation and (3) practical challenges around data and the heterogeity of IT infrastructure. The ability to evaluate chronic disease management interventions is influenced by contextual and cultural factors. CONCLUSIONS: This study contributes to our understanding of some of the most common underlying barriers to chronic care evaluation by highlighting the views and experiences of stakeholders and experts in six European countries. Overcoming the cultural, political and structural barriers to evaluation should be driven by payers and providers, for example by building in incentives such as feedback on performance, aligning financial incentives with programme objectives, collectively participating in designing an appropriate framework for evaluation, and making data use and accessibility consistent with data protection policies. The DISMEVAL project was funded under the European Commission’s Seventh Framework Programme (FP7) (grant no. 223277). The views expressed in this paper are those of the authors alone and the European Commission is therefore not liable for any use that may be made of the information contained herein. We would like to express our gratitude to interview participants for kindly giving their time and sharing their knowledge. Sí

There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers. Funding for this research was received by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics). Hansson also received funding by the Innovative Medicines Initiative project BT-Cure (grant agreement number 115142-1), the BioBanking and Molecular Resource Infrastructure of Sweden project (financed by the Swedish Research Council), and the European Union Seventh Framework Programmes Euro-TEAM, BiobankCloud and BBMRI-LPC. Dawkins acknowledges support-in-part from the Australian National Health and Medical Research Council RD-Connect project APP1055319 under the NHMRC–European Union Collaborative Research Grants scheme. Sí

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment., Highlights • KatG-independent InhA inhibitors mimicking isoniazid cidality • GSK693 first DI showing oral in vivo efficacy similar to isoniazid • Retain activity against M(X)DR clinical isolates • Physicochemical properties akin to antitubercular drugs Last year, Mycobacterium tuberculosis had the doubtful honor of being the top infectious killer worldwide. The current 6-month treatment, which was developed more than 30 years ago, has saved million of lives but bears the drawback of poor compliance; hence, the world needs a new shorter and safer TB treatment. The biochemical screening of GSK compound library performed by Martinez et al. has identified new KatG-independent inhibitor of InhA active against M(X)DR Mtb strains, good drug-like properties, and in vivo activity similar to isoniazid overcoming the resistance and toxicological issues of the former drug.

Supplemental Digital Content is Available in the Text., Background: Viremia copy-years (VCY), a time-updated measure of cumulative HIV exposure, predicts AIDS/death; although its utility in deciding when to start combination antiretroviral therapy (cART) remains unclear. We aimed to assess the impact of initiating versus deferring cART on risk of AIDS/death by levels of VCY both independent of and within CD4 cell count strata ≥500 cells per cubic millimeter. Methods: Using Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) data, we created a series of nested “trials” corresponding to consecutive months for individuals ≥16 years at seroconversion after 1995 who were cART-naive and AIDS-free. Pooling across all trials, time to AIDS/death by CD4, and VCY strata was compared in those initiating vs. deferring cART using Cox models adjusted for: country, sex, risk group, seroconversion year, age, time since last HIV-RNA, and current CD4, VCY, HIV-RNA, and mean number of previous CD4/HIV-RNA measurements/year. Results: Of 9353 individuals, 5312 (57%) initiated cART and 486 (5%) acquired AIDS/died. Pooling CD4 strata, risk of AIDS/death associated with initiating vs. deferring cART reduced as VCY increased. In patients with high CD4 cell counts, ≥500 cells per cubic millimeter, there was a trend for a greater reduction for those initiating vs. deferring with increasing VCY (P = 0.09), with the largest benefit in the VCY ≥100,000 copy-years/mL group [hazard ratio (95% CI) = 0.41 (0.19 to 0.87)]. Conclusions: For individuals with CD4 ≥500 cells per cubic millimeter, limiting the cumulative HIV burden to

WOS: 000372567300063, PubMed ID: 26900688, Background The recent geographical expansion of phlebotomine vectors of Leishmania infantum in the Mediterranean subregion has been attributed to ongoing climate changes. At these latitudes, the activity of sand flies is typically seasonal; because seasonal phenomena are also sensitive to general variations in climate, current phenological data sets can provide a baseline for continuing investigations on sand fly population dynamics that may impact on future scenarios of leishmaniasis transmission. With this aim, in 2011-2013 a consortium of partners from eight Mediterranean countries carried out entomological investigations in sites where L. infantum transmission was recently reported. Methods/Principal Findings A common protocol for sand fly collection included monthly captures by CDC light traps, complemented by sticky traps in most of the sites. Collections were replicated for more than one season in order to reduce the effects of local weather events. In each site, the trapping effort was left unchanged throughout the survey to legitimate inter-seasonal comparisons. Data from 99,000 collected specimens were analyzed, resulting in the description of seasonal dynamics of 56,000 sand flies belonging to L. infantum vector species throughout a wide geographical area, namely P. perniciosus (Portugal, Spain and Italy), P. ariasi (France), P. neglectus (Greece), P. tobbi (Cyprus and Turkey), P. balcanicus and P. kandelakii (Georgia). Time of sand fly appearance/disappearance in collections differed between sites, and seasonal densities showed variations in each site. Significant correlations were found between latitude/mean annual temperature of sites and i) the first month of sand fly appearance, that ranged from early April to the first half of June; ii) the type of density trend, varying from a single peak in July/August to multiple peaks increasing in magnitude from May through September. A 3-modal trend, recorded for P. tobbi in Cyprus, represents a novel finding for a L. infantum vector. Adults ended the activity starting from mid September through November, without significant correlation with latitude/mean annual temperature of sites. The period of potential exposure to L. infantum in the Mediterranean subregion, as inferred by adult densities calculated from 3 years, 37 sites and 6 competent vector species, was associated to a regular bell-shaped density curve having a wide peak center encompassing the July-September period, and falling between early May to late October for more than 99% of values. Apparently no risk for leishmaniasis transmission took place from December through March in the years considered. We found a common pattern of nocturnal females activity, whose density peaked between 11 pm and 2 am. Conclusions Despite annual variations, multiple collections performed over consecutive years provided homogeneous patterns of the potential behavior of leishmaniasis vectors in selected sites, which we propose may represent sentinel areas for future monitoring. In the investigated years, higher potential risk for L. infantum transmission in the Mediterranean was identified in the June-October period (97% relative vector density), however such risk was not equally distributed throughout the region, since density waves of adults occurred earlier and were more frequent in southern territories., EU grantEuropean Union (EU) [FP7-261504 EDENext]; Fundacao para a Ciencia e a Tecnologia, Ministerio da Educacao e Ciencia, Portugal [SFRH/BPD/44082/2008], This study was partially funded by EU grant FP7-261504 EDENext and is catalogued by the EDENext Steering Committee as EDENext376 (http://www.edenext.eu). The work of CM was done under the fellowship SFRH/BPD/44082/2008 from Fundacao para a Ciencia e a Tecnologia, Ministerio da Educacao e Ciencia, Portugal. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of the European Commission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P, A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Massive activation of infected CD4+ T cells during acute HIV-1 infection leads to reservoir seeding and T-cell destruction. During T-cell activation, the antiviral effect of the innate factor SAMHD1 is neutralized through phosphorylation at T592, allowing HIV-1 infection. Dasatinib, a tyrosine kinase inhibitor currently used for treating chronic myeloid leukemia, has been described to control HIV-1 replication through its negative effect on T-cell proliferation and viral entry. We demonstrate that Dasatinib can actually interfere with SAMHD1 phosphorylation in human peripheral blood lymphocytes, preserving its antiviral activity against HIV-1. Dasatinib prevented SAMHD1 phosphorylation in vitro and ex vivo, impairing HIV-1 reverse transcription and proviral integration. This was the major mechanism of action because the presence of Vpx, which degrades SAMHD1, in HIV-1 virions impeded the inhibitory effect of Dasatinib on HIV-1 replication. In fact, infection with VSV-pseudotyped HIV-1 virions and fusion of BlaM-Vpr-containing HIV-1 viruses with activated PBMCs in the presence of Dasatinib suggested that Dasatinib was not acting at fusion level. Finally, PBMCs from patients on chronic treatment with Dasatinib showed a lower level of SAMHD1 phosphorylation in response to activating stimuli and low susceptibility to HIV-1 infection ex vivo. Consequently, Dasatinib is a compound currently used in clinic that preserves the antiviral function of SAMHD1. Using Dasatinib as adjuvant of antiretroviral therapy during early primary HIV-1 infection would contribute to reduce viral replication and spread, prevent reservoir seeding, and preserve CD4 counts and CTL responses. These events would create a more favorable virologic and immunologic environment for future interventional studies aiming at HIV-1 eradication. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2010-18388, SAF2013-44677-R, FIS PI12/00506, and FIS PI12/00969); the SPANISH AIDS Research Network RD12/0017/0015 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Bristol-Myers Squibb (BMS AI471-041); AIM-HIV Network of Excellence of the EU, grant number HEALTH-F3-2012-305938; joined program of the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS AO2014-2); and the European FP7-HEALTH project HIT HIDDEN HIV. The work of Elena Mateos is supported by the Instituto de Salud Carlos III (Spain) (MPY 1371/12). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness. The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM). The work of Dr Benjamin Descours is supported by the 31 European FP7-HEALTH project HIT HIDDEN HIV. Dr. Montserrat Plana is a researcher at the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and is supported by the Spanish Health Institute Carlos III (ISCIII) and the Health Department of the Catalan Government (Generalitat de Catalunya). Dr. Juan Ambrosioni developed this work in the framework of a ‘Juan de la Cierva 2012’ post- doctoral program, Ministerio de Competitividad, Madrid, Spain. Sí

Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with ‘hyper-long' telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression., Telomere shortening has been linked to some aspects of organismal ageing. Here the authors create chimaeric mice that contain a mix of cells with normal or unnaturally long telomeres, and show chimaeric mice are protected from some forms of ageing-associated cellular damage and have accelerated wound-healing.

BACKGROUND: Healthier urban environments influence the distribution of cardiovascular risk factors. Our aim was to design and implement a multicomponent method based on Geographic Information Systems to characterize and evaluate environmental correlates of obesity: the food and the physical activity urban environments. METHODS: Study location comprised a socio-demographically average urban area of 12 contiguous census sections (≈16,000 residents), in Madrid, Spain. We conducted on-field audits on all food stores and street segments. We designed a synthetic index integrating continuous measures of both environments, by kernel density analyses. Index ranges from 0 to 100 (least-most healthy). RESULTS: We found a heterogeneous distribution with 75 and 50 % of the area scoring less than 36.8 and 25.5, respectively. Census sections of study area were categorized by Jenks intervals as high, medium-high, medium-low and low. 41.0 % of residents lived in an area with a low score, 23.6 % medium-low and 31.1 % medium-high and 4.2 % in a high. CONCLUSION: The proposed synthetic index may be a relevant tool to inform urban health interventions, providing a feasible way to integrate different measures of barriers and facilitators of healthy urban environments in terms of food and physical activity. This study was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Starting Grant HeartHealthyHoods Agreement n. 336893. Usama Bilal was supported by a fellowship from the Obra Social La Caixa and by a Johns Hopkins Center for a Livable Future-Lerner Fellowship Sí

The strong association of CD4 count at start of combination therapy with subsequent survival in HIV-infected patients diminished during the first 5 years of treatment. After 5 years, lower baseline CD4 counts were not associated with higher mortality., Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. Methods. We estimated mortality rates (MRs) by time since start of ART (

Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second >European interdisciplinary Ewing sarcoma research summit> assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNAsequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intratumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits., The conference was supported by the European Union’s Seventh Framework Programme grants 261743(ENCCA) and 259348 (ASSET).

INTRODUCTION: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe. METHODS: A cross-sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV-positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign-born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men. RESULTS: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post-migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three-quarters of people on antiretrovirals had an HIV viral load

The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field. EBB thanks EURORDIS for administrative support, Fondazione Telethon for administrative and financial support, the EC for providing funds (grants: FP5 EuroBioBank, contract N. 02769; FP6 TREAT-NMD, contract N. 036825; and FP7 RD-Connect, grant agreement N. 305444), and AFM for the vision of the network and for encouraging the network to get together. EBB gratefully acknowledges patients and collaborating clinicians/researchers for contributing samples and data to the network, and biobank staffs for running the EBB biobanks. The MRC support to the biobank in London and Newcastle is also gratefully acknowledged. Sí

© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)., The metal cadmium (Cd) is a widespread environmental pollutant with documented adverse effects on the kidneys and bones from long-term environmental exposure, but with insufficiently elucidated public health consequences such as risk of cardiovascular disease, hormone-related cancer in adults and developmental effects in children. This study is the first pan-European human biomonitoring project that succeeded in performing harmonized measurements of Cd in urine in a comparable way in mother–child couples from 16 European countries. The aim of the study was to evaluate the overall Cd exposure and significant determinants of Cd exposure. A study population of 1632 women (24–52 years of age), and 1689 children (5–12 years of age), from 32 rural and urban areas, was examined within a core period of 6 months in 2011–2012. Women were stratified as smokers and non-smokers. As expected, smoking mothers had higher geometric mean (gm) urinary cadmium (UCd; 0.24 µg/g crea; n=360) than non-smoking mothers (gm 0.18 µg/g crea; n=1272; p, Financially supported by the 7th EU framework programe(DGResearch – No. 244237-COPHES),LIFE+ 2009(DG Environment – LIFE09ENV/BE000410-DEMOCOPHES),with addi- tional co-funding from DEMOCOPHES partners.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). Contract grant sponsor(s): TREAT-NMD (FP6LSHM-CT-2006-036825, 20123307 UNEW_FY2013, and AFM 16104); European Union Seventh Framework Programme (FP7/2007-2013) (305444 [RD-Connect] and 305121 [Neuromics]). Sí

'Reproduced with permission from Environmental Health Perspectives', Background: For Europe as a whole, data on internal exposure to environmental chemicals do not yet exist. Characterization of the internal individual chemical environment is expected to enhance understanding of the environmental threats to health. Objectives: We developed and applied a harmonized protocol to collect comparable human biomonitoring data all over Europe. Methods: In 17 European countries, we measured mercury in hair and cotinine, phthalate metabolites, and cadmium in urine of 1,844 children (5–11 years of age) and their mothers. Specimens were collected over a 5-month period in 2011–2012. We obtained information on personal characteristics, environment, and lifestyle. We used the resulting database to compare concentrations of exposure biomarkers within Europe, to identify determinants of exposure, and to compare exposure biomarkers with healthbased guidelines. Results: Biomarker concentrations showed a wide variability in the European population. However, levels in children and mothers were highly correlated. Most biomarker concentrations were below the health-based guidance values. Conclusions: We have taken the first steps to assess personal chemical exposures in Europe as a whole. Key success factors were the harmonized protocol development, intensive training and capacity building for field work, chemical analysis and communication, as well as stringent quality control programs for chemical and data analysis. Our project demonstrates the feasibility of a Europe-wide human biomonitoring framework to support the decision-making process of environmental measures to protect public health., The research leading to these results received funding for the COPHES project (COnsortium to Perform Human biomonitoring on a European Scale) from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement 244237. DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) was co-funded (50%:50%) by the European Commission LIFE+ Programme (LIFE09/ENV/BE/000410) and the partners. For information on both projects as well as on the national co-funding institutions, see http://www.eu-hbm.info/. The sponsors had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

All members of the lyssavirus genus cause the disease rabies. European bat lyssavirus 1 (EBLV-1) viruses are divided genetically into three groups according to geographic location and host reservoir. We report here the first genome sequence for an EBLV-1 isolated from Eptesiscus isabellinus in the Iberian Peninsula, Spain. This work was supported by grants from the Department for Environment, Food and Rural Affairs (SE0423 and SE0427) and by the European Union FP7-funded Research Infrastructure Grant European Virus Archive (19 228292). Sí

BACKGROUND: The purpose of the study was to measure clinical quality by doing an audit of clinical records and to compare the performance based on clinical quality indicators (CQI) for hypertension and type 2 diabetes across seven European countries: Estonia, Finland, Germany, Hungary, Italy, Lithuania and Spain. METHODS: Two common chronic conditions in primary care (PC), hypertension and type 2 diabetes, were selected for audit. The assessment of CQI started with a literature review of different databases: Organization for Economic Co-operation and Development, World Health Organization, European Commission European Community Health Indicators, US National Library of Medicine. Data were collected from clinical records. RESULTS: Although it was agreed to obtain the clinical indicators in a similar way from each country, the specific data collection process in every country varied greatly, due to different traditions in collecting and keeping the patients' data, as well as differences in regulation regarding access to clinical information. Also, there was a huge variability across countries in the level of compliance with the indicators. CONCLUSIONS: Measurement of clinical performance in PC by audit is methodologically challenging: different databases provide different information, indicators of quality of care have insufficient scientific proof and there are country-specific regulations. There are large differences not only in quality of health care across Europe but also in how it is measured. EU primecare project was funded under the European Commission’s 7th Framework Programme (grant no. 241595). Sí

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. This study was supported by: UK: the National CJD Research and Surveillance UK Unit is funded by the Department of Health and the Scottish Government Health Department. The National CJD Research and Surveillance Unit is funded by the Policy Research Programme in the Department of Health. Germany: This work was supported by a grant from the European Commission (Protecting the food chain from prions: shaping European priorities through basic and applied research (PRIORITY, N° 222887) Project number: FP7-KBBE-2007-2A). The study was performed within the recently established Clinical Dementia Center at the University Medical Center Göttingen and was partly supported by grants from the EU Joint Programme – Neurodegenerative Disease Research (JPND - DEMTEST "Biomarker based diagnosis of rapid progressive dementias optimization of diagnostic protocols", 01ED1201A). This study was funded by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369-341). Italy: The Italian Registry of CJD and related disorders is funded by the Ministry of Health, National Centre for Disease Prevention and Control, Central Actions.This work was partly supported by grant from the EU Joint Programme – Neurodegenerative Disease Research (JPND-DEMTEST “Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols”, 01ED1201A). The Netherlands: the generation and management of genome-wide association study (GWAS) genotype data for the Rotterdam Study is supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. YSA is supported by Russian Science Foundation (RSCF) grant 14-14-00313. Spain. PSJ was supported by a grant from FIS (PI12/02288) and JPND project DEMTEST (PI11/03028). AC is supported by PI13/01136 Acción Estratégica de Salud del Instituto de Salud Carlos III e INNOPHARMA. Australia: The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) is funded by the Commonwealth Department of Health. SJC is supported by a NHMRC Practitioner Fellowship (#APP1005816). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Sí

This work received support from the Dirección General de Farmacia, Ministerio de Sanidad, Servicios Sociales e Igualdad, Government of Spain, grant EC11-272; European Network of Excellence EUROPRISE (Rational Design of HIV Vaccines and Microbicides), grant LSHP-CT-2006-037611; European Research Infrastructures for Poverty Related Diseases (EURIPRED). Seventh Framework Programme: FP7-Capacities-infrastructures-2012-1, grant agreement 312661; Instituto de Salud Carlos III, Subdirección General de Evaluación, and Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I + D + I, through project RD12/0017/0026; Consellería de Sanidade, Government of Galicia, Spain (MVI 1291/08); and the Osakidetza-Servicio Vasco de Salud, Basque Country, Spain (MVI-1255-08). Marcos Pérez-Losada was supported by a DC D-CFAR Research Award from the District of Columbia Developmental Center for AIDS Research (P30AI087714) and by an University Facilitating Fund award from George Washington University. Aurora Fernández-García is supported by CIBER in Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain. We recently reported the rapid expansion of an HIV-1 subtype F cluster among men who have sex with men (MSM) in the region of Galicia, Northwest Spain. Here we update this outbreak, analyze near full-length genomes, determine phylogenetic relationships, and estimate its origin. For this study, we used sequences of HIV-1 protease-reverse transcriptase and env V3 region, and for 17 samples, near full-length genome sequences were obtained. Phylogenetic analyses were performed via maximum likelihood. Locations and times of most recent common ancestors were estimated using Bayesian inference. Among samples analyzed by us, 100 HIV-1 F1 subsubtype infections of monophyletic origin were diagnosed in Spain, including 88 in Galicia and 12 in four other regions. Most viruses (n = 90) grouped in a subcluster (Galician subcluster), while 7 from Valladolid (Central Spain) grouped in another subcluster. At least 94 individuals were sexually-infected males and at least 71 were MSM. Seventeen near full-length genomes were uniformly of F1 subsubtype. Through similarity searches and phylogenetic analyses, we identified 18 viruses from four other Western European countries [Switzerland (n = 8), Belgium (n = 5), France (n = 3), and United Kingdom (n = 2)] and one from Brazil, from samples collected in 2005?2011, which branched within the subtype F cluster, outside of both Spanish subclusters, most of them corresponding to recently infected individuals. The most probable geographic origin and age of the Galician subcluster was Ferrol, Northwest Galicia, around 2007, while the Western European cluster probably emerged in Switzerland around 2002. In conclusion, a recently expanded HIV-1 subtype F cluster, the largest non-subtype B cluster reported in Western Europe, continues to spread among MSM in Spain; this cluster is part of a larger cluster with a wide geographic circulation in diverse Western European countries. Publisher PDF

10 páginas, 2 tablas., Cystic echinococcosis (CE) is an important helminthic zoonotic disease caused by the Echinococcus granulosus complex. In humans, CE is a chronic disease driven by the growth of echinococcal cysts in different organs. Prognosis of this disease depends onmultiple factors, including location, number, size, and stage of the cysts, making CE a disease of complex management. CE is usually asymptomatic for years and attracts limited attention from funding organizations and health authorities. For this reason, only experts’ recommendations are available but no evidence-based conclusions have been drawn for CE clinical management. One of those pitfalls refers to the lack of evidence to support the use of serological tools for the diagnosis and follow-up of CE patients. In this respect, crude antigens are used to detect specific antibodies in patients, giving rise to false positive results.The advent of molecular techniques allowing the production of recombinant proteins has provided a number of candidate antigens that could overcome the problems associated with the use of crude parasite extracts in the serological assays. In this review, we present the last advances in this field, proposing the use of serology to support cyst stage-specific diagnosis and follow-up., The research that will lead to these results has received funding from the European Community’s Seventh Framework Programmeunder theGrant agreement 602051 (Project HERACLES: Human cystic Echinococcosis ReseArch in CentraL and Eastern Societies; http://www.Heracles-fp7.eu/).

Objective: This article compares trends in CD4þ T-cell recovery and proportions achieving optimal restoration ( 500 cells/ml) after viral suppression following combination antiretroviral therapy (cART) initiation between rapid and nonrapid progressors. Methods: We included HIV-1 seroconverters achieving viral suppression within 6 months of cART. Rapid progressors were individuals experiencing at least one CD4þ less than 200 cells/ml within 12 months of seroconverters before cART. We used piecewise linear mixed models and logistic regression for optimal restoration. Results: Of 4024 individuals, 294 (7.3%) were classified as rapid progressors. At the same CD4þ T-cell count at cART start (baseline), rapid progressors experienced faster CD4þ T-cell increases than nonrapid progressors in first month [difference (95% confidence interval) in mean increase/month (square root scale): 1.82 (1.61; 2.04)], which reversed to slightly slower increases in months 1–18 [0.05 (0.06; 0.03)] and no significant differences in 18–60 months [0.003 (0.01; 0.01)]. Percentage achieving optimal restoration was significantly lower for rapid progressors than nonrapid progressors at months 12 (29.2 vs. 62.5%) and 36 (47.1 vs. 72.4%) but not at month 60 (70.4 vs. 71.8%). These differences disappeared after adjusting for baseline CD4þ T-cell count: odds ratio (95% confidence interval) 0.86 (0.61; 1.20), 0.90 (0.38; 2.17) and 1.56 (0.55; 4.46) at months 12, 36 and 60, respectively. Conclusion: Among people on suppressive antiretroviral therapy, rapid progressors experience faster initial increases of CD4þ T-cell counts than nonrapid progressors, but are less likely to achieve optimal restoration during the first 36 months after cART, mainly because of lower CD4þ T-cell counts at cART initiation. This work was supported by the European Union Seventh Framework Programme (FP7/2007–2013) under EuroCoord grant agreement n° 260694. Sí

An explosive epidemic occurred in Madeira Island (Portugal) from October 2012 to February 2013. Published data showed that dengue virus type 1 introduced from South America was the incriminated virus. We aim to determine the origin of the strain introduced to Madeira by travellers returning to Europe. Using phylogeographic analysis and complete envelope sequences we have demonstrated that the most probable origin of the strain is Venezuela. The research was funded by DengueTools under the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 . LF, NS, MPSS and AT are supported by the Spanish Ministry of Science and Innovation and the Instituto de Salud Carlos III within the Network of Tropical Diseases Research RICET RD06/0021/0020. Sí

No study has systematically examined how researchers address cross-cultural adaptation of burnout. We conducted an integrative review to examine how researchers had adapted the instruments to the different contexts. We reviewed the Content Validity Indexing scores for the Maslach Burnout Inventory-Human Services Survey from the 12-country comparative nursing workforce study, RN4CAST. In the integrative review, multiple issues related to translation were found in existing studies. In the cross-cultural instrument analysis, 7 out of 22 items on the instrument received an extremely low kappa score. Investigators may need to employ more rigorous cross-cultural adaptation methods when attempting to measure burnout. This research is funded by the European Union’s Seventh Framework Programme FP7/2007-2013 under grantagreement n° 223468 (W. Sermeus, PI), the National Institute of Nursing Research, National Institutes of Health(P30NR05043 L. Aiken), and by the Spanish Agency Fondo de Investigación Sanitaria under grant agreementPI08/0599 (C. Fuentelsaz-Gallego, PI). Sí

PSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in several Leishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice. We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced in a L. tarentolae expression system. This was done in individuals cured of cutaneous leishmaniasis due to L. major (CCLm) or L. braziliensis (CCLb) or visceral leishmaniasis due to L. donovani (CVLd) and in healthy individuals. Healthy individuals were subdivided into immune (HHR-Lm and HHR-Li: Healthy High Responders living in an endemic area for L. major or L. infantum infection) or non immune/naive individuals (HLR: Healthy Low Responders), depending on whether they produce high or low levels of IFN-γ in response to Leishmania soluble antigen. Low levels of total IgG antibodies to LaPSA-38S were detected in sera from the studied groups. Interestingly, LaPSA-38S induced specific and significant levels of IFN-γ, granzyme B and IL-10 in CCLm, HHR-Lm and HHR-Li groups, with HHR-Li group producing TNF-α in more. No significant cytokine response was observed in individuals immune to L. braziliensis or L. donovani infection. Phenotypic analysis showed a significant increase in CD4+ T cells producing IFN-γ after LaPSA-38S stimulation, in CCLm. A high positive correlation was observed between the percentage of IFN-γ-producing CD4+ T cells and the released IFN-γ. We showed that the LaPSA-38S protein was able to induce a mixed Th1 and Th2/Treg cytokine response in individuals with immunity to L. major or L. infantum infection indicating that it may be exploited as a vaccine candidate. We also showed, to our knowledge for the first time, the capacity of Leishmania PSA protein to induce granzyme B production in humans with immunity to L. major and L. infantum infection. This study received financial support from EU's Seventh Framework Programme (FP7) (RAPSODI project, grant agreement number 223341). Sí

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges.This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to lowresponse rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people., We would like to thank all of the research assistants and interviewers in the study centers for their enormous efforts to ensure the research leading to these results has received funding from by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 22687 3 the MOBI-Kids project. International coordination of the project is partly supported by a grant from the Spanish Ministry of Science and Innovation (MICCIN). Australia: Australian participation in MOBI-Kids is supported by the Australian National Health and Medical Research Council with a five-year research grant (grant number: 546130 and Chief Investigators are: Malcolm R. Sim, Bruce Armstrong, Elizabeth Milne, and Geza Benke). Austria: Austrian participation in MOBI-Kids is partly supported by a grant from the Ministry of Science. Canada: Canadian participation in MOBI-Kids is supported by a university industry partnership grant from the Canadian Institutes of Health Research (CIHR), with the Canadian Wireless Telecommunications Association (CWTA) serving as the industrial partner. CWTA provides technical information on wireless telecommunications in Canada and facilitates access to billing records from Canadian network operators, but has no involvement in the design, conduct, analysis, or interpretation of the MOBI-KIDS study. Health Canada has also provided financial support to facilitate coordination between Canadian and international MOBI-Kids investigators. Daniel Krewski is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa. France: this project received funds from the French National Agency for Sanitary Safety of Food, Environment and Labour (ANSES, contract FSRF 2008-3), French National Cancer Institute (INCa), Pfizer Foundation and League against cancer. Germany: the German branch of MOBI-Kids is supported by the Federal Office for Radiation Protection. Greece: Greek participation is partially supported by ELKE (Special Account for Research Grants of the National and Kapodistrian University of Athens) and GGET (General Secretariat for Research and Technology). India: MOBI-Kids India is supported by the Board of Research in Nuclear Sciences (BRNS). Italy: Ministry of Health RF-2009-1546284. Japan: Japanese participation in MOBI-Kids is supported by the Ministry of Internal Affairs and Communications. Korea: MOBI-Kids Korea is financially supported by the Ministry of Science, ICT and Future Planning (MSIP), Korea in the ICT R&D Program. New Zealand: MOBI-Kids New Zealand is supported by grants from Cure Kids New Zealand and the New Zealand Health Research Council. Spain: Spanish participation is partially supported by the Spanish Health Research Fund (FIS PI10/02981), the Andalusian Consejeria de Salud (PI-0317/2010) and Conselleria de Sanitat, Generalitat Valenciana under grant number 025/2010. The Netherlands: Dutch participation in MOBI-KIDS is partly supported by The Netherlands Organisation for Health Research and Development (ZonMw) within the program Electromagnetic Fields and Health Research under grant number 85800001, and by the ODAS foundation, a private foundation supporting activities in the field of pediatric oncology and visual disabilities.

© 2014 Published by Elsevier Inc., A communication strategy was developed by The Consortium to Perform Human Biomonitoring on a European Scale (COPHES), as part of its objectives to develop a framework and protocols to enable the collection of comparable human biomonitoring data throughout Europe. The framework and protocols were tested in the pilot study DEMOCOPHES (Demonstration of a study to Coordinate and Perform Human biomonitoring on a European Scale). The aims of the communication strategy were to raise awareness of human biomonitoring, encourage participation in the study and to communicate the study results and their public health significance. It identified the audiences and key messages, documented the procedure for dissemination of results and was updated as the project progressed. A communication plan listed the tools and materials such as press releases, flyers, recruitment letters and information leaflets required for each audience with a time frame for releasing them. Public insight research was used to evaluate the recruitment material, and the feedback was used to improve the documents. Dissemination of results was coordinated in a step by step approach by the participating countries within DEMOCOPHES, taking into account specific national messages according to the needs of each country. Participants received individual results, unless they refused to be informed, along with guidance on what the results meant. The aggregate results and policy recommendations were then communicated to the general public and stakeholders, followed by dissemination at European level. Several lessons were learnt that may assist other future human biomonitoring studies. Recruitment took longer than anticipated and so social scientists, to help with community engagement, should be part of the research team from the start. As a European study, involving multiple countries, additional considerations were needed for the numerous organisations, different languages, cultures, policies and priorities. Therefore, communication documents should be seen as templates with essential information clearly indicated and the option for each country to tailor the material to reflect these differences. Future studies should consider setting up multidisciplinary networks of medical professionals and communication experts, and holding training workshops to discuss the interpretation of results and risk communication. Publicity and wide dissemination of the results helped to raise awareness of human biomonitoring to the general public, policy makers and other key stakeholders. Effective and timely communication, at all stages of a study, is essential if the potential of human biomonitoring research to improve public health is to be realised., COPHES was coordinated by BiPRO GmbH, Germany, with the University of Leuven, Belgium and was funded by DG Research in the Seventh Framework Programme (FP7/2007-2013). DEMOCOPHES (LIFE09 ENV/BE/000410) was coordinated by the Federal Public Service, Health, Food Chain Safety and Environment, Belgium and was jointly financed by the European Commission LIFE ┼ programme (50%) and partners from 21 countries. Information on the national co-funding institutions is accessible via the ‘Partners’ page of the DEMOCOPHES website. Each country obtained appropriate ethical approval for the DEMOCOPHES study. In the UK, the research was approved by the London Riverside South West Research Ethics Committee (reference 11/LO/1383) prior to commencement of the study.

Rare diseases (RD) refer to a collection of approximately 5,000–8,000 individual diseases that have a low prevalence and are often genetic in origin. While RD can manifest throughout life, they frequently affect children and newborns. Common characteristics include being severe, disabling, life-threatening, degenerative and affecting different organ systems. The burden of RD is often exacerbated by a lack of specific treatments. Whilst there is etiological heterogeneity, there is overlap in cellular and molecular pathways. Amongst specialists, there is legitimate hope that based on genetic knowledge and pathway definition, a new medical classification system, currently called “precision medicine”, will be developed, which may change our view on how to apply shared therapeutic targets. Thus, collection of clinical and genetic data and biospecimens (in biobanks) will play an increasing role in diagnoses and development of therapies for RD. Biobanks are maintained collaboratively by researchers or their institutions, and involve a delicate balance between health policy objectives, academic research, public good outcomes, and community trust. Due to the nature of RD, international cooperation is critical for sharing limited numbers of RD samples and achieving a critical mass. Here we review the current and future direction of RD biobanks and discuss research and development stemming from the use of biospecimens to improve management of RD. The authors acknowledge the financial support of the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement numbers 305444 (RD-Connect), 305608 (EURenOmics), and 305121 (NeurOmics); TREAT-NMD operating grants, FP6 LSHM-CT-2006-036825, 20123307 UNEW_FY2013; Telethon grant GTB12001 to TNGB, and AFM 16104; EUROPLAN 2012–2015, coordinated by Italian National Institute of Health-Italian National Centre for Rare Diseases, included in the EUCERD Joint Action (grant number 2011 22 01, cofunded by the European Union Commission (DG-SANCO); Office of Rare Diseases Research at National Center for Advancing Translational Sciences/National Institutes of Health; European Organisation for Rare Diseases; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-ERIC); ISBER/ESBB Rare Diseases Working Group; and Public Population Project in Genomics and Society (P3G). Sí

The novel slow-grower Mycobacterium kumamotonense was previously misidentified as Mycobacteriumtuberculosis complex using commercial probes. Similarly to other slow-growers that cross-react with the tuberclebacilli using commercial probes, M. kumamotonense is carrying two copies of the ribosomal RNA operon (rrn) pergenome. Analysis of the corresponding rrn regions allowed the identification of sequences putatively involved in thatcross-reactivity. We thank E. Palenque for providing the M. kumamotonense strain. The results has received funding from the European Community's Seventh Framework Programme (FP7-HEALTH-2007) under grant agreement n° 200999 and supported by Centro de Estudios de América Latina (UAM-BSCH). Sí

Background The mode of reproduction in Leishmania spp has been argued to be essentially clonal. However, recent data (genetic analysis of populations and co-infections in sand flies) have proposed the existence of a non-obligate sexual cycle in the extracellular stage of the parasite within the sand fly vector. In this article we propose the existence of intraclonal genetic exchange in the natural vector of Leishmania infantum. Methodology/Principal findings We have developed transgenic L. infantum lines expressing drug resistance markers linked to green and red fluorescent reporters. We hypothesized whether those cells with identical genotype can recognize each other and mate. Both types of markers were successfully exchanged within the sand fly midgut of the natural vector Phlebotomus perniciosus when individuals from these species were fed with a mixture of parental clones. Using the yellow phenotype and drug resistance markers, we provide evidence for genetic exchange in L. infantum. The hybrid progeny appeared to be triploid based on DNA content analysis. The hybrid clone analyzed was stable throughout the complete parasite life cycle. The progress of infections by the hybrid clone in BALB/c mice caused a reduction in parasite loads in both spleen and liver, and provided weight values similar to those obtained with uninfected mice. Spleen arginase activity was also significantly reduced relative to parental strains. Conclusions/Significance A L. infantum hybrid lineage was obtained from intraclonal genetic exchange within the midgut of the natural vector, suggesting the ability of this parasite to recognize the same genotype and mate. The yellow hybrid progeny is stable throughout the whole parasite life cycle but with a slower virulence, which correlates well with the lower arginase activity detected both in vitro and in vivo infections., Author Summary Leishmaniasis is one of the most important human neglected parasitic diseases worldwide. When it appears in the visceral form it has the most aggressive outcome, and is fatal if left untreated. The current mode of reproduction of these parasites is under discussion, from propagation to a sexual reproduction process. Here, we describe for the first time the intraclonal genetic exchange between two transgenic L. infantum fluorescent strains in their natural vector Phlebotomus perniciosus. Hybrid clones displayed parental phenotypic traits such as yellow fluorescence and double-drug resistance. The DNA content of the hybrid lineage was 3n, while the parental lineage was 2n. The hybrid clone was able to undergo all the morphogenic transitions required to complete a full life cycle to infect a susceptible mammalian host, and maintained both phenotype and genotype. However, its capacity to generate the same lesions as those observed with parental clones in BALB/c mice was reduced.

WOS:000321397900001 (Nº de Acesso Web of Science) Background Hospital governance increasingly combines management and professional self-governance. This article maps the new emergent modes of control in a comparative perspective and aims to better understand the relationship between medicine and management as hybrid and context-dependent. Theoretically, we critically review approaches into the managerialism-professionalism relationship; methodologically, we expand cross-country comparison towards the meso-level of organisations; and empirically, the focus is on processes and actors in a range of European hospitals. Methods The research is explorative and was carried out as part of the FP7 COST action IS0903 Medicine and Management, Working Group 2. Comprising seven European countries, the focus is on doctors and public hospitals. We use a comparative case study design that primarily draws on expert information and document analysis as well as other secondary sources. Results The findings reveal that managerial control is not simply an external force but increasingly integrated in medical professionalism. These processes of change are relevant in all countries but shaped by organisational settings, and therefore create different patterns of control: (1) ‘integrated’ control with high levels of coordination and coherent patterns for cost and quality controls; (2) ‘partly integrated’ control with diversity of coordination on hospital and department level and between cost and quality controls; and (3) ‘fragmented’ control with limited coordination and gaps between quality control more strongly dominated by medicine, and cost control by management. Conclusions Our comparison highlights how organisations matter and brings the crucial relevance of ‘coordination’ of medicine and management across the levels (hospital/department) and the substance (cost/quality-safety) of control into perspective. Consequently, coordination may serve as a taxonomy of emergent modes of control, thus bringing new directions for cost-efficient and quality-effective hospital governance into perspective.

BACKGROUND: Self-management support is a key component of effective chronic care management, yet in practice appears to be the least implemented and most challenging. This study explores whether and how self-management support is integrated into chronic care approaches in 13 European countries. In addition, it investigates the level of and barriers to implementation of support strategies in health care practice. METHODS: We conducted a review among the 13 participating countries, based on a common data template informed by the Chronic Care Model. Key informants presented a sample of representative chronic care approaches and related self-management support strategies. The cross-country review was complemented by a Dutch case study of health professionals' views on the implementation of self-management support in practice. RESULTS: Self-management support for chronically ill patients remains relatively underdeveloped in Europe. Similarities between countries exist mostly in involved providers (nurses) and settings (primary care). Differences prevail in mode and format of support, and materials used. Support activities focus primarily on patients' medical and behavioral management, and less on emotional management. According to Dutch providers, self-management support is not (yet) an integral part of daily practice; implementation is hampered by barriers related to, among others, funding, IT and medical culture. CONCLUSIONS: Although collaborative care for chronic conditions is becoming more important in European health systems, adequate self-management support for patients with chronic disease is far from accomplished in most countries. There is a need for better understanding of how we can encourage both patients and health care providers to engage in productive interactions in daily chronic care practice, which can improve health and social outcomes. This study was conducted with support from the DISMEVAL consortium. It draws on additional information from DISMEVAL partners and key informants who contributed information on approaches to chronic disease management in selected countries: Fadila Farsi, Hélène Labrosse (DISMEVAL partner, Centre Anticancereux Leon Berard: cancer networks France), Taavi Lai (Estonia, Latvia, Lithuania); Péter Gaál and Márton Csere (Hungary); Walter Ricciardi, Antonio G. De Belvis, Maria Lucia Specchia, TD Luca Valerio (Italy); Liubove Murauskiene, Marija Veniute (Lithuania); and Isabelle Peytremann-Bridevaux, Bernard Burnand and Ignazio Cassis (Switzerland); and was undertaken in cooperation with nine Dutch primary care groups: Regionale Huisartsenzorg Maastricht/Heuvelland, Diabetes Zorgsysteem West-Friesland, Groninger Huisartsen Coöperatie, Huisartsenzorg Drenthe Medische Eerstelijns Ketenzorg, Eerstelijns Centrum Tiel, Coöperatie Zorgcirkels Woerden, Zorggroep Zwolle, Huisartsenketenzorg Arnhem, Cohesie Cure & Care. The DISMEVAL-project was funded under the European Commission’s Seventh Framework Programme (FP7) (grant no. 223277). See www.dismeval. eu for additional information. Sí

We interpret here the variability of levels of carbonaceous aerosols based on a 12 yr database from 78 monitoring stations across Spain specially compiled for this article. Data did not evidence any spatial trends of carbonaceous aerosols across the country. Conversely, results show marked differences in average concentrations from the cleanest, most remote sites (around 1 μg m−3 of non-mineral carbon (nmC), mostly made of organic carbon (OC) with very little elemental carbon (EC), around 0.1 μg m−3; OC / EC = 12–15), to the highly polluted major cities (8–10 μg m−3 of nmC; 3–4 μg m−3 of EC; 4–5 μg m−3 of OC; OC / EC = 1–2). Thus, urban (and very specific industrial) pollution was found to markedly increase levels of carbonaceous aerosols in Spain, with much lower impact of biomass burning and of biogenic emissions. Correlations between yearly averaged OC / EC and EC concentrations adjust very well to a potential equation (OC = 3.37 EC0.326, R2 = 0.8). A similar equation is obtained when including average concentrations obtained at other European sites (OC = 3.60EC0.491, R2 = 0.7). A clear seasonal variability in OC and EC concentrations was detected. Both OC and EC concentrations were higher during winter at the traffic and urban sites, but OC increased during the warmer months at the rural sites. Hourly equivalent black carbon (EBC) concentrations at urban sites accurately depict road traffic contributions, varying with distance from road, traffic volume and density, mixing-layer height and wind speed. Weekday urban rush-hour EBC peaks are mimicked by concentrations of primary gaseous emissions from road traffic, whereas a single midday peak is characteristic of remote and rural sites. Decreasing annual trends for carbonaceous aerosols were observed between 1999 and 2011 at a large number of stations, probably reflecting the impact of the EURO4 and EURO5 standards in reducing the diesel PM emissions. This has resulted in some cases in an increasing trend for NO2 / (OC + EC) ratios as these standards have been much less effective for the abatement of NOx exhaust emissions in passenger diesel cars. This study concludes that EC, EBC, and especially nmC and OC + EC are very good candidates for new air quality standards since they cover both emission impact and health-related issues., This study was supported by the Ministry of Agriculture, Food and the Environment of Spain, the Ministry of Economy and Competitivity (MINECO) of Spain and FEDER funds under the projects VAMOS (CGL2010-19464/CLI), PRISMA (CGL2012-39623-C02-01), GRACCIE (CSD 2007-00067), POLLINDUST (CGL2011-26259) and UHU (CGL2011- 28025); and by AGAUR-Generalitat de Catalunya (2009 SGR 00008) and LIFE + AIRUSE (LIFE11-ENV/ES/000584). The Montseny site forms part of the ACTRIS network (European Union Seventh Framework Programme (FP7/2007-2013) project no. 262254), formerly EUSAAR (EUSAAR R113-CT-2006-026140). Funding was also received for the Andalucía sites from projects 2007-RNM027329 and 2011-RNM7800 (Department of Innovation Science and Enterprise, Andalusia Autonomous Government) M. C. Minguillón was funded by the JAE-Doc CSIC programme, co-funded by the European Social Fund (ESF).

© 2013 Bellanger et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Background: Due to global mercury pollution and the adverse health effects of prenatal exposure to methylmercury (MeHg), an assessment of the economic benefits of prevented developmental neurotoxicity is necessary for any cost-benefit analysis. Methods: Distributions of hair-Hg concentrations among women of reproductive age were obtained from the DEMOCOPHES project (1,875 subjects in 17 countries) and literature data (6,820 subjects from 8 countries). The exposures were assumed to comply with log-normal distributions. Neurotoxicity effects were estimated from a linear dose-response function with a slope of 0.465 Intelligence Quotient (IQ) point reduction per μg/g increase in the maternal hair-Hg concentration during pregnancy, assuming no deficits below a hair-Hg limit of 0.58 μg/g thought to be safe. A logarithmic IQ response was used in sensitivity analyses. The estimated IQ benefit cost was based on lifetime income, adjusted for purchasing power parity. Results: The hair-mercury concentrations were the highest in Southern Europe and lowest in Eastern Europe. The results suggest that, within the EU, more than 1.8 million children are born every year with MeHg exposures above the limit of 0.58 μg/g, and about 200,000 births exceed a higher limit of 2.5 μg/g proposed by the World Health Organization (WHO). The total annual benefits of exposure prevention within the EU were estimated at more than 600,000 IQ points per year, corresponding to a total economic benefit between €8,000 million and €9,000 million per year. About four-fold higher values were obtained when using the logarithmic response function, while adjustment for productivity resulted in slightly lower total benefits. These calculations do not include the less tangible advantages of protecting brain development against neurotoxicity or any other adverse effects. Conclusions: These estimates document that efforts to combat mercury pollution and to reduce MeHg exposures will have very substantial economic benefits in Europe, mainly in southern countries. Some data may not be entirely representative, some countries were not covered, and anticipated changes in mercury pollution all suggest a need for extended biomonitoring of human MeHg exposure., Exposure data were contributed from the DEMOCOPHES project (LIFE09 ENV/BE/000410) carried out thanks to joint financing of 50% from the European Commission programme LIFE + along with 50% from each participating country (see the national implementation websites accessible via http://www.eu-hbm.info/democophes/project-partners). Special thanks go to the national implementation teams. The COPHES project that provided the operational and scientific framework was funded by the European Community's Seventh Framework Programme - DG Research (Grant Agreement Number 244237). Additional exposure data were supported by the PHIME project (FOOD-CT-2006-016253) and ArcRisk (GA 226534). We are grateful to Yue Gao and colleagues for sharing Flanders exposure data from the Flemish Center of Expertise on Environment and Health, financed and steered by the Ministry of the Flemish Community. National exposure data from the 2006–2007 French national survey on nutrition and health (Etude Nationale Nutrition Santé) were made available by Nadine Fréry, French Institute for Public Health Surveillance. Data from the Norwegian Mother and Child Cohort Study (a validation sample) were kindly provided by Anne Lise Brantsæter, National Institute of Public Health, Oslo. The UK mercury data were obtained from the ALSPAC pregnancy blood analyses carried out at the Centers for Disease Control and Prevention with funding from NOAA (the US National Oceanographic and Atmospheric Administration). The studies in the Faroe Islands were supported by the US National Institutes of Health (ES009797 and ES012199). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.

Background: Mosquito feeding behaviour determines the degree of vector–host contact and may have a serious impact on the risk of West Nile virus (WNV) epidemics. Feeding behaviour also interacts with other biotic and abiotic factors that affect virus amplification and transmission. Methodology/Principal Findings: We identified the origin of blood meals in five mosquito species from three different wetlands in SW Spain. All mosquito species analysed fed with different frequencies on birds, mammals and reptiles. Both ‘mosquito species’ and ‘locality’ explained a similar amount of variance in the occurrence of avian blood meals. However, ‘season of year’ was the main factor explaining the presence of human blood meals. The differences in diet resulted in a marked spatial heterogeneity in the estimated WNV transmission risk. Culex perexiguus, Cx. modestus and Cx. pipiens were the main mosquito species involved in WNV enzootic circulation since they feed mainly on birds, were abundant in a number of localities and had high vector competence. Cx. perexiguus may also be important for WNV transmission to horses, as are Cx. pipiens and Cx. theileri in transmission to humans. Estimates of the WNV transmission risk based on mosquito diet, abundance and vector competence matched the results of previous WNV monitoring programs in the area. Our sensitivity analyses suggested that mosquito diet, followed by mosquito abundance and vector competence, are all relevant factors in understanding virus amplification and transmission risk in the studied wild ecosystems. At some of the studied localities, the risk of enzootic circulation of WNV was relatively high, even if the risk of transmission to humans and horses was less. Conclusions/Significance: Our results describe for first time the role of five WNV candidate vectors in SW Spain. Interspecific and local differences in mosquito diet composition has an important effect on the potential transmission risk of WNV to birds, horses and humans

Understanding the role of humans in the dispersal of predominately animal pathogens is essential for their control. We used newly developed Bayesian phylogeographic methods to unravel the dynamics and determinants of the spread of dog rabies virus (RABV) in North Africa. Each of the countries studied exhibited largely disconnected spatial dynamics with major geo-political boundaries acting as barriers to gene flow. Road distances proved to be better predictors of the movement of dog RABV than accessibility or raw geographical distance, with occasional long distance and rapid spread within each of these countries. Using simulations that bridge phylodynamics and spatial epidemiology, we demonstrate that the contemporary viral distribution extends beyond that expected for RABV transmission in African dog populations. These results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens., Author Summary At least 15 million doses of anti-rabies post-exposure prophylaxis are administered annually worldwide, and an estimated 55,000 people die of rabies every year. Over 99% of these deaths occur in developing countries, predominantly in Asia and in Africa where rabies is endemic in domestic dogs. Despite the global health burden due to rabies, little is known about the patterns of the spread of dog rabies in these endemic regions. We used recently developed Bayesian analytical methods to unravel the dynamics and determinants of the spatial diffusion of dog rabies viruses in North Africa based on viral genetic data. Our analysis reveals a combination of restricted spread across administrative borders, the occasional long-distance movement of rabies viruses, and a strong fit between spatial spread of the virus and road distances between localities. Together, these data indicate that by transporting dogs, humans have played a key role in the dispersal of a major animal pathogen. Our studies therefore provide essential new information on the transmission dynamics of rabies in Africa, and in doing so will greatly assist in future intervention strategies.

BACKGROUND: To estimate the incidence of hazardous drinking in middle-aged people during an economic recession and ascertain whether individual job loss and contextual changes in unemployment influence the incidence rate in that period. METHODS: Longitudinal study based on two waves of the SHARE project (Survey of Health, Ageing and Retirement in Europe). Individuals aged 50-64 years from 11 European countries, who were not hazardous drinkers at baseline (n = 7,615), were selected for this study. We estimated the cumulative incidence of hazardous drinking (≥40g and ≥20g of pure alcohol on average in men and women, respectively) between 2006 and 2012. Furthermore, in the statistical analysis, multilevel Poisson regression models with robust variance were fitted and obtained Risk Ratios (RR) and their 95% Confidence Intervals (95%CI). RESULTS: Over a 6-year period, 505 subjects became hazardous drinkers, with cumulative incidence of 6.6 per 100 persons between 2006 and 2012 (95%CI:6.1-7.2). Age [RR = 1.02 (95%CI:1.00-1.04)] and becoming unemployed [RR = 1.55 (95%CI:1.08-2.23)] were independently associated with higher risk of becoming a hazardous drinker. Conversely, having poorer self-perceived health was associated with lower risk of becoming a hazardous drinker [RR = 0.75 (95%CI:0.60-0.95)]. At country-level, an increase in the unemployment rate during the study period [RR = 1.32 (95%CI:1.17-1.50)] and greater increases in the household disposable income [RR = 0.97 (95%CI:0.95-0.99)] were associated with risk of becoming a hazardous drinker. CONCLUSIONS: Job loss among middle-aged individuals during the economic recession was positively associated with becoming a hazardous drinker. Changes in country-level variables were also related to this drinking pattern. This work was supported by the Health Strategic Action grant [grant number PI13/00183] and the Spanish Network on Addictive Disorders [grant numbers RD06/0001/1018, and RD12/0028/0018]. Moreover, this paper uses data from SHARE Wave 4 release 1.1.1, as of March 28th 2013 (DOI: 10.6103/SHARE.w4.111) and SHARE Wave 2 release 2.6.0, as of November 29th (DOI: 10.6103/SHARE.w2.260). The SHARE data collection has been primarily funded by the European Commission through the 5th Framework Programme (project QLK6-CT-2001-00360 in the thematic programme Quality of Life), through the 6th Framework Programme (projects SHARE-I3, RII-CT-2006-062193, COMPARE, CIT5- CT-2005-028857, and SHARELIFE, CIT4- CT-2006-028812) and through the 7th Framework Programme (SHARE-PREP, N° 211909, SHARE-LEAP, N° 227822 and SHARE M4, N° 261982). Additional funding from the U.S. National Institute on Aging (U01 AG09740-13S2, P01 AG005842, P01 AG08291, P30 AG12815, R21 AG025169, Y1-AG-4553-01, IAG BSR06-11 and OGHA 04-064) and the German Ministry of Education and Research as well as from various national sources is gratefully acknowledged (see www.share-project.org for a full list of funding institutions). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Summary: Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation. Notably, we found that 5-hydroxymethylcytosine (5hmC) is the most-influential hub of this network, connecting DNA demethylation to nucleosome remodeling complexes and to key transcription factors of pluripotency. Moreover, an evolutionary analysis revealed a central role of 5hmC in the co-evolution of chromatin-related proteins. Further analysis of regions where 5hmC co-localizes with specific interactors shows that each interaction points to chromatin remodeling, stemness, differentiation, or metabolism. Our results highlight the importance of cytosine modifications in the epigenetic communication of ESCs. : 5-hydroxymethylcytosine (5hmC) plays a key role in the epigenomic communication network of embryonic stem cells. Juan et al. build a communication network based in co-localization of epigenomic data and literature. The analysis of the network and its components reveals that proteins reading and editing 5hmC co-evolve and serve as links between diverse molecular processes.

[Background] Genomic studies of endangered species provide insights into their evolution and demographic history, reveal patterns of genomic erosion that might limit their viability, and offer tools for their effective conservation. The Iberian lynx (Lynx pardinus) is the most endangered felid and a unique example of a species on the brink of extinction., [Results] We generate the first annotated draft of the Iberian lynx genome and carry out genome-based analyses of lynx demography, evolution, and population genetics. We identify a series of severe population bottlenecks in the history of the Iberian lynx that predate its known demographic decline during the 20th century and have greatly impacted its genome evolution. We observe drastically reduced rates of weak-to-strong substitutions associated with GC-biased gene conversion and increased rates of fixation of transposable elements. We also find multiple signatures of genetic erosion in the two remnant Iberian lynx populations, including a high frequency of potentially deleterious variants and substitutions, as well as the lowest genome-wide genetic diversity reported so far in any species., [Conclusions] The genomic features observed in the Iberian lynx genome may hamper short- and long-term viability through reduced fitness and adaptive potential. The knowledge and resources developed in this study will boost the research on felid evolution and conservation genomics and will benefit the ongoing conservation and management of this emblematic species., The financial support for this work was provided by Banco de Santander, CSIC, and Fundación General CSIC through a “Proyectos Cero” grant. FC and BM-C were hired under the EcoGenes project funded by the European FP7 program (264125-FP7-REGPOT-2010-1) and AVl and FCa under the INB Project PT13/0001/ 0021 (ISCIII - Subdirección General de Evaluación y Fomento de la Investigación/ FEDER “Una Manera de hacer Europa”). EBD-CSIC and CRG received support from the Spanish Ministry of Economy and Competitiveness under the “Centro de Excelencia Severo Ochoa 2013-2017” program, grants SEV-2012-0262 and SEV-2012-0208. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

We evaluated the impact of coding variation on HIV control by exome sequencing with emphasis on known HIV host dependency factors. Outside of the MHC region, exonic variants with large effect sizes are not a major contributor to HIV control., Background Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.