The changing nature of risk and risk management: the challenge of borders, uncertainty and resilience

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Presymptomatic risk assessment for chronic non-communicable diseases

The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.Comment: Plos ONE paper. Previous version was withdrawn to be updated by the journal's pdf versio

Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection

Although certain microbial lipids are toxins, the structural features important for cytotoxicity remain unknown. Increased functional understanding is essential for developing therapeutics against toxic microbial lipids. Group B Streptococci (GBS) are bacteria associated with preterm births, stillbirths, and severe infections in neonates and adults. GBS produce a pigmented, cytotoxic lipid, known as granadaene. Despite its importance to all manifestations of GBS disease, studies towards understanding granadaene’s toxic activity are hindered by its instability and insolubility in purified form. Here, we report the synthesis and screening of lipid derivatives inspired by granadaene, which reveal features central to toxin function, namely the polyene chain length. Furthermore, we show that vaccination with a non-toxic synthetic analog confers the production of antibodies that inhibit granadaene-mediated hemolysis ex vivo and diminish GBS infection in vivo. This work provides unique structural and functional insight into granadaene and a strategy to mitigate GBS infection, which will be relevant to other toxic lipids encoded by human pathogens.This work was supported by funding from the National Institutes of Health Grants R01AI112619, R01AI133976, R01AI100989, and R21AI125907 and seed funds from Seattle Childrens Research Institute to L.

Long term extension of a randomised controlled trial of probiotics using electronic health records

Most randomised controlled trials (RCTs) are relatively short term and, due to costs and available resources, have limited opportunity to be re-visited or extended. There is no guarantee that effects of treatments remain unchanged beyond the study. Here, we illustrate the feasibility, benefits and cost-effectiveness of enriching standard trial design with electronic follow up. We completed a 5-year electronic follow up of a RCT investigating the impact of probiotics on asthma and eczema in children born 2005-2007, with traditional fieldwork follow up to two years. Participants and trial outcomes were identified and analysed after five years using secure, routine, anonymised, person-based electronic health service databanks. At two years, we identified 93% of participants and compared fieldwork with electronic health records, highlighting areas of agreement and disagreement. Retention of children from lower socio-economic groups was improved, reducing volunteer bias. At 5 years we identified a reduced 82% of participants. These data allowed the trial's first robust analysis of asthma endpoints. We found no indication that probiotic supplementation to pregnant mothers and infants protected against asthma or eczema at 5 years. Continued longer-term follow up is technically straightforward

A mouse model reproducing the pathophysiology of neonatal group B streptococcal infection

Group B streptococcal (GBS) meningitis remains a devastating disease. The absence of an animal model reproducing the natural infectious process has limited our understanding of the disease and, consequently, delayed the development of effective treatments. We describe here a mouse model in which bacteria are transmitted to the offspring from vaginally colonised pregnant females, the natural route of infection. We show that GBS strain BM110, belonging to the CC17 clonal complex, is more virulent in this vertical transmission model than the isogenic mutant BM110∆cylE, which is deprived of hemolysin/cytolysin. Pups exposed to the more virulent strain exhibit higher mortality rates and lung inflammation than those exposed to the attenuated strain. Moreover, pups that survive to BM110 infection present neurological developmental disability, revealed by impaired learning performance and memory in adulthood. The use of this new mouse model, that reproduces key steps of GBS infection in newborns, will promote a better understanding of the physiopathology of GBS-induced meningitis.The authors gratefully acknowledge the help of Encarnaca̧ ̃o Ribeiro for excellent technical assistance, Joana Tavares for assisting with IVIS Lumina LT, Susana Roque for the luminex instrument experiments, the Molecular Microbiology group at i3S for microscope use, and the Portuguese architect and artist Gil Ferreira da Silva for the artworks included in the last figure. This work was supported by funds from Foundation for Science and Technology (FCT), European Regional Development Fund (FEDER) and Compete under project POCI-01-0145-FEDER-016607 (PTDC/IMI-MIC/1049/2014) and from the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). T.S. and A.M. were supported by Investigador FCT (IF/00875/2012 and IF/00753/2014), POPH and Fundo Social Europeu. E.B.A. and C.C.P. hold postdoctoral fellowships from FCT (PTDC/IMI-MIC/1049/2014 and SFRH/BPD/91962/2012). Ar.F. and P.T.C. were supported by Laboratoire d’Excellence (LABEX) Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID).info:eu-repo/semantics/publishedVersio

Mouse DRG Cell Line with Properties of Nociceptors

In vitro cell lines from DRG neurons aid drug discovery because they can be used for early stage, high-throughput screens for drugs targeting pain pathways, with minimal dependence on animals. We have established a conditionally immortal DRG cell line from the Immortomouse. Using immunocytochemistry, RT-PCR and calcium microfluorimetry, we demonstrate that the cell line MED17.11 expresses markers of cells committed to the sensory neuron lineage. Within a few hours under differentiating conditions, MED17.11 cells extend processes and following seven days of differentiation, express markers of more mature DRG neurons, such as NaV1.7 and Piezo2. However, at least at this time-point, the nociceptive marker NaV1.8 is not expressed, but the cells respond to compounds known to excite nociceptors, including the TRPV1 agonist capsaicin, the purinergic receptor agonist ATP and the voltage gated sodium channel agonist, veratridine. Robust calcium transients are observed in the presence of the inflammatory mediators bradykinin, histamine and norepinephrine. MED17.11 cells have the potential to replace or reduce the use of primary DRG culture in sensory, pain and developmental research by providing a simple model to study acute nociception, neurite outgrowth and the developmental specification of DRG neurons

Metacarpal trabecular bone varies with distinct hand-positions used in hominid locomotion

Trabecular bone remodels during life in response to loading and thus should, at least in part, reflect potential variation in the magnitude, frequency and direction of joint loading across different hominid species. Here we analyse the trabecular structure across all non-pollical metacarpal distal heads (Mc2-5) in extant great apes, expanding on previous volume of interest and whole-epiphysis analyses that have largely focussed on only the first or third metacarpal. Specifically, we employ both a univariate statistical mapping and a multivariate approach to test for both inter-ray and interspecific differences in relative trabecular bone volume fraction (RBV/TV) and degree of anisotropy (DA) in Mc2-5 subchondral trabecular bone. Results demonstrate that while DA values only separate Pongo from African apes (Pan troglodytes, Pan paniscus, Gorilla gorilla), RBV/TV distribution varies with the predicted loading of the metacarpophalangeal (McP) joints during locomotor behaviours in each species. Gorilla exhibits a relatively dorsal distribution of RBV/TV consistent with habitual hyper-extension of the McP joints during knuckle-walking, whereas Pongo has a palmar distribution consistent with flexed McP joints used to grasp arboreal substrates. Both Pan species possess a disto-dorsal distribution of RBV/TV, compatible with multiple hand postures associated with a more varied locomotor regime. Further inter-ray comparisons reveal RBV/TV patterns consistent with varied knuckle-walking postures in Pan species in contrast to higher RBV/TV values toward the midline of the hand in Mc2 and Mc5 of Gorilla, consistent with habitual palm-back knuckle-walking. These patterns of trabecular bone distribution and structure reflect different behavioural signals that could be useful for determining the behaviours of fossil hominins

Disease awareness campaigns in printed and online media in Latvia : Cross-sectional study on consistency with WHO ethical criteria for medicinal drug promotion and European standards

Funding Information: Teresa Leonardo Alves declares no conflicts of interest. She has worked in the past for not-for-profit organizations which have advocated against the relaxation of the direct-to-consumer advertising ban in the European Union, namely Prescrire (2012–2016) and Health Action International (2006–2011). Elita Poplavska is a board member of not-for-profit organizations - Health Projects for Latvia and Health Action International (which aim to promote rational use of medicines and reduce influence of pharmaceutical advertisement). Signe Mezinska is a board member of not-for-profit organizations - Health Projects for Latvia and Health Action International (which aim to promote rational use of medicines and reduce influence of pharmaceutical advertisement). Ieva Salmane-Kulikovska declares no conflicts of interest. Liga Andersone declares no conflicts of interest. Aukje Mantel-Teeuwisse is the Managing Director of the WHO Collaborating Centre for Pharmaceutical Policy & Regulation, which receives no direct funding or donations from private parties, including the pharmaceutical industry. Research funding from public-private partnerships, e.g. IMI, Lygature (https://www.lygature.org), is accepted under the condition that no company-specific product or company-related study is conducted. The Centre has received unrestricted research funding from public sources, e.g. Netherlands Organisation for Health Research and Development (ZonMW), Zorg Instituut Nederland (ZIN), the Dutch Medicines Evaluation Board (MEB), and the Dutch Ministry of Health. Barbara Mintzes has acted as an expert witness on behalf of plaintiffs in a Canadian class action suit on cardiovascular risks of testosterone therapy. Publisher Copyright: © 2018 The Author(s).Background: European legislation prohibits direct-to-consumer advertising of prescription medicines, but allows drug manufacturers to provide information to the public on health and diseases. Our aim was to measure the frequency of disease awareness campaigns in Latvian media and assess their compliance with international and European standards. Methods: Materials on health/disease and treatments were collected between April and September 2015 from 12 newspapers and magazines and six online portals. Disease awareness campaigns were assessed using a previously developed instrument based on the WHO Ethical Criteria for Medicinal Drug promotion and European standards (EU law and pharmaceutical industry self-regulatory guidelines). Collected materials were used to examine the information provided on medical conditions and their diagnosis and treatment. The inter-rater reliability was calculated. Results: We collected 263 materials from print (n = 149) and online media (n = 114); 94 were news items and 169 were disease-awareness advertisements. Cancer, cardiovascular problems, allergies and respiratory diseases were common topics. Of the 157 campaigns assessed, non-compliance was identified in 149 cases (inter-rater reliability 90%), mainly due to misleading or incomplete information, lack of balance and the absence of a listed author/sponsor. Six disease awareness campaigns directly mentioned a pharmaceutical product by brand name and other four included the logo or name of a manufacturer, referred to a condition and indirectly mentioned a treatment, all in contravention with European law. Conclusions: The compliance of disease awareness campaigns in Latvian media with international and European standards is low. This raises concerns about the nature of information being conveyed. Through lack of balance, missing sponsorship information, and misleading or incomplete information, these campaigns could contribute to inaccurate self-diagnosis and generate demand among those who might not need medical treatment.publishersversionPeer reviewe

Glycosaminoglycan Binding Facilitates Entry of a Bacterial Pathogen into Central Nervous Systems

Certain microbes invade brain microvascular endothelial cells (BMECs) to breach the blood-brain barrier (BBB) and establish central nervous system (CNS) infection. Here we use the leading meningitis pathogen group B Streptococcus (GBS) together with insect and mammalian infection models to probe a potential role of glycosaminoglycan (GAG) interactions in the pathogenesis of CNS entry. Site-directed mutagenesis of a GAG-binding domain of the surface GBS alpha C protein impeded GBS penetration of the Drosophila BBB in vivo and diminished GBS adherence to and invasion of human BMECs in vitro. Conversely, genetic impairment of GAG expression in flies or mice reduced GBS dissemination into the brain. These complementary approaches identify a role for bacterial-GAG interactions in the pathogenesis of CNS infection. Our results also highlight how the simpler yet genetically conserved Drosophila GAG pathways can provide a model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications

Group B <em>Streptococcus </em>engages an inhibitory siglec through sialic acid mimicry to blunt innate immune and inflammatory responses <em>in vivo</em>

Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection