A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.

BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care

Meeting Report: Hazard Assessment for Nanoparticles—Report from an Interdisciplinary Workshop

In this report we present the findings from a nanotoxicology workshop held 6–7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders

Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA)

The International Agency for Research on Cancer (IARC) Monographs Programme identifies chemicals, drugs, mixtures, occupational exposures, lifestyles and personal habits, and physical and biological agents that cause cancer in humans and has evaluated about 1000 agents since 1971. Monographs are written by ad hoc Working Groups (WGs) of international scientific experts over a period of about 12 months ending in an eight-day meeting. The WG evaluates all of the publicly available scientific information on each substance and, through a transparent and rigorous process,1 decides on the degree to which the scientific evidence supports that substance's potential to cause or not cause cancer in humans. For Monograph 112,2 17 expert scientists evaluated the carcinogenic hazard for four insecticides and the herbicide glyphosate.3 The WG concluded that the data for glyphosate meet the criteria for classification as a probable human carcinogen. The European Food Safety Authority (EFSA) is the primary agency of the European Union for risk assessments regarding food safety. In October 2015, EFSA reported4 on their evaluation of the Renewal Assessment Report5 (RAR) for glyphosate that was prepared by the Rapporteur Member State, the German Federal Institute for Risk Assessment (BfR). EFSA concluded that ?glyphosate is unlikely to pose a carcinogenic hazard to humans and the evidence does not support classification with regard to its carcinogenic potential?. Addendum 1 (the BfR Addendum) of the RAR5 discusses the scientific rationale for differing from the IARC WG conclusion. Serious flaws in the scientific evaluation in the RAR incorrectly characterise the potential for a carcinogenic hazard from exposure to glyphosate. Since the RAR is the basis for the European Food Safety Agency (EFSA) conclusion,4 it is critical that these shortcomings are corrected

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p