A Review of Nitrates in Drinking Water: Maternal Exposure and Adverse Reproductive and Developmental Outcomes

In this review we present an update on maternal exposure to nitrates in drinking water in relation to possible adverse reproductive and developmental effects, and also discuss nitrates in drinking water in the United States. The current standard for nitrates in drinking water is based on retrospective studies and approximates a level that protects infants from methemoglobinemia, but no safety factor is built into the standard. The current standard applies only to public water systems. Drinking water source was related to nitrate exposure (i.e., private systems water was more likely than community system water to have nitrate levels above the maximum contaminant limit). Animal studies have found adverse reproductive effects resulting from higher doses of nitrate or nitrite. The epidemiologic evidence of a direct exposure–response relationship between drinking water nitrate level and adverse reproductive effect is still not clear. However, some reports have suggested an association between exposure to nitrates in drinking water and spontaneous abortions, intrauterine growth restriction, and various birth defects. Uncertainties in epidemiologic studies include the lack of individual exposure assessment that would rule out confounding of the exposure with some other cause. Nitrates may be just one of the contaminants in drinking water contributing to adverse outcomes. We conclude that the current literature does not provide sufficient evidence of a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects. Future studies incorporating individual exposure assessment about users of private wells—the population most at risk—should be considered

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism

Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE

Proteomics and in silico approaches to extend understanding of the glutathione transferase superfamily of the tropical liver fluke Fasciola gigantica

Fasciolosis is an important foodborne, zoonotic disease of livestock and humans, with global annual health and economic losses estimated at several billion US$. Fasciola hepatica is the major species in temperate regions, while F. gigantica dominates in the tropics. In the absence of commercially available vaccines to control fasciolosis, increasing reports of resistance to current chemotherapeutic strategies and the spread of fasciolosis into new areas, new functional genomics approaches are being used to identify potential new drug targets and vaccine candidates. The glutathione transferase (GST) superfamily is both a candidate drug and vaccine target. This study reports the identification of a putatively novel Sigma class GST, present in a water-soluble cytosol extract from the tropical liver fluke F. gigantica. The GST was cloned and expressed as an enzymically active recombinant protein. This GST shares a greater identity with the human schistosomiasis GST vaccine currently at Phase II clinical trials than previously discovered F. gigantica GSTs, stimulating interest in its immuno-protective properties. In addition, in silico analysis of the GST superfamily of both F. gigantica and F. hepatica has revealed an additional Mu class GST, Omega class GSTs, and for the first time, a Zeta class member

Brain activity underlying negative self- and other-perception in adolescents: The role of attachment-derived self-representations

One of teenagers' key developmental tasks is to engage in new and meaningful relationships with peers and adults outside the family context. Attachment-derived expectations about the self and others in terms of internal attachment working models have the potential to shape such social reorientation processes critically and thereby influence adolescents' social-emotional development and social integration. Because the neural underpinnings of this developmental task remain largely unknown, we sought to investigate them by functional magnetic resonance imaging. We asked n = 44 adolescents (ages 12.01-18.84 years) to evaluate positive and negative adjectives regarding either themselves or a close other during an adapted version of the well-established self-other trait-evaluation task. As measures of attachment, we obtained scores reflecting participants' positive versus negative attachment-derived self- and other-models by means of the Relationship Questionnaire. We controlled for possible confounding factors by also obtaining scores reflecting internalizing/externalizing problems, schizotypy, and borderline symptomatology. Our results revealed that participants with a more negative attachment-derived self-model showed increased brain activity during positive and negative adjective evaluation regarding the self, but decreased brain activity during negative adjective evaluation regarding a close other, in bilateral amygdala/parahippocampus, bilateral anterior temporal pole/anterior superior temporal gyrus, and left dorsolateral prefrontal cortex. These findings suggest that a low positivity of the self-concept characteristic for the attachment anxiety dimension may influence neural information processing, but in opposite directions when it comes to self- versus (close) other-representations. We discuss our results in the framework of attachment theory and regarding their implications especially for adolescent social-emotional development and social integration

Alignment of the CMS tracker with LHC and cosmic ray data

© CERN 2014 for the benefit of the CMS collaboration, published under the terms of the Creative Commons Attribution 3.0 License by IOP Publishing Ltd and Sissa Medialab srl. Any further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation and DOI.The central component of the CMS detector is the largest silicon tracker ever built. The precise alignment of this complex device is a formidable challenge, and only achievable with a significant extension of the technologies routinely used for tracking detectors in the past. This article describes the full-scale alignment procedure as it is used during LHC operations. Among the specific features of the method are the simultaneous determination of up to 200 000 alignment parameters with tracks, the measurement of individual sensor curvature parameters, the control of systematic misalignment effects, and the implementation of the whole procedure in a multi-processor environment for high execution speed. Overall, the achieved statistical accuracy on the module alignment is found to be significantly better than 10μm

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment