Metabolism and Excretion Rates of Parent and Hydroxy-PAHs in Urine Collected after Consumption of Traditionally Smoked Salmon for Native American Volunteers

Few studies have been published on the excretion rates of parent polycyclic aromatic hydrocarbons (PAHs) and hydroxy-polycyclic aromatic hydrocarbons (OH-PAHs) following oral exposure. This study investigated metabolism and excretion rates of 4 parent PAHs and 10 OH-PAHs after the consumption of smoked salmon. Nine members of the Confederated Tribes of the Umatilla Indian Reservation consumed 50 g of traditionally smoked salmon with breakfast and five urine samples were collected during the following 24 hours. The concentrations of OH-PAHs increased from 43.9 µg/g creatinine for 2-OH-Nap to 349 ng/g creatinine for 1-OH-Pyr, 3 to 6 hr post-consumption. Despite volunteers following a restricted diet, there appeared to be a secondary source of naphthalene and fluorene, which led to excretion efficiencies greater than 100%. For the parent PAHs that were detected in urine, the excretion efficiencies ranged from 13% for phenanthrene (and its metabolite) to 240% for naphthalene (and its metabolites). The half-lives for PAHs ranged from 1.4 hr for retene to 3.3 hr for pyrene. The half-lives for OH-PAHs were higher and ranged from 1.7 hr for 9-OH-fluorene to 7.0 hr for 3-OH-fluorene. The concentrations of most parent PAHs, and their metabolites, returned to the background levels 24 hr post-consumption

Dock2 generates characteristic spatiotemporal patterns of Rac activity to regulate neutrophil polarisation, migration and phagocytosis

IntroductionRac-GTPases and their Rac-GEF activators play important roles in neutrophil-mediated host defence. These proteins control the adhesion molecules and cytoskeletal dynamics required for neutrophil recruitment to inflamed and infected organs, and the neutrophil effector responses that kill pathogens.MethodsHere, we used live cell TIRF-FRET imaging in neutrophils from Rac-FRET reporter mice with deficiencies in the Rac-GEFs Dock2, Tiam1 or Prex1/Vav1 to evaluate if these proteins activate spatiotemporally distinct pools of Rac, and to correlate patterns of Rac activity with the neutrophil responses they control.ResultsAll the GEFs were required for neutrophil adhesion, and Prex1/Vav1 were important during spreading and for the velocity of migration during chemotaxis. However, Dock2 emerged as the prominent regulator of neutrophil responses, as this GEF was required for neutrophil polarisation and random migration, for migration velocity during chemokinesis, for the likelihood to migrate and for the speed of migration and of turning during chemotaxis, as well as for rapid particle engulfment during phagocytosis. We identified characteristic spatiotemporal patterns of Rac activity generated by Dock2 which correlate with the importance of the Rac-GEF in these neutrophil responses. We also demonstrate a requirement for Dock2 in neutrophil recruitment during aseptic peritonitis.DiscussionCollectively, our data provide a first direct comparison of the pools of Rac activity generated by different types of Rac-GEFs, and identify Dock2 as a key regulator of polarisation, migration and phagocytosis in primary neutrophils

OpenSAFELY: a platform for analysing electronic health records designed for reproducible research

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY’s reproducibility-by-design approach in detail

Heritage designation and scale: a World Heritage case study of the Ningaloo Coast

© 2015 Tod Jones, Roy Jones and Michael Hughes As heritage research has engaged with a greater plurality of heritage practices, scale has emerged as an important concept in Heritage Studies, albeit relatively narrowly defined as hierarchical levels (household, local, national, etcetera). This paper argues for a definition of scale in heritage research that incorporates size (geographical scale), level (vertical scale) and relation (an understanding that scale is constituted through dynamic relationships in specific contexts). The paper utilises this definition of scale to analyse heritage designation first through consideration of changing World Heritage processes, and then through a case study of the world heritage designation of the Ningaloo Coast region in Western Australia. Three key findings are: both scale and heritage gain appeal because they are abstractions, and gain definition through the spatial politics of interrelationships within specific situations; the spatial politics of heritage designation comes into focus through attention to those configurations of size, level and relation that are invoked and enabled in heritage processes; and researchers choice to analyse or ignore particular scales and scalar politics are political decisions. Utilising scale as size, level and relation enables analyses that move beyond heritage to the spatial politics through which all heritage is constituted

The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study.

PURPOSE: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries. METHODS: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to "health district" size: populations of 100,000-250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1-9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1-9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes. RESULTS: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries. CONCLUSION: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015

Effects of acute tryptophan depletion on executive function in healthy male volunteers

BACKGROUND: Neurocognitive impairment is frequently described in a number of psychiatric disorders and may be a direct consequence of serotonergic dysfunction. As impairments in executive functions are some of the most frequently described, the purpose of this study was to examine the performance of normal volunteers on a range of executive tasks following a transient reduction of central serotonin (5-HT) levels using the method of acute tryptophan depletion (ATD). METHODS: Fifteen healthy male subjects participated in a within-subject, double-blind, counterbalanced crossover study. ATD was induced by ingestion of a 100 g amino-acid drink. Executive function was evaluated using the Wisconsin Card Sorting Test, Stroop, Verbal Fluency and Trail Making. Visual analogue scales were administered to assess mood. RESULTS: Plasma free and total tryptophan concentrations were significantly reduced by the depleting drink (P < 0.001). ATD selectively improved motor speed/ attention on the Trails A test (P = 0.027), with no effect on subjective ratings of mood. Interaction effects between drink and the order of drink administration were observed on most neurocognitive tests. CONCLUSIONS: The improvement in simple motor speed/ attention following ATD is in keeping with the ascribed role of 5-HT in the cortex, however performance on tests of executive function is not robustly altered. The presence of interaction effects on most tasks suggests that subtle changes may occur but are masked, possibly by simple learning effects, in the context of a crossover design. This has implications for the design of future studies, particularly those examining executive functions

Hazardous drinking among young adults seeking outpatient mental health services

BACKGROUND: Alcohol use can have a significant negative impact on young adults in mental health treatment. This cross-sectional study examined prevalence and factors associated with hazardous drinking among young adults seeking outpatient mental health services, rate of alcohol use disorders (AUDs), and the relationship between hazardous drinking and other types of substance use. METHODS: Participants were 487 young adults ages 18–25 who completed self-administered computerized screening questions for alcohol and drug use. Alcohol use patterns were assessed and predictors of hazardous drinking (≥5 drinks on one or more occasions in the past year) were identified using logistic regression. RESULTS: Of the 487 participants, 79.8 % endorsed prior-year alcohol use, 52.3 % reported one or more episodes of hazardous drinking in the prior year and 8.2 % were diagnosed with an AUD. Rates of recent and lifetime alcohol, tobacco and marijuana use were significantly greater in those with prior-year hazardous drinking. In logistic regression, prior-year hazardous drinking was associated with lifetime marijuana use (OR 3.30, p < 0.001; 95 % CI 2.05, 5.28), lifetime tobacco use (OR 1.88, p = 0.004; 95 % CI 1.22, 2.90) and older age (OR 1.18 per year, p < 0.001; 95 % CI 1.08, 1.29). CONCLUSIONS: In an outpatient mental health setting, high rates of hazardous drinking were identified, and drinking was associated with history of other substance use. Results highlight patient characteristics associated with hazardous drinking that mental health providers should be aware of in treating young adults, especially older age and greater use of tobacco and marijuana