The Daily Mile as a public health intervention : a rapid ethnographic assessment of uptake and implementation in South London, UK

Background: Existing evidence identifies health benefits for children of additional daily physical activity (PA) on a range of cardiovascular and metabolic outcomes. The Daily Mile (TDM) is a popular scheme designed to increase children’s PA within the school day. Emerging evidence indicates that participation in TDM can increase children’s PA, reduce sedentarism and reduce skinfold measures. However, little is known about the potential effects of TDM as a public health intervention, and the benefits and disbenefits that might flow from wider implementation in ‘real world’ settings. Methods: We aimed to identify how TDM is being implemented in a naturalistic setting, and what implications this has for its potential impact on population health. We undertook a rapid ethnographic assessment of uptake and implementation in Lewisham, south London. Data included interviews (n = 22) and focus groups (n = 11) with stakeholders; observations of implementation in 12 classes; and analysis of routine data sources to identify school level factors associated with uptake. Results: Of the 69 primary schools in one borough, 33 (48%) had adopted TDM by September 2018. There were no significant differences between adopters and non-adopters in mean school population size (means 377 vs 397, P = 0.70), mean percentage of children eligible for free school meals (16.2 vs 14.3%, P = 0.39), or mean percentage of children from Black and Minority Ethnic populations (76.3 vs 78.2%, P = 0.41). Addressing obesity was a key incentive for adoption, although a range of health and educational benefits were also hypothesised to accrue from participation. Mapping TDM to the TIDierR-PHP checklist to describe the intervention in practice identified that considerable adaption happened at the level of borough, school, class and pupil. Population health effects are likely to be influenced by the interaction of intervention and context at each of these levels. Conclusions: Examining TDM in ‘real world’ settings surfaces adaptions and variations in implementation. This has implications for the likely effects of TDM, and points more broadly to an urgent need for more appropriate methods for evaluating public health impact and implementation in complex contexts

Legacy Hg–Cu contamination of active stream sediments

The purpose of this study is to evaluate the longitudinal trends of mercury (Hg) and copper (Cu) in active channel sediments downstream from the Gold Hill mining district in the Piedmont of North Carolina. Mining for gold (Au

Legacy Hg-Cu Contamination of Active Stream Sediments in the Gold Hill Mining District, North Carolina

The purpose of this study is to evaluate the longitudinal trends of mercury (Hg) and copper (Cu) in active channel sediments downstream from the Gold Hill mining district in the Piedmont of North Carolina. Mining for gold (Au) and Cu from 1844 to 1915 released both Hg (associated with Au processing) and Cu in a 254 km2 watershed. Multiple linear regression is used to quantify spatial and geochemical trends in 93 active channel samples collected from contaminated main stem and background tributary sites. Simple two-parameter regression models combining the effects of both watershed-scale dispersal processes (distance downstream) and reach-scale sediment transport (percent sand) explain 85 percent of the variance in Hg and 90 percent of the variance in Cu in active channel sediments. Contamination trends in two different sediment media, low bar and higher elevation bench deposits, were effectively similar when local grain size influence was accounted for in the two-parameter models. Background geochemistry models explain 84 percent of the variance of Hg and Cu in uncontaminated tributary samples using parameters related to grain-size, secondary geochemical substrates, and mineral weathering sources. More than 45 percent of the variance of Hg and 20 percent of Cu in contaminated sediment can be explained by background parameters. Geochemical signatures differ between Hg and Cu in active channel sediments due to variations in mining inputs, background geochemistry, and present-day pollution sources

Metal Contamination from Gold Mining in the Cid District, North Carolina

The purpose of this paper was to assess contamination from 19th century gold (Au) mining in the Cid district, North Carolina. Sediment samples collected from active channel sediments and floodplain cores were analyzed for mercury (Hg), copper (Cu), lead (Pb), and zinc (Zn). Analysis of trace metal concentrations shows that although Hg contamination exists at relatively low levels (i.e., no samples exceeded the probable effect concentration for Hg), the active channel sediments and historical floodplain deposits are contaminated by Hg downstream from all mines in the district. We also found significant contamination by Cu, Pb, and Zn. The use of Hg and other metals as tracers associated with mining activities suggests that long-term rates of floodplain sedimentation in the Cid district (0.3-0.9 cm/yr) were less than half as high as those in the nearby Gold Hill district. This suggests that the intensity of land disturbance in the Cid district was less than in the more intensively mined Gold Hill district

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC

<div><p>Head and neck squamous cell carcinoma (HNSCC) accounts for 3–5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.</p></div

Association of NRG1 expression with AREG and TGFα correlate with KTN3379 activity.

<p><b>(A and B)</b> A search of 303 HNSCC patient samples revealed a significant association between NRG1 expression and expression of EGFR ligands AREG (R² = 0.33) and TGFα (R² = 0.25). However, no association was found between NRG1 expression and any of the EGFR ligands in colorectal cancer patient samples (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181356#pone.0181356.s007" target="_blank">S7 Fig</a>). <b>(C and D)</b> High levels of secreted AREG or TGFα protein were found associated with improved KTN3379 activity in HNSCC cell lines. Levels of secreted AREG and TGFα derived from a panel of 8 serum-starved HNSCC cell lines were measured after 48 hours. Supernatant-derived ligand concentrations (in pg/mL) are plotted as a function of the combined anti-proliferative activity of KTN3379 with cetuximab. A linear regression fit of the data gave R² values of 0.50 and 0.24 for AREG and TGFα, respectively. A similar result was observed when ligand concentration data were plotted against KTN3379-mediated phospho-AKT inhibition (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181356#pone.0181356.s008" target="_blank">S8 Fig</a>). <b>(E and F)</b> High levels of EGFR homodimers (H11D) are associated with KTN33379 activity. EGFR homodimer (H11D) levels were evaluated in 8 HNSCC cell lines using a VeraTag immunoassay. H11D values were log-transformed and plotted against the combined anti-proliferative activity of KTN3379 with cetuximab (E), or KTN3379-mediated phospho-AKT inhibition in serum-grown cells (F). Linear regression analysis demonstrates a significant correlation between H11D levels and anti-proliferative activity (R² = 0.48) or phospho-AKT inhibition (R² = 0.76).</p

KTN3379 enhances cetuximab anti-proliferative activity <i>in vitro</i> and in tumor xenograft models of HNSCC.

<p><b>(A)</b> Titration of KTN3379 (red) enhanced cetuximab (blue) anti-proliferative activity in 4 of 8 HNSCC cell lines (top row) and showed modest enhancement of cetuximab-treated activity in a subset of cell lines (Detroit562 and SCC35). In contrast, neither cetuximab nor KTN3379 showed anti-proliferative activity in other HNSCC lines (UNC10 and SCC9). Combination of KTN3379 and cetuximab is shown in purple. <b>(B)</b> KTN3379 demonstrated significant single agent activity in 2 HNSCC xenograft models (FaDu and OE21), and enhanced the anti-tumor activity of cetuximab. Animals were dosed intraperitoneally twice weekly at 10 mg/kg. Asterisks denote statistical significance; * p-value <0.05; ** p-value <0.01; *** p-value <0.001; **** p-value <0.0001; ns = not significant.</p

Prevalence of NRG1 expression in HNSCC and other tumor types.

<p><b>(A)</b> NRG1 RNA overexpression was found to be most prevalent in HNSCC compared to other major tumor types, and overexpressed in nearly half of all head and neck tumors examined. RNA overexpression is defined as > 4-fold expression over the median expression across all samples (> 29,000). By contrast, NRG1 was overexpressed only in ~ 1% of colorectal cancer. TCGA data were used for this analysis. <b>(B and C)</b> A quantitative ISH-based assay demonstrates detectable NRG1 expression in the majority of human HNSCC tumors <b>(B)</b> and is independent of the histological site <b>(C)</b>. Values reflect the ratio of the NRG1 probe signal over that of a control probe.</p