Heavy metal toxicity and the aetiology of glaucoma

Despite recent advances, our understanding of the aetiological mechanisms underlying glaucoma remains incomplete. Heavy metals toxicity has been linked to the development of neurodegenerative diseases and various ocular pathologies. Given the similarities in pathophysiology between glaucoma and some neurodegenerative disorders, it is plausible that heavy metal toxicity may play a role in the development of glaucoma. Heavy metal exposure may be occupational, or through water or dietary contamination. In this report, we review mechanisms for systemic and neurotoxicity for arsenic, cadmium, chromium, cobalt, lead, mercury, and manganese, and weigh the evidence for an association between glaucoma and the accumulation of heavy metals either in ocular tissues or in the central nervous system

Reducing delays in the diagnosis and treatment of muscle-invasive bladder cancer using simulation modelling

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record Objective: To develop a simulation model to identify key bottlenecks in the bladder cancer pathway at Royal Cornwall Hospital and predict the impact of potential changes to reduce these delays. Materials and methods: The diagnosis and treatment of muscle-invasive bladder cancer can suffer numerous delays, which can significantly affect patient outcomes. We developed a discrete event computer simulation model of the flow of patients through the bladder cancer pathway at the hospital, using anonymised patient records from 2014 and 2015. The changes tested in the model were for patients suspected to have muscle-invasive disease on flexible cystoscopy. Those patients were ‘fast-tracked’ to receive their transurethral resection of bladder tumour (TURBT) treatment using operating slots kept free for these patients. A staging computed tomography scan was booked in the haematuria clinic. Pathology requests were marked as 48 hour turnaround. The nurse specialist would then speak to the patient whilst they were on the ward following their TURBT to give information about their ongoing treatment and provide support. Results: The model predicted that if the changes were implemented, delays in the system could be reduced by around 5 weeks. The changes were implemented, and analysis of 3 months of the data post-implementation shows that the average time in the system was reduced by 5 weeks. The environment created by the changes in the pathway improved referral to treatment times in both muscle-invasive and non-muscle-invasive groups. Conclusion: The simulation model proved an invaluable tool for facilitating the implementation of changes. Simple changes to the pathway led to significant reductions in delays for bladder cancer patients at Royal Cornwall Hospital. Level of evidence: Not applicable for this cohort study.National Institute for Health Research (NIHR

Finely Resolved On-Road PM2.5 and Estimated Premature Mortality in Central North Carolina

To quantify the on-road PM2.5-related premature mortality at a national scale, previous approaches to estimate concentrations at a 12-km × 12-km or larger grid cell resolution may not fully characterize concentration hotspots that occur near roadways and thus the areas of highest risk. Spatially resolved concentration estimates from on-road emissions to capture these hotspots may improve characterization of the associated risk, but are rarely used for estimating premature mortality. In this study, we compared the on-road PM2.5-related premature mortality in central North Carolina with two different concentration estimation approaches—(i) using the Community Multiscale Air Quality (CMAQ) model to model concentration at a coarser resolution of a 36-km × 36-km grid resolution, and (ii) using a hybrid of a Gaussian dispersion model, CMAQ, and a space–time interpolation technique to provide annual average PM2.5 concentrations at a Census-block level (∼105,000 Census blocks). The hybrid modeling approach estimated 24% more on-road PM2.5-related premature mortality than CMAQ. The major difference is from the primary on-road PM2.5 where the hybrid approach estimated 2.5 times more primary on-road PM2.5-related premature mortality than CMAQ due to predicted exposure hotspots near roadways that coincide with high population areas. The results show that 72% of primary on-road PM2.5 premature mortality occurs within 1,000 m from roadways where 50% of the total population resides, highlighting the importance to characterize near-road primary PM2.5 and suggesting that previous studies may have underestimated premature mortality due to PM2.5 from traffic-related emissions

The impact of parental aspirations on private school enrolment: evidence from Andhra Pradesh, India

This paper presents an analysis of the role of parental aspirations in determining private school choice in Andhra Pradesh, using quantitative and qualitative data from the Young Lives cohort study over two rounds. Aspirations are measured using a range of indicators of what educational attainment level and future occupational status parents desire for their children. We find robustly, across all measures of aspirations and different empirical specifications, that parental aspirations have a significant positive impact on the probability that the child is enrolled in a private school. This finding is further supported by qualitative evidence that also suggests that higher parental aspirations for the future situation of their child will lead to higher investment in education because parents perceive education as key to future success. Thus, our findings suggest that parental aspirations are among the demand factors that may explain the recent dramatic increase in private school enrolment in Andhra Pradesh among the poorest groups. This is mainly because parents believe that private schools can provide a better future for their children, which motivates them to make the necessary investment.</p

Modeled Full‐Flight Aircraft Emissions Impacts on Air Quality and Their Sensitivity to Grid Resolution

Aviation is a unique anthropogenic source with four‐dimensional varying emissions, peaking at cruise altitudes (9–12 km). Aircraft emission budgets in the upper troposphere lower stratosphere region and their potential impacts on upper troposphere and surface air quality are not well understood. Our key objective is to use chemical transport models (with prescribed meteorology) to predict aircraft emissions impacts on the troposphere and surface air quality. We quantified the importance of including full‐flight intercontinental emissions and increased horizontal grid resolution. The full‐flight aviation emissions in the Northern Hemisphere contributed ~1.3% (mean, min–max: 0.46, 0.3–0.5 ppbv) and 0.2% (0.013, 0.004–0.02 μg/m3) of total O3 and PM2.5 concentrations at the surface, with Europe showing slightly higher impacts (1.9% (O3 0.69, 0.5–0.85 ppbv) and 0.5% (PM2.5 0.03, 0.01–0.05 μg/m3)) than North America (NA) and East Asia. We computed seasonal aviation‐attributable mass flux vertical profiles and aviation perturbations along isentropic surfaces to quantify the transport of cruise altitude emissions at the hemispheric scale. The comparison of coarse (108 × 108 km2) and fine (36 × 36 km2) grid resolutions in NA showed ~70 times and ~13 times higher aviation impacts for O3 and PM2.5 in coarser domain. These differences are mainly due to the inability of the coarse resolution simulation to capture nonlinearities in chemical processes near airport locations and other urban areas. Future global studies quantifying aircraft contributions should consider model resolution and perhaps use finer scales near major aviation source regions.Plain Language SummaryIn the Northern hemisphere, aircraft emissions contribute ~1.3 % and 0.2 % of total O3 and PM2.5 concentrations at the surface. Incorporating full‐flight aircraft emissions at a fine resolution improved model estimates of NO2 by ~5–11% when compared to field campaign observations in upper troposphere lower stratosphere region. Coarse resolution showed ~70 times and ~13 times higher aviation impacts for O3 and PM2.5 when compared to fine resolution over North America. We attribute these overestimates to physical and chemical processes in the choice of grid resolution, as well as due to intercontinental transport of pollution.Key PointsIn the Northern Hemisphere (108 km model resolution), aircraft emissions contribute ~1.3% and 0.2% of total O3 and PM2.5 at surfaceIncorporating full‐flight aircraft emissions at a fine resolution reduced model bias by up to ~5‐11% for NO2 in UTLS regionThe 108 km resolution showed ~70 times and ~13 times higher impacts for O3 and PM2.5 in North America than 36 km due to grid resolution and transpor

Transcriptome and genome evolution during HER2-amplified breast neoplasia

Background The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia’s fitness is less understood. Methods Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. Results By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage. Conclusion By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level

Most canine ameloblastomas harbor HRAS mutations, providing a novel large-animal model of RAS-driven cancer

Abstract Canine acanthomatous ameloblastomas (CAA), analogs of human ameloblastoma, are oral tumors of odontogenic origin for which the genetic drivers have remained undefined. By whole-exome sequencing, we have now discovered recurrent HRAS and BRAF activating mutations, respectively, in 63% and 8% of CAA. Notably, cell lines derived from CAA with HRAS mutation exhibit marked sensitivity to MAP kinase (MAPK) pathway inhibitors, which constrain cell proliferation and drive ameloblast differentiation. Our findings newly identify a large-animal spontaneous cancer model to study the progression and treatment of RAS-driven cancer. More broadly, our study highlights the translational potential of canine cancer genome sequencing to benefit both humans and their companion animals

Risks and protective factors for children experiencing adverse events

For children growing up in poverty, risk is part of everyday life. Experiences of chronic poverty are often compounded by multiple and recurrent risks and shocks or adverse events. ‘Shocks’ are unexpected events, such as drought, price fluctuations or family illness or death, that have a negative impact on the household economy. Children’s life chances in education, health, and well-being are closely bound up with, and shaped by, the situation of their households, and their socio-cultural environment, as well as the unequal distribution of power, wealth, and opportunities in societies; all these factors frequently disadvantage the same families (Boyden and Dercon 2012; Pells 2012). However, children are not only affected by shocks, but are also social agents, active in decisions made and strategies adopted in attempting to mitigate the impact of adverse circumstances on their household and on their lives

‘Those who are good to us, we call them friends’: Social support and social networks for children growing up in poverty in rural Andhra Pradesh, India

Ideas about‘social capital’ (variously derived from Bourdieu 1986, Coleman 1988 and Putnam 20001) continue to circulate in research literature across a spectrum of disciplines, including sociology and development studies, despite numerous critiques (see Fine 2010 for a summary). It is broadly accepted that social networks and social resources, and social support (social capital), in the form of personal, familial and community-level relationships are crucially important to children as they grow up (Morrow 1999, 2001). Yet this is an under-researched topic in developing countries, where the unprecedented pace of change puts pressure on children to pursue particular trajectories through formal schooling, while traditional values simultaneously insist that they follow pathways constrained by norms that are patterned by gender, class, caste and ethnicity and intergenerational norms of reciprocity and responsibility. Drawing on qualitative data gathered from children from the ‘Young Lives’ study2 in Andhra Pradesh, India, we analyse children’s descriptions of sources of support, whom they turn to when in difficulty, and why. This chapter is a preliminary attempt to use Bourdieu’s distinctive theoretical ideas about social capital as relational, interconnected and underpinned by economic capital, to explore patterns of inequality in developing countries in the twenty-first Century