Is the ocean surface a source of nitrous acid (HONO) in the marine boundary layer?

Nitrous acid, HONO, is a key net photolytic precursor to OH radicals in the atmospheric boundary layer. As OH is the dominant atmospheric oxidant, driving the removal of many primary pollutants and the formation of secondary species, a quantitative understanding of HONO sources is important to predict atmospheric oxidising capacity. While a number of HONO formation mechanisms have been identified, recent work has ascribed significant importance to the dark, ocean-surface-mediated conversion of NO₂ to HONO in the coastal marine boundary layer. In order to evaluate the role of this mechanism, here we analyse measurements of HONO and related species obtained at two contrasting coastal locations – Cabo Verde (Atlantic Ocean, denoted Cape Verde herein), representative of the clean remote tropical marine boundary layer, and Weybourne (United Kingdom), representative of semi-polluted northern European coastal waters. As expected, higher average concentrations of HONO (70 ppt) were observed in marine air for the more anthropogenically influenced Weybourne location compared to Cape Verde (HONO < 5 ppt). At both sites, the approximately constant HONO/NO₂ ratio at night pointed to a low importance for the dark, ocean-surface-mediated conversion of NO₂ into HONO, whereas the midday maximum in the HONO/NO₂ ratios indicated significant contributions from photo-enhanced HONO formation mechanisms (or other sources). We obtained an upper limit to the rate coefficient of dark, ocean-surface HONO-to-NO₂ conversion of CHONO = 0.0011 ppb h⁻¹ from the Cape Verde observations; this is a factor of 5 lower than the slowest rate reported previously. These results point to significant geographical variation in the predominant HONO formation mechanisms in marine environments and indicate that caution is required when extrapolating the importance of such mechanisms from individual study locations to assess regional and/or global impacts on oxidising capacity. As a significant fraction of atmospheric processing occurs in the marine boundary layer, particularly in the tropics, better constraint of the possible ocean surface source of HONO is important for a quantitative understanding of chemical processing of primary trace gases in the global atmospheric boundary layer and associated impacts upon air pollution and climate

Pre-Diagnostic Plasma 25-Hydroxyvitamin D Levels and Risk of Non-Melanoma Skin Cancer in Women

Recent reports have shown that vitamin D status was inversely associated with the risk of various cancers. However, few studies examined the association between vitamin D levels and risk of skin cancer.We prospectively evaluated the association between baseline plasma 25(OH)D levels and the risk of incident squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) among 4,641 women from the Nurses' Health Study (NHS) and the NHS II with 510 incident BCC cases and 75 incident SCC cases. We used multivariate logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Plasma 25(OH)D levels were positively associated with risk of BCC after adjusting for age at blood draw, season of blood draw, lab batch, hair color, burning tendency, the number of sunburns, and ultra-violet B flux of residence at blood collection. Women in the highest quartile of 25(OH)D had more than 2-fold increased risk of BCC compared with women in the lowest quartile (OR = 2.07, 95% CI = 1.52-2.80, P for trend <0.0001). We also found a significantly positive association between plasma 25(OH)D levels and SCC risk after adjusting for the same covariates (OR, highest vs. lowest quartile = 3.77, 95% CI = 1.70-8.36, P for trend= 0.0002).In this prospective study of women, plasma vitamin D levels were positively associated with non-melanoma skin cancer risk. Considering that most circulating vitamin D is due to sun exposure, the positive association between plasma vitamin D and non-melanoma skin cancer is confounded by sun exposure. Our data suggest that one-time measurement of plasma vitamin D levels may reasonably reflect long-term sun exposure and predict the risk of non-melanoma skin cancer

High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease

BACKGROUND: The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases. METHODS: We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used. RESULTS: We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis. CONCLUSION: Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naïve methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease

Ants, Cataglyphis cursor, Use Precisely Directed Rescue Behavior to Free Entrapped Relatives

Although helping behavior is ubiquitous throughout the animal kingdom, actual rescue activity is particularly rare. Nonetheless, here we report the first experimental evidence that ants, Cataglyphis cursor, use precisely directed rescue behavior to free entrapped victims; equally important, they carefully discriminate between individuals in distress, offering aid only to nestmates. Our experiments simulate a natural situation, which we often observed in the field when collecting Catagyphis ants, causing sand to collapse in the process. Using a novel experimental technique that binds victims experimentally, we observed the behavior of separate, randomly chosen groups of 5 C. cursor nestmates under one of six conditions. In five of these conditions, a test stimulus (the “victim”) was ensnared with nylon thread and held partially beneath the sand. The test stimulus was either (1) an individual from the same colony; (2) an individual from a different colony of C cursor; (3) an ant from a different ant species; (4) a common prey item; or, (5) a motionless (chilled) nestmate. In the final condition, the test stimulus (6) consisted of the empty snare apparatus. Our results demonstrate that ants are able to recognize what, exactly, holds their relative in place and direct their behavior to that object, the snare, in particular. They begin by excavating sand, which exposes the nylon snare, transporting sand away from it, and then biting at the snare itself. Snare biting, a behavior never before reported in the literature, demonstrates that rescue behavior is far more sophisticated, exact and complexly organized than the simple forms of helping behavior already known, namely limb pulling and sand digging. That is, limb pulling and sand digging could be released directly by a chemical call for help and thus result from a very simple mechanism. However, it's difficult to see how this same releasing mechanism could guide rescuers to the precise location of the nylon thread, and enable them to target their bites to the thread itself

The Implementation of Managed Entry Agreements in Central and Eastern Europe : Findings and Implications

Funding Information: In Bosnia and Herzegovina, both The Federation of Bosnia and Herzegovina and the Republic of Srpska, also have special funds and budgets in place for the financing of expensive medicines, which are innovative and under patent. Similar earmarked funds are available in Scotland (the New Medicines Fund funded by the Pharmaceutical Price Regulation Scheme [PPRS] rebates) [35] and England (the Cancer Drugs Fund) [36]. However, support for such earmarked funds is mixed. While they facilitate access, critics raised issues about fairness towards other disease areas and patient groups that are not eligible for special funding [3, 39]. Further, the views of a Patient and Clinician Engagement meeting in Scotland [37] and the end-of-life criteria in England [38] offer opportunities for special considerations affecting medicines for end-of-life and very rare conditions to be taken into account in the health technology assessment process. Funding Information: The authors would like to acknowledge Dr. Jan Jones from the Scottish Medicines Consortium, Scotland, for contributing to the discussion with information on Scotland, Drs. Lyudmila Bezmelnitsyna and Anastasia Isaeva for contributing to data collection in Russia and Dr. Kate?ina Podrazilov? from SZP ?R for providing information on the Czech Republic. Alessandra Ferrario was a Research Officer at the LSE Health at the time this research was conducted. She is now a postdoctoral Research Fellow at the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, USA. Email: [email protected] No sources of funding were used for this study. The authors declare they have no conflicts of interest. However, Di?na Ar?ja, Maria Dimitrova, Jurij F?rst, Ieva Grei?i?t?-Kuprijanov, Iris Hoxha, Arianit Jakupi, Erki Laidm?e, Vanda Markovic-Pekovic, Dmitry Meshkov, Guenka Petrova, Maciej Pomorski and Patricia Vella Bonanno work directly for national health authorities or are advisers to them. Alessandra Ferrario, Tomasz Bochenek, Ileana Mardare, Dominik Tomek, Luka Voncina, Alan Haycox, Panos Kanavos,?Olga L?blov?, and Brian Godman are academics and independent researchers also working with national and regional health authorities and others to improve the quality and efficiency of prescribing, and Tarik Catic, D?vid Dank?,and Tanja Novakovic are involved with pharmaceutical, pharmacoeconomics and outcomes research groups in their countries. Olga L?blov? has also carried out remunerated consultancy activities for A&R Partners, Baxter AG and Instytut Arcana and Ileana Mardare has signed a consulting contract with Ewopharma A.G. Romania. The content of the paper and the conclusions are those of each author and may not necessarily reflect those of any organisation that employs them. Publisher Copyright: © 2017, The Author(s).Background: Managed entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available. Method: We conducted a survey on the implementation of MEAs in CEE between January and March 2017. Results: Sixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%). Conclusions: Experience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.publishersversionPeer reviewe

A CD8+ T cell transcription signature predicts prognosis in autoimmune disease.

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of potentially toxic immunosuppressive therapy. Gene expression-based biomarkers facilitating such tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice. We show that transcriptional profiling of purified CD8(+) T cells, which avoids the confounding influences of unseparated cells, identifies two distinct subject subgroups predicting long-term prognosis in two autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium-sized and small blood vessels, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction. We show that the subset of genes defining the poor prognostic group is enriched for genes involved in the interleukin-7 receptor (IL-7R) pathway and T cell receptor (TCR) signaling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8(+) T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest new potential therapeutic targets in autoimmunity

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes

<p>Abstract</p> <p>Background</p> <p>Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.</p> <p>Methods</p> <p>rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.</p> <p>Results</p> <p>Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV₁and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.</p> <p>Conclusion</p> <p>Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.</p