Long-term concentrations of nitrogen dioxide and mortality: a meta-analysis of cohort studies.

BACKGROUND: Concentrations of outdoor nitrogen dioxide (NO2) have been associated with increased mortality. Hazard ratios (HRs) from cohort studies are used to assess population health impact and burden. We undertook meta-analyses to derive concentration-response functions suitable for such evaluations and assessed their sensitivity to study selection based upon cohort characteristics. METHODS: We searched online databases and existing reviews for cohort studies published to October 2016 reporting HRs for NO2 and mortality. We calculated meta-analytic summary estimates using fixed/random effects models. RESULTS: We identified 48 articles analyzing 28 cohorts. Meta-analysis of HRs found positive associations between NO2 and all-cause (1.02 (95% CI: 1.01, 1.03); prediction interval (PI): (0.99, 1.06) per 10µg/m increment in NO2), cardiovascular (1.03 (95% CI: 1.02,1.05); PI: (0.98, 1.08)) , respiratory (1.03 (95% CI: 1.01,1.05); PI: (0.97, 1.10)) and lung cancer mortality (1.05 (95% CI: 1.02,1.08); PI: (0.94, 1.17)) with evidence of substantial heterogeneity between studies. In subgroup analysis, summary HRs varied by age at cohort entry, spatial resolution of pollution estimates, and adjustment for smoking and body mass index at the individual level; for some sub-groups the HR was close to unity, with lower confidence limits below 1. CONCLUSIONS: Given the many uncertainties inherent in the assessment of this evidence base and the sensitivity of health impact calculations to small changes in the magnitude of the HRs, calculation of the impact on health of policies to reduce long-term exposure to NO2 should use prediction intervals and report ranges of impact rather than focusing upon point estimates.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

Examining the Expectations of Early Years Teachers in the UAE Regarding a Successful Start to School for Children With and Without Special Educational Needs

Starting school has been shown to correlate with later school outcomes. The success of the transition of special educational needs (SEN) pupils depends on the child’s adaptation to the new environment and on the teachers and school supports to facilitate learning. Previous research indicates that expectations of teachers toward pupils with SEN have been low. The aim of this study was to examine Early Years teachers’ expectations with respect to the transition experience of children with Downs Syndrome and those without SEN in the U.A.E. Teachers working in the U.A.E. in Early Years’ education completed a questionnaire twice, once thinking about their expectations of a child without any SEN and once thinking about a child with Downs Syndrome. Findings demonstrated a different pattern of expectations depending on whether the child had Downs Syndrome or no SEN, indicating, in general, a lower set of academic expectations for children with Downs Syndrome

A semi-Markov model for stroke with piecewise-constant hazards in the presence of left, right and interval censoring.

This paper presents a parametric method of fitting semi-Markov models with piecewise-constant hazards in the presence of left, right and interval censoring. We investigate transition intensities in a three-state illness-death model with no recovery. We relax the Markov assumption by adjusting the intensity for the transition from state 2 (illness) to state 3 (death) for the time spent in state 2 through a time-varying covariate. This involves the exact time of the transition from state 1 (healthy) to state 2. When the data are subject to left or interval censoring, this time is unknown. In the estimation of the likelihood, we take into account interval censoring by integrating out all possible times for the transition from state 1 to state 2. For left censoring, we use an Expectation-Maximisation inspired algorithm. A simulation study reflects the performance of the method. The proposed combination of statistical procedures provides great flexibility. We illustrate the method in an application by using data on stroke onset for the older population from the UK Medical Research Council Cognitive Function and Ageing Study

Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies

The first human monoclonal islet cell antibodies of the IgG class (MICA 1-6) obtained from an individual with Type 1 (insulin-dependent) diabetes mellitus were cytoplasmic islet cell antibodies selected by the indirect immunofluorescence test on pancreas sections. Surprisingly, they all recognized the 64 kDa autoantigen glutamate decarboxylase. In this study we investigated which typical features of cytoplasmic islet cell antibodies are represented by these monoclonals. We show by double immunofluorescence testing that MICA 1-6 stain pancreatic beta cells which is in agreement with the beta-cell specific expression of glutamate decarboxylase. In contrast an islet-reactive IgM monoclonal antibody obtained from a pre-diabetic individual stained all islet cells but lacked the tissue specificity of MICA 1-6 and must therefore be considered as a polyreactive IgM-antibody. We further demonstrate that MICA 1-6 revealed typical features of epitope sensitivity to biochemical treatment of the target tissue which has been demonstrated for islet cell antibodies, and which has been used to argue for a lipid rather than a protein nature of target antigens. Our results provide direct evidence that the epitopes recognized by the MICA are destroyed by methanol/chloroform treatment but reveal a high stability to Pronase digestion compared to proinsulin epitopes. Conformational protein epitopes in glutamate decarboxylase therefore show a sensitivity to biochemical treatment of sections such as ganglioside epitopes. MICA 1-6 share typical features of islet cell and 64 kDa antibodies and reveal that glutamate decarboxylase-reactive islet cell antibodies represent a subgroup of islet cell antibodies present in islet cell antibody-positive sera

Evidence for Shear Stress-Mediated Dilation of the Internal Carotid Artery in Humans.

Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries. To explore the hypothesis that shear stress contributes to hypercapnic internal carotid dilation in humans, temporal changes in internal and common carotid shear rate and diameter, along with changes in middle cerebral artery velocity, were simultaneously assessed in 18 subjects at rest and during hypercapnia (6% carbon dioxide). Middle cerebral artery velocity increased significantly (69±10-103±17 cm/s; P<0.01) along with shear in both the internal (316±52-518±105 1/s; P<0.01) and common (188±40-275±61 1/s; P<0.01) carotids. Diameter also increased (P<0.01) in both carotid arteries (internal: +6.3±2.9%; common: +5.8±3.0%). Following hypercapnia onset, there was a significant delay between the onset of internal carotid shear (22±12 seconds) and diameter change (85±51 seconds). This time course is associated with shear-mediated dilation of larger conduit arteries in humans. There was a strong association between change in shear and diameter of the internal carotid (r=0.68; P<0.01). These data indicate, for the first time in humans, that shear stress is an important stimulus for hypercapnic vasodilation of the internal carotid artery. The combination of a hypercapnic stimulus and continuous noninvasive, high-resolution assessment of internal carotid shear and dilation may provide novel insights into the function and health of the clinically important extracranial arteries in humans

Heating cancer stem cells to reduce tumor relapse

Tumour relapse is believed to be caused by rare cancer-cells with stem-cell properties (cancer stem cells) that are intrinsically resistant to available treatments. The identification of novel strategies to increase their sensitivity has major clinical implications. Latest clinical trials have shown a positive antitumoral effect of hyperthermia in combination with chemotherapy or radiotherapy. In a recent paper, the combination of increased temperature at the tumour site, generated by laser treatment of intravenously-injected gold nanoshells, and ionizing radiations enhances radiosensitivity of cancer stem cells and tumor response. At the root of the success of hyperthermia in enhancing radio-sensitization of cancer stem cells is the inhibition of their capacity to repair DNA damage, affecting the survival rate of these cells

The impact of predation by marine mammals on Patagonian toothfish longline fisheries

Predatory interaction of marine mammals with longline fisheries is observed globally, leading to partial or complete loss of the catch and in some parts of the world to considerable financial loss. Depredation can also create additional unrecorded fishing mortality of a stock and has the potential to introduce bias to stock assessments. Here we aim to characterise depredation in the Patagonian toothfish (Dissostichus eleginoides) fishery around South Georgia focusing on the spatio-temporal component of these interactions. Antarctic fur seals (Arctocephalus gazella), sperm whales (Physeter macrocephalus), and orcas (Orcinus orca) frequently feed on fish hooked on longlines around South Georgia. A third of longlines encounter sperm whales, but loss of catch due to sperm whales is insignificant when compared to that due to orcas, which interact with only 5% of longlines but can take more than half of the catch in some cases. Orca depredation around South Georgia is spatially limited and focused in areas of putative migration routes, and the impact is compounded as a result of the fishery also concentrating in those areas at those times. Understanding the seasonal behaviour of orcas and the spatial and temporal distribution of “depredation hot spots” can reduce marine mammal interactions, will improve assessment and management of the stock and contribute to increased operational efficiency of the fishery. Such information is valuable in the effort to resolve the human-mammal conflict for resources

15-deoxy-Delta(12,14)-Prostaglandin J(2) inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism

Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors

A Human Development Framework for CO2 Reductions

Although developing countries are called to participate in CO2 emission reduction efforts to avoid dangerous climate change, the implications of proposed reduction schemes in human development standards of developing countries remain a matter of debate. We show the existence of a positive and time-dependent correlation between the Human Development Index (HDI) and per capita CO2 emissions from fossil fuel combustion. Employing this empirical relation, extrapolating the HDI, and using three population scenarios, the cumulative CO2 emissions necessary for developing countries to achieve particular HDI thresholds are assessed following a Development As Usual approach (DAU). If current demographic and development trends are maintained, we estimate that by 2050 around 85% of the world's population will live in countries with high HDI (above 0.8). In particular, 300Gt of cumulative CO2 emissions between 2000 and 2050 are estimated to be necessary for the development of 104 developing countries in the year 2000. This value represents between 20% to 30% of previously calculated CO2 budgets limiting global warming to 2{\deg}C. These constraints and results are incorporated into a CO2 reduction framework involving four domains of climate action for individual countries. The framework reserves a fair emission path for developing countries to proceed with their development by indexing country-dependent reduction rates proportional to the HDI in order to preserve the 2{\deg}C target after a particular development threshold is reached. Under this approach, global cumulative emissions by 2050 are estimated to range from 850 up to 1100Gt of CO2. These values are within the uncertainty range of emissions to limit global temperatures to 2{\deg}C.Comment: 14 pages, 7 figures, 1 tabl

Statistical modeling of ground motion relations for seismic hazard analysis

We introduce a new approach for ground motion relations (GMR) in the probabilistic seismic hazard analysis (PSHA), being influenced by the extreme value theory of mathematical statistics. Therein, we understand a GMR as a random function. We derive mathematically the principle of area-equivalence; wherein two alternative GMRs have an equivalent influence on the hazard if these GMRs have equivalent area functions. This includes local biases. An interpretation of the difference between these GMRs (an actual and a modeled one) as a random component leads to a general overestimation of residual variance and hazard. Beside this, we discuss important aspects of classical approaches and discover discrepancies with the state of the art of stochastics and statistics (model selection and significance, test of distribution assumptions, extreme value statistics). We criticize especially the assumption of logarithmic normally distributed residuals of maxima like the peak ground acceleration (PGA). The natural distribution of its individual random component (equivalent to exp(epsilon_0) of Joyner and Boore 1993) is the generalized extreme value. We show by numerical researches that the actual distribution can be hidden and a wrong distribution assumption can influence the PSHA negatively as the negligence of area equivalence does. Finally, we suggest an estimation concept for GMRs of PSHA with a regression-free variance estimation of the individual random component. We demonstrate the advantages of event-specific GMRs by analyzing data sets from the PEER strong motion database and estimate event-specific GMRs. Therein, the majority of the best models base on an anisotropic point source approach. The residual variance of logarithmized PGA is significantly smaller than in previous models. We validate the estimations for the event with the largest sample by empirical area functions. etc